Ultragenyx Pharmaceutical Annual Report 2023

Plain-text annual report

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 Form 10-K ☑ ☐ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the ﬁscal year ended December 31, 2023 OR TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transion period from to Commission File No. 001-36276 Ultragenyx Pharmaceucal Inc. (Exact name of registrant as speciﬁed in its charter) Delaware (State or other jurisdicon of incorporaon or organizaon) 60 Leveroni Court Novato, California (Address of principal execuve oﬃces) 27-2546083 (I.R.S. Employer Idenﬁcaon No.) 94949 (Zip Code) (415) 483-8800 (Registrant’s telephone number, including area code) Securies registered pursuant to Secon 12(b) of the Exchange Act: Title of each class Trading Symbol(s) Name of each exchange on which registered Common Stock, $0.001 par value RARE The Nasdaq Global Select Market Indicate by check mark if the registrant is a well-known seasoned issuer, as deﬁned in Rule 405 of the Securies Act. YES ☑ NO ☐ Indicate by check mark if the registrant is not required to ﬁle reports pursuant to Secon 13 or Secon 15(d) of the Exchange Act. YES ☐ NO ☑ Securies registered pursuant to Secon 12(g) of the Exchange Act: None. Indicate by check mark whether the registrant (1) has ﬁled all reports required to be ﬁled by Secon 13 or 15(d) of the Exchange Act during the preceding 12 months (or for such shorter period that the registrant was required to ﬁle such reports), and (2) has been subject to such ﬁling requirements for the past 90 days. YES ☑ NO ☐ Indicate by check mark whether the registrant has submied electronically every Interacve Data File required to be submied pursuant to Rule 405 of Regulaon S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such ﬁles). Yes ☑ NO ☐ Indicate by check mark whether the registrant is a large accelerated ﬁler, an accelerated ﬁler, a non-accelerated ﬁler, a smaller reporng company, or an emerging growth company. See the deﬁnions of “large accelerated ﬁler,” “accelerated ﬁler,” “smaller reporng company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act. Large accelerated ﬁler ☑ Accelerated ﬁler ☐ Non- accelerated ﬁler ☐ Smaller reporng company ☐ Emerging growth company ☐ If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transion period for complying with any new or revised ﬁnancial accounng standards provided pursuant to Secon 13(a) of the Exchange Act. ☐ Indicate by check mark whether the registrant has ﬁled a report on and aestaon to its management’s assessment of the eﬀecveness of its internal control over ﬁnancial reporng under Secon 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounng ﬁrm that prepared or issued its audit report. ☑ If securies are registered pursuant to Secon 12(b) of the Act, indicate by check mark whether the ﬁnancial statements of the registrant included in the ﬁling reﬂect the correcon of an error to previously issued ﬁnancial statements. ☐ Indicate by check mark whether any of those error correcons are restatements that required a recovery analysis of incenve-based compensaon received by any of the registrant’s execuve oﬃcers during the relevant recovery period pursuant to §240.10D-1(b). ☐ Indicate by check mark whether the registrant is a shell company (as deﬁned in Rule 12b-2 of the Exchange Act). YES ☐ NO ☑ The aggregate market value of the vong and non-vong common equity held by non-aﬃliates of the Company as of June 30, 2023 was approximately $3.1 billion, based upon the closing price on The Nasdaq Global Select Market reported for such date. Shares of common stock held by each execuve oﬃcer and director and by each person who is known to own 10% or more of the outstanding common stock have been excluded as such persons may be deemed aﬃliates of the Company. This determinaon of aﬃliate status is not necessarily a conclusive determinaon for other purposes. As of February 15, 2024, the Company had 82,335,687 shares of common stock issued and outstanding. DOCUMENTS INCORPORATED BY REFERENCE Porons of the registrant’s deﬁnive proxy statement relang to its 2024 Annual Meeng of Stockholders, to be held on or about June 18, 2024, are incorporated by reference into Part III of this Annual Report on Form 10-K where indicated. Such proxy statement will be ﬁled with the U.S. Securies and Exchange Commission within 120 days aer the end of the ﬁscal year to which this report relates. Table of Contents PART I Item 1. Business Item 1A. Risk Factors Item 1B. Unresolved Staﬀ Comments Item 1C. Cybersecurity Item 2. Properes Item 3. Legal Proceedings Item 4. Mine Safety Disclosures Item 5. Market for Registrant’s Common Equity, Related Stockholder Maers and Issuer Purchases of Equity Securies PART II Item 6. Reserved Item 7. Management’s Discussion and Analysis of Financial Condion and Results of Operaons Item 7A. Quantave and Qualitave Disclosures About Market Risk Item 8. Financial Statements and Supplementary Data Item 9. Changes in and Disagreements With Accountants on Accounng and Financial Disclosure Item 9A. Controls and Procedures Item 9B. Other Informaon Item 9C. Disclosure Regarding Foreign Jurisdicons that Prevent Inspecons PART III Item 10. Directors, Execuve Oﬃcers and Corporate Governance Item 11. Execuve Compensaon Item 12. Security Ownership of Certain Beneﬁcial Owners and Management and Related Stockholder Maers Item 13. Certain Relaonships and Related Transacons, and Director Independence Item 14. Principal Accountant Fees and Services PART IV Item 15. Exhibits and Financial Statement Schedules Item 16. Form 10-K Summary SIGNATURES Page 4 30 66 66 66 67 67 68 68 69 79 80 80 80 81 81 82 82 82 82 82 83 88 89 CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS This Annual Report on Form 10-K, or Annual Report, contains forward-looking statements that involve risks and uncertaines. We make such forward- looking statements pursuant to the safe harbor provisions of the Private Securies Ligaon Reform Act of 1995 and other federal securies laws. All statements other than statements of historical fact contained in this Annual Report are forward-looking statements. In some cases, you can idenfy forward- looking statements by words such as “ancipate,” “believe,” “contemplate,” “connue,” “could,” “esmate,” “expect,” “forecast,” “intend,” “may,” “plan,” “potenal,” “predict,” “project,” “seek,” “should,” “target,” “will,” “would,” or the negave of these words, or other comparable terminology. These forward- looking statements include, but are not limited to, statements about: • • • • • • • • • • • • • • • • • • • • our commercializaon, markeng, and manufacturing capabilies and strategy; our expectaons regarding the ming of clinical study commencements and reporng results from same; the ming and likelihood of regulatory approvals for our product candidates; the ancipated indicaons for our product candidates, if approved; the potenal market opportunies for commercializing our products and product candidates; our expectaons regarding the potenal market size and the size of the paent populaons for our products and product candidates, if approved for commercial use; esmates of our expenses, revenue, capital requirements, and our needs for addional ﬁnancing; our ability to develop, acquire, and advance product candidates into, and successfully complete, clinical studies; the implementaon of our business model and strategic plans for our business, products and product candidates and the integraon and performance of any businesses we have acquired or may acquire; the iniaon, ming, progress, and results of ongoing and future preclinical and clinical studies, and our research and development programs; the scope of protecon we are able to establish and maintain for intellectual property rights covering our products and product candidates; our ability to maintain and establish collaboraons or strategic relaonships or obtain addional funding; our ability to maintain and establish relaonships with third pares, such as contract research organizaons, contract manufacturing organizaons, suppliers, and distributors; our ﬁnancial performance and the expansion of our organizaon; our ability to obtain supply of our products and product candidates; the scalability and commercial viability of our manufacturing methods and processes; developments and projecons relang to our competors and our industry; stagnang or worsening business and economic condions and increasing geopolical instability, including inﬂaonary pressures, general economic slowdown or a recession, high interest rates, foreign exchange rate volality, ﬁnancial instuon instability, a potenal government shutdown, and changes in monetary policy; the impact of market condions and volality on unrealized gains or losses on our nonqualiﬁed deferred compensaon plan investments and our ﬁnancial results; and other risks and uncertaines, including those listed under “Part I, Item 1A. Risk Factors.” Any forward-looking statements in this Annual Report reﬂect our current views with respect to future events or to our future ﬁnancial performance and involve known and unknown risks, uncertaines, and other factors that may cause our actual results, performance, or achievements to be materially diﬀerent from any future results, performance, or achievements expressed or implied by these forward-looking statements. Factors that may cause actual results to diﬀer materially from current expectaons include, among other things, those discussed under Part I, Item 1A. Risk Factors and elsewhere in this Annual Report. Given these uncertaines, you should not place undue reliance on these forward-looking statements. Except as required by law, we assume no obligaon to update or revise these forward-looking statements for any reason, even if new informaon becomes available in the future. 3 This Annual Report also contains esmates, projecons, and other informaon concerning our industry, our business, and the markets for certain diseases, including data regarding the esmated size of those markets, and the incidence and prevalence of certain medical condions. Informaon that is based on esmates, forecasts, projecons, market research, or similar methodologies is inherently subject to uncertaines and actual events or circumstances may diﬀer materially from events and circumstances reﬂected in this informaon. Unless otherwise expressly stated, we obtained such industry, business, market, and other data from reports, research surveys, studies, and similar data prepared by market research ﬁrms and other third pares, industry, medical and general publicaons, government data, and similar sources. As used in this Annual Report, “Ultragenyx,” “we,” “our,” and similar terms refer to Ultragenyx Pharmaceucal Inc. and its subsidiaries, unless the context indicates otherwise. Item 1. Business Overview PART I We are a biopharmaceucal company commied to bringing novel products to paents for the treatment of serious rare and ultrarare genec diseases. We have built a diverse porolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treang the underlying disease. We were founded in April 2010 by our President and Chief Execuve Oﬃcer, Emil Kakkis, M.D., Ph.D., and are led by a management team experienced in the development and commercializaon of rare disease therapeucs. Our strategy is predicated upon me- and cost-eﬃcient drug development, with the goal of delivering safe and eﬀecve therapies to paents with the utmost urgency. Our Strategy The crical components of our business strategy include the following: • • • • Focus on rare and ultrarare genec diseases with signiﬁcant unmet medical need and clear biology. There are numerous rare and ultrarare genec diseases that currently have no drug therapy approved that treat the underlying disease. Paents suﬀering from these diseases oen have a signiﬁcant morbidity and/or mortality. We focus on developing and commercializing therapies for mulple such indicaons with the utmost urgency. We also focus on diseases that have biology that is well understood. We believe that developing drugs that directly impact known disease pathways will increase the probability of success of our development programs. Our modalies of biologics, small molecules, adeno-associated virus, or AAV, gene therapy, and nucleic acids provide us with what we believe is an opmal set of opons to treat genec diseases by selecng the best treatment strategy available for each disease. In-license promising product candidates; retain global commercializaon rights to product candidates. Our current product candidates are generally in-licensed from academic instuons or derived from partnerships with other pharmaceucal companies. We believe pares agree to license product candidates to us because they are conﬁdent in our team’s experse in rare disease drug development and commercializaon. We generally intend to retain global commercializaon rights to our products and product candidates whenever possible to maximize the potenal value of our product porolio. Focus on excellent, rapid, and eﬃcient clinical and regulatory execuon on mulple programs in parallel. We believe that building a successful and sustainable rare disease-focused company requires very speciﬁc experse in the areas of paent idenﬁcaon, clinical study design and conduct, and regulatory strategy. Because rare disease programs involve fewer paents and may have accelerated paths to market, we are able to feasibly develop mulple clinical-stage product candidates in parallel, resulng in a more diversiﬁed porolio that provides mulple opportunies to create value, with some economies of scale. Commercialize through paent-focused global organizaon. We seek to commercialize our products throughout the developed world, in North America, the European Union, or the EU, the United Kingdom, or the U.K., Lan America, Turkey, Asia, and select internaonal markets. We have established our own commercial organizaon in these markets and a network of third-party distributors in smaller markets. We believe our commercial organizaon is highly specialized and focused, due to the nature of rare disease treatment. 4 Approved Products and Clinical Product Candidates Our current approved therapies and clinical-stage pipeline consist of four product categories: biologics, small molecules, AAV gene therapy, and nucleic acid product candidates. We have four commercially approved products, Crysvita® (burosumab) for the treatment of X-linked hypophosphatemia, or XLH, and tumor-induced osteomalacia, or TIO, Mepsevii® (vestronidase alfa) for the treatment of mucopolysaccharidosis VII, or MPSVII or Sly Syndrome, Dojolvi® (triheptanoin) for the treatment of long-chain fay acid oxidaon disorders, or LC-FAOD, and Evkeeza® (evinacumab) for the treatment of homozygous familial hypercholesterolemia, or HoFH. The following table summarizes our approved products and pipeline of clinical product candidates: 5 Approved Products Crysvita for the treatment of XLH and TIO Crysvita is a fully human monoclonal anbody administered via subcutaneous injecon, that targets ﬁbroblast growth factor 23, or FGF23, developed for the treatment of XLH. XLH is a rare, hereditary, progressive, and lifelong musculoskeletal disorder characterized by renal phosphate wasng caused by excess FGF23 producon. There are approximately 48,000 paents with XLH in the developed world, including approximately 36,000 adults and 12,000 children. Crysvita is the only approved treatment that addresses the underlying cause of XLH. Crysvita is approved in the U.S., the EU and certain other regions for the treatment of XLH in adult and pediatric paents one year of age and older. Crysvita is also approved in the U.S. and certain other regions for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia, or TIO, associated with phosphaturic mesenchymal tumors that cannot be curavely resected or localized in adults and pediatric paents 2 years of age and older. There are approximately 2,000 to 4,000 paents with TIO in the developed world. TIO can lead to severe hypophosphatemia, osteomalacia, fractures, fague, bone and muscle pain, and muscle weakness. We are collaborang with Kyowa Kirin Co., Ltd., or KKC, and Kyowa Kirin, a wholly owned subsidiary of KKC, on the development and commercializaon of Crysvita globally. Please see “—License and Collaboraon Agreements—Approved Products— Kyowa Kirin Co., Ltd.” for a descripon of our collaboraon and license agreement with KKC. Mepsevii for the treatment of MPS VII Mepsevii is an enzyme replacement therapy administered intravenously, or IV, that replaces the missing enzyme (beta-glucuronidase), developed for the treatment of Mucopolysaccharidosis VII, also known as MPS VII or Sly syndrome. MPS VII is a rare lysosomal storage disease that oen leads to mul- organ dysfuncon, pervasive skeletal disease, and death. MPS VII and is one of the rarest MPS disorders, aﬀecng an esmated 200 paents in the developed world. Mepsevii is approved in the U.S., the EU and certain other regions for the treatment of children and adults with MPS VII. Please see “—License and Collaboraon Agreements—Approved Products—Saint Louis University” for a descripon of our license agreement with Saint Louis University. Dojolvi for the treatment of LC-FAOD Dojolvi is a highly puriﬁed, synthec, 7-carbon fay acid triglyceride administered orally, designed to provide medium-chain, odd-carbon fay acids as an energy source and metabolite replacement, developed for people with long-chain fay acid oxidaon disorders, or LC-FAOD. LC-FAOD represents a set of rare metabolic diseases that prevents the conversion of fat into energy and can cause low blood sugar, muscle rupture, and heart and liver disease. Dojolvi is approved in the U.S. and certain other regions as a source of calories and fay acids for the treatment of pediatric and adult paents with molecularly conﬁrmed LC-FAOD. There are approximately 8,000 to 14,000 paents in the developed world with LC-FAOD. Please see “—License and Collaboraon Agreements—Approved Products—Baylor Research Instute” for a descripon of our license agreement with Baylor Research Instute. Evkeeza for the treatment of HoFH Evkeeza is a fully human monoclonal anbody administered by IV, that binds to and blocks the funcon of angiopoien-like 3, or ANGPTL3, a protein that plays a key role in lipid metabolism, developed for the treatment of homozygous familial hypercholesterolemia, or HoFH, a rare inherited condion. HoFH occurs when two copies of the familial hypercholesterolemia, or FH-causing genes are inherited, one from each parent, resulng in dangerously high levels (>400 mg/dL) of LDL-C, or bad cholesterol. Paents with HoFH are at risk for premature atheroscleroc disease and cardiac events as early as their teenage years. Evkeeza is approved in the U.S., where it is marketed by our partner Regeneron Pharmaceucals, or Regeneron. It is also approved in the European Economic Area, or EEA, as a ﬁrst-in-class therapy for use together with diet and other low-density lipoprotein-cholesterol, or LDL-C, lowering therapies to treat adults and adolescents aged ﬁve years and older with clinical HoFH. There are approximately 3,000 to 5,000 paents with HoFH in the developed world outside of the U.S. Please see “—License and Collaboraon Agreements—Approved Products—Regeneron” for a descripon of our license agreement with Regeneron Pharmaceucals. 6 Clinical Product Candidates UX143 (setrusumab) for the treatment of Osteogenesis Imperfecta, or OI UX143 (setrusumab) is a fully human monoclonal anbody administered by IV that inhibits sclerosn, a protein that acts on a key bone-signaling pathway by inhibing the acvity of bone-forming cells and promong bone resorpon. Setrusumab is being developed for the treatment of OI, or brile bone disease, which is caused by variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. There are an esmated 60,000 paents in the developed world aﬀected by OI. UX143 has received orphan drug designaon from the U.S. Food and Drug Administraon, or FDA, and European Medicines Agency, or EMA, rare pediatric disease designaon from the FDA, and was accepted into the EMA’s Priority Medicines program, or PRIME, program. Setrusumab is subject to our collaboraon agreement with Mereo and is the lead clinical asset in our bone endocrinology franchise. In June 2023, we, along with our collaboraon partner, Mereo, announced posive data from the dose-selecon Phase 2 poron of the Phase 2/3 Orbit study, which demonstrated that setrusumab rapidly induced bone producon in paents aged ﬁve to 25 with OI. Across all paents evaluated as of the data cut-oﬀ, setrusumab demonstrated stascally signiﬁcant increases in levels of serum P1NP, a sensive marker of bone formaon, and a substanal and signiﬁcant improvement in bone mineral density (BMD) by three months. As of the data cut-oﬀ for our June 2023 announcement, serum P1NP levels through at least one month of treatment were available from all 24 paents enrolled in the Phase 2 poron of Orbit and demonstrated that treatment with setrusumab signiﬁcantly increased serum P1NP in both dosing cohorts, peaking at one to two weeks and again, as expected, aer the two-month dosing mepoint. Lumbar spine BMD data were available in 17 of 24 Orbit paents at the 3-month mepoint. Treatment with setrusumab for three months resulted in an increase in lumbar spine BMD from baseline of 9.4% at 20 mg/kg (n=10), which represents a substanal mean change in Z-score of +0.65 from -2.12 (n=11) at baseline. In October 2023 at the American Society for Bone and Mineral Research 2023 Annual Meeng (ASBMR), we and Mereo announced addional interim data from the Phase 2 poron of the Phase 2/3 Orbit study that demonstrated that treatment with UX143 signiﬁcantly reduced incidence of fractures in paents with OI with at least six months of follow-up and connued to demonstrate ongoing and meaningful improvements in lumbar spine BMD. As of the data cut-oﬀ on August 4, 2023 and following at least six months of treatment with setrusumab, the annualized fracture rate across all 24 paents in the Phase 2 poron of the study was reduced by 67%. The median annualized fracture rate of 0.72 in the two years prior to treatment was reduced to 0.00 (n=24, p=0.042) during the mean treatment duraon period of nine months. Such fractures excluded fractures of the ﬁngers, toes, skull and face consistent with the Phase 3 study design. As of the data cut-oﬀ for our October 2023 announcement, there were no treatment-related serious adverse events observed in the study. The Phase 3 poron of the Orbit study is expected to enroll approximately 150 paents and be fully enrolled around the end of the ﬁrst quarter of 2024. Addional, longer-term Phase 2 data from the Orbit study are expected in 2024. The Phase 3 Cosmic study is an acve-controlled study evaluang the eﬀect of setrusumab compared to intravenous bisphosphonate (IV-BP) therapy on annualized total fracture rate in paents aged 2 to <5 years. Cosmic is targeng to enroll approximately 50 paents or more at more than 20 global sites and is expected to complete enrollment in the ﬁrst half of 2024. Please see “—License and Collaboraon Agreements—Clinical Product Candidates—Mereo” for a descripon of our license and collaboraon agreement with Mereo. GTX-102 for the treatment of Angelman Syndrome GTX-102 is an ansense oligonucleode, or ASO, administered by intrathecal injecon (IT) that inhibits expression of the paternal UBE3A ansense. GTX-102 is being developed for the treatment of Angelman syndrome, a debilitang and rare neurogenec disorder caused by loss-of-funcon of the maternally inherited allele of the UBE3A gene. There are an esmated 60,000 paents in the developed world aﬀected by Angelman syndrome. GTX-102 has received Fast Track Designaon, Orphan Drug Designaon and Rare Pediatric Disease Designaon from the FDA and has been accepted into the EMA’s Priority Medicines program, or PRIME, program. In May 2023, we announced that the FDA reviewed and agreed to a protocol amendment to the Phase 1/2 study of GTX-102 in pediatric paents with Angelman syndrome that enables us to harmonize dose ranges in the U.S. with those being used in ex-U.S. cohorts of the study. The Phase 1/2, open-label, dose-escalang study is evaluang the safety and tolerability of GTX-102 in pediatric paents with Angelman syndrome with a genecally conﬁrmed diagnosis of full maternal UBE3A gene deleon. The study is looking to verify the GTX-102 dose range and treatment regimen that are expected to be used in the Phase 3 program. In October 2023, at the Company's Analyst Day, we presented data from the extension cohorts (Cohorts 4-7) in the Phase 1/2 study for GTX-102 that demonstrated clinically meaningful improvements in mulple domains. We presented quantave data that showed improvements across mulple clinical domains compared to natural history data, where available, and clinical changes were 7 associated with quantave changes in EEG. Long-term data showed paents who stopped and restarted treatment reacquired previously gained developmental skills when they were re-dosed with the current regimen. As of the data cut-oﬀ date, October 3, 2023, there had been no addional treatment-related serious adverse events, or SAEs, since November 2022. In January 2024, we announced that enrollment in the expansion cohorts had been completed with a total of 53 paents enrolled. Across the Phase 1/2, including the dose escalaon and expansion cohorts, there are a total of 74 paents enrolled in the Phase 1/2 study. The expansion cohorts will evaluate many of the same safety, pharmacokinec, and eﬃcacy measures as the previously enrolled dose escalaon cohorts plus some new evaluaons. The next safety and eﬃcacy data update is expected in the ﬁrst half of 2024 and is planned to include at least 20 expansion cohort paents with a minimum of Day 170 data. Please see “—License and Collaboraon Agreements—Clinical Product Candidates—GeneTx” for a descripon of our license agreement with GeneTx. UX111 for the treatment of Sanﬁlippo syndrome type A or MPS IIIA UX111 (formerly ABO-102) is an adeno-associated virus 9, or AAV9, gene therapy product candidate, administered by a one-me IV infusion that provides the cross-correcng enzyme that enables the break down of Heparan sulfate, or HS. UX111 is being developed for the treatment of paents with Sanﬁlippo syndrome type A, or MPS IIIA, a rare lysosomal storage disease with no approved treatment, which primarily aﬀects the central nervous system. There are an esmated 3,000 to 5,000 paents in the developed world aﬀected by Sanﬁlippo syndrome type A. The program was acquired through an exclusive license agreement with Abeona Therapeucs, or Abeona, that was announced in May 2022. The UX111 program has received Regenerave Medicine Advanced Therapy, or RMAT, Fast Track, Rare Pediatric Disease, and Orphan Drug Designaons in the U.S., and PRIME and Orphan Medicinal Product designaons in the EU. Abeona previously announced the compleon of a successful Type B meeng with the FDA regarding the pivotal Transpher A trial to support ﬁling and approval for UX111. Ultragenyx presented new data from the ongoing pivotal Transpher A study evaluang the eﬃcacy and safety of UX111 in children with MPS IIIA at the 20th Annual WORLDSymposiumTM. The presentaon showed that the observed reducons of HS exposure in cerebrospinal ﬂuid can predict improved long-term cognive funcon in paents with MPS IIIA following treatment with UX111. Discussions with the FDA seeking an accelerated review path are ongoing. Please see “—License and Collaboraon Agreements—Clinical Product Candidates—Abeona” for a descripon of our license agreement with Abeona. DTX401 for the treatment of glycogen storage disease type Ia, or GSDIa DTX401 is an adeno-associated virus 8, or AAV8, gene therapy clinical candidate, administered by a one-me IV infusion that is designed to deliver stable expression and acvity of G6Pase-α, an essenal enzyme in glycogen and glucose metabolism. DTX401 is being developed for the treatment of paents with glycogen storage disease type Ia, or GSDIa, and is the most common genecally inherited glycogen storage disease, with an esmated 6,000 paents in the developed world. A Pediatric Invesgaon Plan, or PIP, was accepted by the EMA. The DTX401 program has received RMAT, Fast Track, and Orphan Drug designaons in the U.S., and PRIME and Orphan Medicinal Product Designaons in the EU. We currently plan to move manufacturing of DTX401 from a third party to our gene therapy manufacturing facility, which could lengthen our meline to ﬁling a biologics license applicaon, or BLA. In May 2023, we announced the last paent had been dosed in the Phase 3 study of DTX401. The 48-week study has fully enrolled paents eight years of age and older, randomized 1:1 to DTX401 (1.0 x 10^13 GC/kg dose) or placebo. The primary endpoint is the reducon in oral glucose replacement with cornstarch while maintaining glucose control. We expect to share results from this Phase 3 study in the ﬁrst half of 2024. Please see “—License and Collaboraon Agreements—Clinical Product Candidates—REGENXBIO Inc.” for a descripon of our license agreement with REGENXBIO Inc. DTX301 for the treatment of ornithine transcarbamylase, or OTC, deﬁciency DTX301 is an AAV8 gene therapy product candidate, administered by a one-me IV infusion that is designed to deliver stable expression and acvity of the ornithine transcarbamylase, or OTC, gene. DTX301 is being developed for the treatment of paents with OTC deﬁciency, which is the most common urea cycle disorder, and there are approximately 10,000 paents in the developed world with OTC deﬁciency, of which we esmate approximately 80% are classiﬁed as late-onset, our target populaon. DTX301 has received Orphan Drug Designaon in both the U.S. and in the EU and Fast Track Designaon in the U.S. We are currently randomizing and dosing paents in our 64-week Phase 3 study of DTX301. The paents in the study will be randomized 1:1 to DTX301 (1.7 x 10^13 GC/kg dose) or placebo. We plan to enroll approximately 50 paents 12 years of age and older. The co-primary endpoints are the percentage of paents who achieve a response, as measured by disconnuaon or 8 reducon in baseline disease management, and the 24-hour plasma ammonia levels. We expect to complete enrollment for the Phase 3 study in the ﬁrst half of 2024. Please see “—License and Collaboraon Agreements—Clinical Product Candidates—REGENXBIO Inc.” for a descripon of our license agreement with REGENXBIO Inc. UX701 for the treatment of Wilson Disease UX701 is an AAV type 9 gene therapy, administered by a one-me IV infusion that is designed to deliver a truncated form of the ATP7B gene. UX701 is being developed for the treatment of paents with Wilson disease, which aﬀects more than 50,000 paents in the developed world. UX701 has received Orphan Drug Designaon in the U.S. and in the EU. UX701 has received a Fast Track Designaon from the FDA. In October 2023 at the Company's Analyst Day, we announced that four out of ﬁve paents in the ﬁrst cohort (5.0 x 10^12 GC/kg) had reducons in urinary copper and were tapering oﬀ of chelators and/or zinc therapy, including two of three earlier treated paents in the cohort that were then completely oﬀ standard of care therapy. As of the data cut-oﬀ date, October 8, 2023, UX701 had been generally well tolerated with no treatment-related SAEs. We have enrolled and dosed paents in the three dose escalang cohorts of the ﬁrst stage of the pivotal Cyprus2+ study of UX701 for the treatment of Wilson disease. During this stage, the safety and eﬃcacy of UX701 is being evaluated that will enable a dose to be selected for further evaluaon in the second, randomized, placebo-controlled stage of this seamless pivotal study. Data from Stage 1 are expected in mid 2024, which will be followed by the iniaon and dosing of paents in Stage 2 in the second half of 2024. Please see “—License and Collaboraon Agreements—Clinical Product Candidates— REGENXBIO Inc.” for a descripon of our license and collaboraon agreement with REGENXBIO Inc. Compeon In the case of indicaons that we are targeng, it is possible that other companies may produce, develop, and commercialize compounds that might treat these diseases. With respect to Crysvita, although we are not aware of any other products currently in clinical development for the treatment of XLH and TIO, it is possible that competors may produce, develop, and commercialize therapeucs, or ulize other approaches such as gene therapy, to treat XLH and TIO. Most pediatric paents with XLH are managed using oral phosphate replacement and/or vitamin D therapy, which is relavely inexpensive and therefore may adversely aﬀect our ability to commercialize Crysvita, if approved, in some countries. With respect to Mepsevii, we are not aware of any other compounds currently in clinical development for MPS VII, but it is possible that other companies may produce, develop, and commercialize compounds that might treat this disease. Addionally, gene therapy and other therapeuc approaches may emerge for the treatment of lysosomal diseases. Bone marrow or stem cell transplants have also been used in MPS VII and in other lysosomal storage diseases and represent a potenal compeng therapy. Stem cell transplants have been eﬀecve in treang so ssue storage and in having an impact on brain disease, but have not to date proven eﬀecve in treang bone and connecve ssue disease. Typically, enzyme replacement therapy has had an impact on bone and connecve ssue disease in other disorders when paents were treated early. With respect to Dojolvi, LC-FAOD is commonly treated with diet therapy and MCT oil. Dojolvi may compete with this approach. Although we believe that Dojolvi should be considered a drug and will be regulated that way, it is possible that other companies or individuals may aempt to produce triheptanoin for use in LC-FAOD. Invesgators are tesng triheptanoin in clinical studies across mulple indicaons, including LC-FAOD. It is also possible that other companies may produce, develop, and commercialize other medium odd-chain fay acids, or completely diﬀerent compounds, to treat LC-FAOD. Other companies may also ulize other approaches, such as gene therapy, to treat LC-FAOD. In addion, Reneo Pharmaceucals is developing REN001, a PPAR delta agonist, in Phase 1b for LC-FAOD and other genec myopathies. With respect to Evkeeza, the current treatments for paents with HoFH involve various lipid-lowering agents to reduce serum LDL and total cholesterol levels. Drug therapies include stans (e.g., Rosuvastan, Simvastan, etc.), fenoﬁbrate, ezemibe (Ezetrol), evolocumab (Repatha), and lomitapide (Juxtapid/Lojuxta). Other than lomitapide, these agents rely on an LDL-receptor based mechanism to reduce cholesterol, which may be absent in HoFH paents, parcularly those with LDLR-null mutaons. In addion, Arrowhead Pharmaceucals is developing ARO-ANG3 and Eli Lilly/Dicerna is developing LY3561774, both RNAi-based inhibitors of ANGPTL3 in Phase 2 studies across various indicaons including HoFH. With respect to UX143, there are currently no approved drugs for OI. Most pediatric paents with OI are managed with oﬀ-label use of bisphosphonates to increase bone density and reduce frequency of bone fracture. We are aware of another 9 an-sclerosn anbody, romosozumab, that is in Phase 3 clinical tesng by Amgen. In addion, two an-TGFβ anbodies, fresolimumab and SAR439459, are in Phase 1 clinical tesng by Sanoﬁ-Genzyme. With respect to GTX-102, there are currently no approved drugs for Angelman syndrome. Many paents take general treatments to try to manage speciﬁc symptoms, such as seizures or sleep disturbances, but there are no treatments available that address the underlying biology of the disease. We are aware of other preclinical and clinical development programs for Angelman syndrome, including Phase 2 programs from Biogen in collaboraon with Ionis, ION582 an ASO, and Neuren Pharmaceucals, NNZ-2591 an IGF-1 analog. With respect to UX111, there are currently no approved pharmacologic treatments for paents with MPS IIIA. Paents receive supporve or symptomac treatment, but these approaches generally do not prevent funconal decline. We are aware of other gene therapies, including LYS-SAF302, in Phase 2/3 for MPSIIIA by Lysogene, and EGT-101, in Phase 1/2 for MPSIIIA by Esteve. In addion, Orchard Therapeucs is developing OTL-201, an ex-vivo gene therapy in Phase 1/2 for MPSIIIA. With respect to DTX401, there are currently no pharmacologic treatments for paents with GSDIa. We are aware of an mRNA therapy, mRNA-3745, in Phase 1 for GSDIa by Moderna. With respect to DTX301, the current treatments for paents with OTC deﬁciency are nitrogen scavenging drugs and severe limitaons in dietary protein. Drug therapy includes sodium phenylbutyrate (Buphenyl) and glycerol phenylbutyrate (Ravic), both nitrogen scavengers that help eliminate excess nitrogen, in the form of ammonia, by facilitang its excreon. A novel formulaon of sodium phenylbutyrate, ACER-001 by Acer Therapeucs, was approved in December 2022. During a metabolic crisis, paents rounely receive carbohydrate and lipid rich nutrion, including overnight feeding through a nasogastric tube, to limit bodily protein breakdown and ammonia producon. In acute cases, ammonia must be removed by dialysis or hemoﬁltraon. Liver transplant may also be a soluon for OTC deﬁciency. In addion, Arcturus Therapeucs is developing ARCT-810, a messenger RNA therapy, in Phase 2 for OTC deﬁciency. With respect to UX701, there are no currently approved treatments that address the underlying cause of Wilson disease. Many paents are on chelator therapies, but these fail to address the mutated ATP7B copper transporter gene. We are aware of another gene therapy, VTX-801, that is in Phase 1 for Wilson disease by Vivet Therapeucs, in collaboraon with Pﬁzer. License and Collaboraon Agreements Our products and some of our current product candidates have been either in-licensed from academic instuons or derived from partnerships with other pharmaceucal companies. Following is a descripon of our signiﬁcant license and collaboraon agreements. Approved Products Kyowa Kirin Co., Ltd. In August 2013, we entered into a collaboraon and license agreement with KKC. Under the terms of this collaboraon and license agreement, as amended, we and KKC collaborate on the development and commercializaon of Crysvita in the ﬁeld of orphan diseases in the U.S. and Canada, or the Proﬁt- Share Territory, and in the EU, U.K., and Switzerland, or the European Territory, and we have the right to develop and commercialize such products in the ﬁeld of orphan diseases in Mexico and Central and South America, or Lan America. In the ﬁeld of orphan diseases, and except for ongoing studies being conducted by KKC, we were the lead party for development acvies in the Proﬁt-Share Territory and in the European Territory unl the applicable transion date. We shared the costs for development acvies in the Proﬁt-Share Territory and the European Territory conducted pursuant to the development plan before the applicable transion date equally with KKC. In April 2023, which was the transion date for the Proﬁt-Share Territory, KKC became the lead party and became responsible for the costs of the development acvies. However, we will connue to share the costs of the studies commenced prior to the applicable transion date equally with KKC. Crysvita was approved in the EU and U.K. in February 2018 and was approved by the FDA in April 2018. As described below, we and KKC shared commercial responsibilies and proﬁts in the Proﬁt-Share Territory unl April 2023, KKC has the commercial responsibility in the European Territory, and we are responsible for commercializing Crysvita in Lan America. 10 In the Proﬁt-Share Territory, KKC booked sales of products and we had the sole right to promote the products, with KKC having the right to increasingly parcipate in the promoon of the products unl the transion date of April 2023, which was ﬁve years from commercial launch. In 2022, we entered into an amendment to the collaboraon agreement which granted us the right to connue to support KKC in commercial ﬁeld acvies in the U.S. through April 2024, subject to the limitaons and condions set forth in the amendment. The pares subsequently mutually agreed to extend our right to connue to support KKC in commercial ﬁeld acvies in the U.S. through December 31, 2024, and as a result, we will connue to support commercial ﬁeld eﬀorts in the U.S. through a cost share arrangement through December 2024. Aer December 31, 2024, our rights to promote Crysvita in the U.S. will be limited to medical genecists and we will solely bear our expenses for the promoon of Crysvita in the Proﬁt-Share Territory. See “Item I.A. Risk Factors” for addional informaon on the risks related to the expiraon of our exclusive right to promote Crysvita in the Proﬁt-Share Territory. In the European Territory, KKC books sales of products and has the sole right to promote and sell the products, with the excepon of Turkey. In Turkey, we have rights to commercialize Crysvita and KKC has the opon to assume responsibility for such commercializaon eﬀorts, aer a certain minimum period. In Lan America, we book sales of products and have the sole right to promote and sell the products. Under the collaboraon agreement, KKC manufactures and supplies Crysvita for sales in Lan American territories and we pay KKC a transfer price of 30% of net sales. Prior to December 31, 2022, the transfer price on net sales was 35%. We also pay KKC a low single-digit royalty on net sales in Lan America. The remaining proﬁt or loss from commercializing products in the Proﬁt-Share Territory was shared between us and KKC on a 50/50 basis unl April 2023. In April 2023, commercializaon responsibilies for Crysvita in the Proﬁt-Share Territory transioned to KKC and KKC assumed responsibility for the commercializaon of Crysvita in the Proﬁt-Share Territory at and aer April 2023. Thereaer, we are entled to receive a ered double-digit revenue share from the mid-20% range up to a maximum rate of 30%, intended to approximate the proﬁt-share. Our and KKC’s obligaons to pay royales will connue on a country-by-country basis for so long as we or KKC, as applicable, are selling products in such country. In July 2022, we sold to OCM LS23 Holdings LP, an investment vehicle for the Ontario Municipal Employees Rerement System, or OMERS, our right to receive 30% of the future royalty payments due to us based on net sales of Crysvita in the U.S. and Canada, subject to a cap, beginning in April 2023. KKC pays us a royalty of up to 10% based on net sales in the European Territory. We sold our interest in the European Territory royalty to RPI Finance Trust, an aﬃliate of Royalty Pharma, in December 2019. The collaboraon and license agreement will connue for as long as products in the ﬁeld of orphan diseases are sold in the Proﬁt-Share Territory, European Territory, Turkey, or Lan America, unless the agreement is terminated in accordance with its terms. KKC may terminate the agreement in certain countries or territories based upon our failure to meet certain milestones. Furthermore, either party may terminate the agreement for the material breach or bankruptcy of the other party. In any event of terminaon by KKC, unless such terminaon is the result of KKC’s terminaon for certain types of breach of the agreement by us, we may receive low single-digit to low double-digit royales on net post-terminaon sales by KKC in one or more countries or territories, the amount of which varies depending on the ming of, and reason for, such terminaon. In any event of terminaon, our rights to Crysvita under the agreement and our obligaons to share development costs will cease, and the program will revert to KKC, worldwide if the agreement is terminated as a whole or solely in the terminated countries if the agreement is terminated solely with respect to certain countries. Saint Louis University In November 2010, we entered into a license agreement with Saint Louis University, or SLU, wherein SLU granted us certain exclusive rights to intellectual property related to Mepsevii. Under the terms of the license agreement, SLU granted us an exclusive worldwide license to make, have made, use, import, oﬀer for sale, and sell therapeucs related to SLU’s beta-glucuronidase product for use in the treatment of human diseases. Under the license agreement, we are obligated to pay to SLU a low single-digit royalty on net sales of the licensed products in the U.S., Europe, or Japan, subject to certain potenal deducons. Our obligaon to pay royales to SLU in these territories connues unl the expiraon of any orphan drug exclusivity. 11 Baylor Research Instute In September 2012, we entered into a license agreement, which was subsequently amended, with Baylor Research Instute, or BRI, under which we exclusively licensed certain intellectual property related to Dojolvi. The license includes patents, patent applicaons, know-how, and intellectual property related to the composion and formulaon of Dojolvi as well as its use in treang a number of orphan diseases, including LC-FAOD. The license grant includes the sole right to develop, manufacture, and commercialize licensed products for all human and animal uses. Under the license agreement, we are obligated to use commercially reasonable eﬀorts to develop and commercialize licensed products in select orphan indicaons. If we fail to meet our diligence obligaons with respect to a speciﬁed orphan indicaon or set of orphan indicaons, BRI may convert our license to a non-exclusive license with respect to such orphan indicaon or set of orphan indicaons unl we receive regulatory approval for licensed products in the applicable orphan indicaon or set of orphan indicaons. We are also obligated to pay a mid- single-digit royalty on net sales to BRI, subject to certain reducons and oﬀsets. Our obligaon to pay royales to BRI connues on a licensed product-by-licensed product and country-by-country basis unl the later of the expiraon of the ﬁrst regulatory exclusivity granted with respect to such product in such country or the expiraon of the last-to-expire licensed patent claiming such product in such country, in each case in connecon with approval in such country for LC-FAOD or an orphan disease covered by our license from BRI. During the year ended December 31, 2022, the sales milestone triggering a $2.5 million payment was achieved. Going forward, we may make future payments of up to $2.5 million conngent upon aainment of certain development milestones and $5.0 million if certain sales milestones are achieved. Regeneron In January 2022, we announced a collaboraon with Regeneron to commercialize Evkeeza for HoFH outside of the U.S. Evkeeza is approved in the U.S., where it is marketed by Regeneron, and in the EU and U.K. as a ﬁrst-in-class therapy for use together with diet and other low-density lipoprotein-cholesterol- lowering therapies to treat adults and adolescents aged 12 years and older with HoFH. Pursuant to the terms of the agreement, we received the rights to develop, commercialize and distribute the product for HoFH in countries outside of the U.S. Upon closing of the transacon in January 2022, we paid Regeneron a $30.0 million upfront payment. During the year ended December 31, 2023, a $10.0 million regulatory milestone was achieved. Going forward, we are obligated to pay Regeneron up to $53.0 million in future milestone payments, conngent upon the achievement of certain regulatory and sales milestones. We may share in certain costs for global trials led by Regeneron and also received the right to opt into other potenal indicaons. Under the collaboraon agreement, Regeneron supplies the product and charges us a transfer price from the low 20% range up to 40% of net sales. Clinical Product Candidates REGENXBIO Inc. In October 2013, we entered into an exclusive license agreement with REGENXBIO Inc., or REGENX, under which we were granted an opon to develop products to treat hemophilia A, OTC deﬁciency and GSDIa. Under the 2013 license agreement, REGENX granted us an exclusive worldwide license to make, have made, use, import, sell, and oﬀer for sale licensed products with respect to such disease indicaons, subject to certain exclusions. We do not have the right to control prosecuon of the in-licensed patent applicaons, and our rights to enforce the in-licensed patents are subject to certain limitaons. Under the 2013 license agreement, we pay or will pay REGENX an annual maintenance fee and certain milestone fees per disease indicaon, low to mid- single-digit royalty percentages on net sales of licensed products, and milestone and sublicense fees, if any, owed by REGENX to its licensors as a result of our acvies under the 2013 license agreement. We are required to develop licensed products in accordance with certain milestones. In the event that we fail to meet a parcular milestone within established deadlines, we can extend the relevant deadline by providing a separate payment to REGENX. In March 2015, we entered into an opon and license agreement with REGENX, which was subsequently amended, pursuant to which we have an exclusive worldwide license to make, have made, use, import, sell, and oﬀer for sale licensed products to treat Wilson disease and CDKL5 deﬁciency. We do not have the right to control prosecuon of the in-licensed patent applicaons, and our rights to enforce the in-licensed patents are subject to certain limitaons. Under the 2015 opon and license agreement, as amended, we pay or will pay REGENX an annual maintenance fee and certain milestone fees per disease indicaon, mid- to high single-digit royalty percentages on net sales of licensed products, and mid- single to low double-digit percentages of any sublicense fees we receive from sublicenses for the licensed intellectual property rights. We are required to develop licensed products in accordance with certain milestones. In the event that we fail to meet a parcular milestone within established deadlines, we can extend the relevant deadline by providing a separate payment to REGENX. 12 In March 2020, we entered into a license agreement with REGENX, for an exclusive, sublicensable, worldwide license to REGENX’s NAV AAV8 and AAV9 vectors for the development and commercializaon of gene therapy treatments for a rare metabolic disorder. In return for these rights, we made an upfront payment and pay or will pay certain annual fees, milestone payments and royales on any net sales of products incorporang the licensed intellectual property that range from a high single-digit to low double-digit. University of Pennsylvania In May 2016, we entered into a research, collaboraon and license agreement with the University of Pennsylvania under which we are collaborang on the pre-clinical development of gene therapy products for the treatment of phenylketonuria and Wilson disease, each, a Subﬁeld. Under the agreement, we were granted an exclusive, worldwide, royalty-bearing right and license to certain patent rights arising out of the research program, and a non-exclusive, worldwide, royalty-bearing right and license to certain University of Pennsylvania intellectual property, in each case to research, develop, make, have made, use, sell, oﬀer for sale, commercialize and import licensed products in each Subﬁeld for the term of the agreement. We will fund the cost of the research program and will be responsible for clinical development, manufacturing and commercializaon of each Subﬁeld. In addion, we are required to make milestone payments (up to a maximum of $5.0 million per Subﬁeld) if certain development milestones are achieved over me. We will also make milestone payments of up to $25.0 million per approved product, if certain commercial milestones are achieved, and will pay low to mid- single-digit royales on net sales of each Subﬁeld’s licensed products. GeneTx In August 2019, we entered into a Program Agreement and a Unitholder Opon Agreement with GeneTx Biotherapeucs LLC, or GeneTx, to collaborate on the development of GeneTx’s GTX-102, an ASO for the treatment of Angelman syndrome. In July 2022, pursuant to the terms of the Unitholder Opon Agreement, as amended, we exercised the Opon to acquire GeneTx and entered into a Unit Purchase Agreement, or the Purchase Agreement, pursuant to which we purchased all the outstanding units of GeneTx. In accordance with the terms of the Purchase Agreement, we paid the opon exercise price of $75.0 million, an addional $15.6 million to acquire the outstanding cash of GeneTx, and adjustments for working capital and transacon expenses of $0.6 million, for a total purchase consideraon of $91.2 million. We may be required to make payments of up to $190.0 million upon the achievement of certain milestones, including up to $30.0 million in milestone payments upon achievement of the earlier of iniaon of a Phase 3 clinical study or product approvals in Canada and the U.K., up to $85.0 million in addional regulatory approval milestones for the achievement of U.S. and EU product approvals, and up to $75.0 million in commercial milestone payments based on annual worldwide net product sales. We will also pay ered mid- to high single-digit percentage royales based on licensed product annual net sales. If we receive and resell an FDA priority review voucher, or PRV, in connecon with a new drug applicaon approval, GeneTx is entled to receive a poron of proceeds from the sale of the PRV or a cash payment from us, if we choose to retain the PRV. As part of our acquision of GeneTx, we assumed a License Agreement with Texas A&M University, or TAMU. Under this agreement, TAMU is eligible to receive from us up to $23.5 million upon the achievement of various future milestones, a nominal annual license fee that may increase up to a maximum of $2.0 million, as well as royales in the mid-single-digits of net sales. Mereo In December 2020, we entered into a License and Collaboraon Agreement with Mereo to collaborate on the development of setrusumab. Under the terms of the agreement, we will lead future global development of setrusumab in both pediatric and adult paents with OI and were granted an exclusive license to develop and commercialize setrusumab in the U.S., Turkey, and the rest of the world, excluding the European Economic Area, United Kingdom, and Switzerland, or the Mereo Territory, where Mereo retains commercial rights. Each party will be responsible for post-markeng commitments and commercial supply in their respecve territories. Upon the closing of the transacons under the License and Collaboraon Agreement with Mereo in January 2021, we made a payment of $50.0 million to Mereo. During the year ended December 31, 2023, we made a $9.0 million payment to Mereo upon the achievement of a clinical milestone. Going forward, we may be required to make payments of up to $245.0 million upon the achievement of certain clinical, regulatory, and commercial milestones. We will pay for all global development costs as well as ered double-digit percentage royales to Mereo on net sales in the U.S., Turkey, and the rest of the world, and Mereo will pay us a ﬁxed double-digit percentage royalty on net sales in the Mereo Territory. Abeona In May 2022, we announced an exclusive License Agreement with Abeona for an AAV gene therapy for the treatment of MPS IIIA, or UX111. Under the terms of the agreement, we assumed responsibility for the UX111 program and in return, we are obligated 13 to pay Abeona certain UX111-related prior development costs and other transion costs. Abeona is eligible to receive ered royales of up to 10% on net sales and commercial milestone payments of up to $30.0 million following regulatory approval of the product. Addionally, we entered into an Assignment and Assumpon Agreement with Abeona to transfer and assign to us the exclusive license agreement between Naonwide Children’s Hospital, or NCH, and Abeona for certain rights related to UX111. Under this agreement, NCH is eligible to receive from us up to $1.0 million in development and regulatory milestones as well as royales in the low single-digits of net sales. Preclinical Pipeline Solid Biosciences Inc. In October 2020, we entered into a strategic Collaboraon and License Agreement with Solid Biosciences Inc., or Solid, and received an exclusive license for any pharmaceucal product that expresses Solid’s proprietary microdystrophin construct from AAV8 and variants thereof in clade E for use in the treatment of Duchenne muscular dystrophy and other diseases resulng from lack of funconal dystrophin, including Becker muscular dystrophy. We are collaborang to develop products that combine Solid’s diﬀerenated microdystrophin construct, our Pinnacle PCLTM producer cell line plaorm, or Pinnacle PCL Plaorm, manufacturing plaorm, and our AAV8 variants. Solid may provide some development support and was granted an exclusive opon to co-invest in products we develop for proﬁt-share parcipaon in certain territories. We also entered into a Stock Purchase Agreement with Solid in October 2020 pursuant to which we purchased 521,719 shares (as adjusted for the October 2022 reverse stock split) of Solid’s common stock for an aggregate price of $40.0 million. Patents and Proprietary Rights The proprietary nature of, and protecon for, our products, product candidates, processes, and know-how are important to our business. Our success depends in part on our ability to protect our products, product candidates, processes, and know-how, to operate without infringing on the proprietary rights of others, and to prevent others from infringing our proprietary rights. We seek patent protecon in the U.S. and internaonally for our products, product candidates, and processes. Our policy is to patent or in-license the technologies, invenons, and improvements that we consider important to the development of our business. In addion to patent protecon, we rely on trade secrets, know-how, and connuing innovaon to develop and maintain our compeve posion. We also use other means to protect our products and product candidates, including the pursuit of markeng or data exclusivity periods, orphan drug status, and similar rights that are available under regulatory provisions in certain countries, including the U.S., Europe, Japan, and China. See “Government Regulaon—U.S. Government Regulaon — Orphan Designaon and Exclusivity,” “Government Regulaon—U.S. Government Regulaon — Pediatric Studies and Exclusivity,” “Government Regulaon—U.S. Government Regulaon — Biosimilars and Exclusivity,” “Government Regulaon—U.S. Government Regulaon — Abbreviated New Drug Applicaons for Generic Drugs and New Chemical Enty Exclusivity,” “Government Regulaon—U.S. Government Regulaon — Patent Term Restoraon,” “Government Regulaon—EU Regulaon — Orphan Designaon and Exclusivity,” and “Government Regulaon—EU Regulaon — New Chemical Enty Exclusivity” below for addional informaon. We seek regulatory approval for our products and product candidates in disease areas with high unmet medical need, signiﬁcant market potenal, and where we expect to have a proprietary posion through patents covering various aspects of our product candidates, such as composion, dosage, formulaon, use, and manufacturing process, among others. Our success depends in part on an intellectual property porolio that supports our future revenue streams and erects barriers to our competors. We are maintaining and building our patent porolio by ﬁling new patent applicaons, prosecung exisng applicaons, and licensing and acquiring new patents and patent applicaons. Despite these measures, any of our intellectual property and proprietary rights could be challenged, invalidated, circumvented, infringed, or misappropriated, or such intellectual property and proprietary rights may not be suﬃcient to achieve or maintain market exclusivity or otherwise to provide compeve advantages. We also cannot be certain that patents will be granted with respect to any of our pending patent applicaons or with respect to any patent applicaons ﬁled by us in the future, nor can we be sure that any of our exisng patents or any patents granted to us in the future will be commercially useful in protecng our products, product candidates, or processes. For more informaon, please see “Item I.A. Risk Factors Risks Related to Our Intellectual Property.” As of December 31, 2023, we own, jointly own, or have exclusive rights to more than 250 issued and in-force patents (not including individually validated naonal patents in European Patent Convenon member countries) that cover one or more of our products or product candidates, methods of their use, or methods of their manufacture, including more than 50 in-force patents issued by the U.S. Patent and Trademark Oﬃce, or the USPTO. Furthermore, as of December 31, 2023, we own, jointly own, or have exclusive rights to more than 350 pending patent applicaons, including more than 50 pending U.S. applicaons. 14 With respect to our owned or in-licensed issued patents in the U.S. and Europe, we may be entled to obtain an extension of patent term to extend the patent expiraon date. For example, in the U.S., this extended coverage period is known as patent term extension, or PTE, and can only be obtained provided we apply for and receive a markeng authorizaon for a product. The period of extension may be up to ﬁve years beyond the expiraon of the patent, but cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension may be extended. In Europe, a Supplementary Protecon Cerﬁcate, or SPC, may be available to extend the term of certain European patents covering our products; this requires applicaon for an SPC in individual European Patent Convenon, or EPC, member countries following product approval. However, there is no guarantee that the applicable authories, including the FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions. In the U.S., the exact duraon of the extension depends on the me we spend in clinical studies as well as geng markeng approval from the FDA. The exclusivity posions for our commercial products and our clinical-stage product candidates as of December 31, 2023, are summarized below. Crysvita (Burosumab) Exclusivity We have in-licensed rights from KKC to patents and patent applicaons relang to Crysvita and its use for the treatment of XLH, TIO, and various other hypophosphatemic condions. Pursuant to this license, we have rights to six issued U.S. patents, as well as issued patents and patent applicaons in other jurisdicons. The U.S. patents expire between 2028 and 2035. In addion to the foregoing patent protecons, Crysvita is protected in the U.S. by regulatory exclusivity unl 2030 and by orphan drug exclusivity for treang XLH and TIO unl 2025 and 2027, respecvely. Mepsevii (Vestronidase Alfa) Exclusivity We own four issued U.S. patents and corresponding issued foreign patents covering Mepsevii and its use in the treatment of lysosomal storage disorders such as MPS VII. These patents expire in 2035. Mepsevii is also protected in the U.S. by regulatory exclusivity unl 2029 and by orphan drug exclusivity for treang MPS VII unl November 2024. Dojolvi (Triheptanoin) Exclusivity We have an exclusive license from BRI to patents and patent applicaons relang to Dojolvi and its use for the treatment of FAOD. Pursuant to this license, we have rights to two issued U.S. patents covering Dojolvi which expire in 2025 and 2029. Beyond the patent porolio in-licensed from BRI, we own a pending U.S. patent applicaon, corresponding foreign patent applicaons, and issued patents in Australia, Brazil, Canada, Israel, Korea, Malaysia, and Taiwan relang to our pharmaceucal-grade Dojolvi composion; these owned patents and any addional patents issuing from these owned applicaons are expected to expire in 2034. Dojolvi is also protected in the U.S. by regulatory exclusivity unl 2025 and orphan drug exclusivity for treang FAOD unl 2027. Evkeeza (Evinacumab) Exclusivity We have an exclusive license from Regeneron to certain Regeneron patents for the development and commercializaon of Evkeeza outside of the U.S. for the treatment of HoFH and other hyperlipidemia/hypercholesterolemia indicaons. The in-licensed Regeneron patent porolio includes a patent family containing several issued foreign patents that expire in 2032 and cover the Evkeeza anbody; Regeneron has ﬁled supplementary protecon cerﬁcates to extend the rights associated with the European patent within this family unl 2036 in certain countries. The in-licensed Regeneron patent porolio contains ﬁve other patent families, one of which includes several pending patent applicaons directed to a stabilized pharmaceucal formulaon comprising Evkeeza; we expect any patents emanang from this patent family to expire in 2040. In addion to the foregoing patent protecons, Evkeeza is protected in Europe by data exclusivity unl 2029 and markeng exclusivity unl 2031. DTX401 (Pariglasgene Brecaparvovec) Exclusivity We have two in-licenses to patents and patent applicaons covering elements of our DTX401 product candidate. First, we have in-licensed an issued U.S. patent owned by the University of Pennsylvania, or UPENN, and sublicensed to us by REGENX relang to the AAV8 capsid used in DTX401 that expired in January 2024. Second, we have a non-exclusive license from the Naonal Instutes of Health, or NIH, to an issued U.S. patent expiring in 2034 (not accounng for any available PTE) and corresponding foreign patents covering a recombinant nucleic acid construct used in DTX401 that includes a codon-opmized version of the G6Pase gene. 15 DTX301 (Avalotcagene Ontaparvovec) Exclusivity We have a license to two patent families covering elements of our DTX301 product candidate. These patent families are owned by UPENN and sublicensed to us by REGENX. The in-licensed UPENN patent porolio includes an issued U.S. patent relang to the AAV8 capsid used in DTX301 that expired in January 2024, as well as three issued U.S. patents expiring in 2035 (not accounng for any available PTE) and corresponding foreign patents and patent applicaons covering the codon-opmized version of the OTC gene used in DTX301. UX143 (Setrusumab) Exclusivity We have in-licensed rights from Mereo to patents and patent applicaons relang to setrusumab and its use for the treatment of OI. Pursuant to our license from Mereo, we have exclusive rights outside of Europe to a Mereo patent family that includes three issued U.S. patents and corresponding issued foreign patents that relate to the setrusumab anbody, nucleic acids encoding setrusumab, processes for producing setrusumab, and setrusumab’s use as a medicament. Patents emanang from this patent family expire in 2028 (not accounng for any available PTE). We also have exclusive rights outside of Europe to two addional Mereo patent families, including an issued U.S. patent expiring in 2037 (not accounng for any available PTE), relang to methods of using an-sclerosn anbodies including setrusumab for the treatment of OI. Beyond these Mereo patents and patent applicaons, we jointly own with Mereo a patent family relang to dosing regimens for the use of an-sclerosn anbodies including setrusumab in the treatment of OI; we expect any patents emanang from this patent family to expire in 2042 (not accounng for any available PTE). UX111 Exclusivity We have an exclusive license from Naonwide Children’s Hospital, or NCH, to a pending U.S. patent applicaon covering a method of treang MPS IIIA by intravenously administering a recombinant AAV9 vector comprising a U1a promoter and a polynucleode sequence encoding N-sulfoglucosamine sulfohydrolase, or SGSH; we expect any patent emanang from this applicaon to expire in 2032 (not accounng for any available PTE). GTX-102 Exclusivity We have an exclusive license from TAMU to a patent family ﬁled in the U.S. and several foreign jurisdicons relang to UBE3A ansense oligonucleodes including GTX-102 and their use for the treatment of Angelman syndrome. The in-licensed TAMU patent family includes three issued U.S. patents expiring in 2038 (not accounng for any available PTE). UX701 Exclusivity We have two licenses to patents and patent applicaons covering elements of our UX701 product candidate. First, we have in-licensed patents owned by UPENN and sublicensed to us by REGENX relang to the AAV9 capsid used in UX701 that expire between September 2024 and 2026 in the U.S., and in September 2024 in foreign countries. Second, we have an exclusive license from UPENN to a patent family ﬁled in the U.S. and several foreign jurisdicons relang to AAV vectors containing certain regulatory and coding sequences packaged in UX701; this patent family includes an issued U.S. patent expiring in 2039 (not accounng for any available PTE). Beyond these in-licenses, we own a patent family covering AAV vectors expressing a novel truncated version of the ATP7B protein produced by UX701; we expect any patents emanang from this patent family to expire in 2040 (not accounng for any available PTE). Trademarks We own registered trademarks covering the Ultragenyx word mark in the U.S. and mulple other jurisdicons. In addion, we have a pending trademark applicaon in the U.S. covering a stylized design of our Ultragenyx logo. We also own registered trademarks in the U.S. and other territories relang to our Mepsevii and Dojolvi brand names for vestronidase alfa and triheptanoin, respecvely. We addionally have licenses from KKC and Regeneron to registered trademarks covering the Crysvita and Evkeeza brand names, respecvely, in territories where we have rights to commercialize these products. Other We rely upon unpatented trade secrets, know-how, and connuing technological innovaon to develop and maintain our compeve posion. We seek to protect our ownership of know-how and trade secrets through an acve program of legal mechanisms including assignments, conﬁdenality agreements, material transfer agreements, research collaboraons, and licenses. 16 Manufacturing While we currently contract with third pares for the manufacturing and tesng of most of our products and product candidates for use in preclinical, clinical, and commercial applicaons, we opened our ﬁrst GMP manufacturing facility based in Bedford, Massachuses in June 2023. This facility is focused on drug substance and drug product manufacturing of AAV gene therapy products and will support our clinical and commercial pipeline. This new capability will combine with our exisng gene therapy process and analycal development and QC lab capabilies in nearby Woburn, Massachuses to form a fully integrated gene therapy development, manufacturing, and tesng unit. The use of contracted manufacturing and reliance on collaboraon partners has historically minimized our direct investment in manufacturing facilies and addional staﬀ early in development. Although we rely on contract manufacturers, we have personnel with extensive manufacturing experience to oversee our contract manufacturers. All of our third-party manufacturers are subject to periodic audits to conﬁrm compliance with applicable regulaons and must pass inspecon before we can manufacture our drugs for commercial sales. For the other non-gene therapy modalies, we primarily use third-party manufacturers to meet our projected needs for commercial manufacturing. Third pares with whom we currently work might need to increase their scale of producon, or we will need to secure alternate suppliers. We believe that there are alternate sources of supply that can sasfy our clinical and commercial requirements, although we cannot be certain that idenfying and establishing relaonships with such sources, if necessary, would not result in signiﬁcant delay or material addional costs. Products Mepsevii The Mepsevii drug substance is manufactured by Rentschler Biopharma SE, or Rentschler, under non-exclusive commercial supply and services agreements eﬀecve December 2017 and January 2018, respecvely. The drug substance agreement had an inial term of ﬁve years, which was automacally extended for another ﬁve years following the inial term and will connue in full force and eﬀect for its term unless earlier terminated. Following the inial term, we and Rentschler can withdraw from the agreement without cause upon prior noce for speciﬁed periods. In addion, either party may terminate the agreement if the other party breaches a material provision and such breach remains uncured for a speciﬁed period following receipt by the breaching party of wrien noce of such breach. We can also terminate the agreement if Rentschler loses the right to operate under the agreement. Either party can also terminate the agreements if Rentschler is unable to deliver its agreed upon services for a certain period in the case of a force majeure event. The cell line to produce Mepsevii is speciﬁc for this product and is in our control and stored in mulple secure locaons. All other raw materials are commercially available. We transferred the ﬁll and ﬁnish acvies for the manufacture of Mepsevii drug product to a new site, BSP Pharmaceucals S.p.A., or BSP, located in Lana, Italy as the Rentschler manufacturing site in Laupheim, Germany was disconnued. The site change was approved by relevant global authories, including the FDA, on May 5, 2022. Suﬃcient inventory levels were maintained during the transfer of the ﬁll and ﬁnish acvies for Mepsevii to BSP. Crysvita The drug substance and drug product for burosumab are made by KKC in Japan under the collaboraon and license agreement with KKC. The cell line to produce burosumab is speciﬁc for this product and is in KKC’s control. All other raw materials are commercially available. Dojolvi The pharmaceucal-grade drug substance for Dojolvi is manufactured by IOI Oleo GmbH, or IOI Oleo, in Germany under an exclusive worldwide supply agreement, subject to certain limitaons, executed in 2012 and subsequently amended and restated in 2023. The agreement has an indeﬁnite term but can be terminated by either party with 36 months prior noce. Addionally, if a party materially breaches an obligaon under the agreement and does not cure such breach within 60 days of receiving noce of the breach from the non-breaching party, the non-breaching party may terminate the agreement immediately upon wrien noce to the breaching party. In March 2023, the Dojolvi drug product, or DP, manufacturer Aenova Haupt Pharma Wolfratshausen GmbH, or Haupt Pharma noﬁed us of their intent to close the facility by the end of 2023. In response to this informaon, we produced addional DP batches prior to the facility closure at the end of 2023 and have idenﬁed a new DP manufacturer. We are currently in the process of qualifying the new DP manufacturer and conducng transfer acvies and expect to complete these acvies before the end of 2024. Our current DP inventories are expected to support demand through at least the end of 2025. 17 Evkeeza On January 7, 2022, we announced a license and collaboraon agreement with Regeneron for us to clinically develop, commercialize and distribute Evkeeza in countries outside of the U.S. Evkeeza is a fully human monoclonal anbody that binds to and blocks the funcon of angiopoien-like 3, or ANGPTL3, a protein that plays a key role in lipid metabolism. The Evkeeza drug substance is manufactured by Regeneron at their manufacturing facility in Rensselaer, New York and the drug product is manufactured by Baxter Pharmaceucal Soluons, LLC. at their manufacturing facility in Bloomington, Indiana. Release tesng of the drug product is performed by Regeneron and third-party suppliers. We ulize third-party suppliers to perform packaging, labelling, distribuon, and tesng as needed for Evkeeza. Product Candidates The drug substances and drug products for our product candidates are manufactured using our network of GMP contract manufacturing organizaons, or CMOs, which are carefully selected and acvely managed for high quality, reliable clinical supply. The CMOs are located in Western Europe or North America. Commercializaon and Product Support We have built our own commercial organizaons in North America, Europe, Lan America and Japan to eﬀecvely support the commercializaon of our products and product candidates, if approved. Our intenon is to expand our product porolio and its geographic accessibility through the connued development of our proprietary pipeline or through strategic partnerships. We may elect to ulize strategic partners, distributors, or contract management organizaons to assist in the commercializaon of our products in certain geographies. The commercial infrastructure for rare disease products typically consists of a targeted, specialty ﬁeld organizaon that educates a limited and focused group of physicians supported by ﬁeld management and internal support teams, which includes markeng, paent support services, distribuon, and market access. One challenge, unique to commercializing therapies for rare diseases, is the diﬃculty in idenfying eligible paents due to the very small and somemes heterogeneous paent populaons along with oen undeﬁned clinical or genec tests to conﬁrm diagnosis. Our commercial and medical aﬀairs teams focus on maximizing paent idenﬁcaon for both clinical development and commercializaon purposes in rare diseases. Addional capabilies important to the rare disease marketplace in the U.S. include the management of key stakeholders such as managed care organizaons, specialty pharmacies, specialty distributors, and government payers. In many countries outside the U.S. single naonal payers are crical to providing reimbursement access. To develop the appropriate commercial infrastructure, we will have to invest a signiﬁcant amount of ﬁnancial and management resources, some of which will be commied prior to regulatory approval of the products that they are intended to support. We connue to support commercial and medical aﬀairs organizaons as well as other capabilies across North America, Europe, Lan America, and Japan to meet the educaonal needs of the healthcare providers and paents in the rare disease community, focusing on providing accurate disease state informaon and balanced product informaon across our porolio for appropriate management of paents with rare disorders. Medical aﬀairs is comprised of the following capabilies in support of our mission: medical informaon, paent advocacy, paent diagnosis liaisons, medical science liaisons, research and educaonal grants. Medical aﬀairs will engage as early as Phase 1 and will connue work throughout the lifecycle of each product and product candidate as dictated by the speciﬁc scienﬁc needs in each therapeuc area. Government Regulaon Government authories in the U.S. (including federal, state, and local authories) and in other countries, extensively regulate, among other things, the manufacturing, research and clinical development, markeng, labeling and packaging, storage, distribuon, post-approval monitoring and reporng, adversing and promoon, pricing, and export and import of pharmaceucal products, such as those we are developing. We must obtain the requisite approvals from regulatory authories in the U.S. and foreign countries prior to the commencement of clinical studies or markeng of the product in those countries. Accordingly, our operaons are and will be subject to a variety of regulaons and other requirements, which vary from country to country. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulaons require the expenditure of substanal me and ﬁnancial resources that has a signiﬁcant impact on our capital expenditures and results of operaons. 18 Global Regulaon of Clinical Studies Clinical studies involve the administraon of an invesgaonal medicinal product to human subjects under the supervision of qualiﬁed invesgators in accordance with protocols, Good Clinical Pracces, or GCP, the ethical principles that have their origin in the Declaraon of Helsinki and applicable regulatory requirements. A protocol for each clinical study and any subsequent protocol amendments are typically submied to the FDA or other applicable regulatory authories as part of an invesgaonal new drug applicaon, or IND, or clinical trial applicaon, or CTA. Addionally, approval must also be obtained from each clinical study site’s instuonal review board, or IRB, or Ethics Commiee, or EC, before the studies may be iniated, and the IRB or EC must monitor the study unl completed. There are also requirements governing the reporng of ongoing clinical studies and clinical study results to public registries. The clinical invesgaon of a drug is generally divided into three or four phases. Although the phases are usually conducted sequenally, they may overlap or be combined. • • • • Phase 1. The drug is inially introduced into healthy human subjects or paents with the target disease or condion. These studies are designed to evaluate the safety, dosage tolerance, pharmacokinecs, and pharmacologic acons of the invesgaonal new drug in humans, and if possible, to gain early evidence on eﬀecveness. Phase 2. The drug is administered to a limited paent populaon to evaluate dosage tolerance and opmal dosage, idenfy possible adverse side eﬀects and safety risks, and preliminarily evaluate eﬃcacy. Phase 3. The drug is administered to an expanded paent populaon, generally at geographically dispersed clinical study sites to generate enough data to stascally evaluate dosage, clinical eﬀecveness, and safety, to establish the overall beneﬁt-risk relaonship of the invesgaonal new drug product, and to provide an adequate basis for product approval. Phase 4. In some cases, addional studies and paent follow-up are conducted to gain experience from the treatment of paents in the intended therapeuc indicaon. Regulatory authories may condion approval of a markeng applicaon for a product candidate on the sponsor’s agreement to conduct addional clinical studies aer approval. In other cases, a sponsor may voluntarily conduct addional clinical studies aer approval to gain more informaon about the drug. Such post-approval studies are typically referred to as Phase 4 clinical studies. A pivotal study is a clinical study that adequately meets regulatory authority requirements for the evaluaon of a drug candidate’s eﬃcacy and safety such that it can be used to jusfy the approval of the product. Generally, pivotal studies are Phase 3 studies, but regulatory authories may accept results from Phase 2 studies if the study design provides a well-controlled and reliable assessment of clinical beneﬁt, parcularly in situaons where there is an unmet medical need and the results are suﬃciently robust. U.S. Government Regulaon In the U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmec Act, or FDCA, and its implemenng regulaons, and biologics under the FDCA and the Public Health Service Act, or PHSA, and its implemenng regulaons. FDA approval is required before any new drug or dosage form, including a new use of a previously approved drug, can be marketed in the U.S. Drugs and biologics are also subject to other federal, state, and local statutes and regulaons. The process required by the FDA before product candidates may be marketed or sold in the U.S. generally involves the following: • • • • • • • compleon of extensive preclinical laboratory tests and preclinical animal studies performed in accordance with the Good Laboratory Pracces, or GLP, regulaons and the U.S. Department of Agriculture’s Animal Welfare Act; submission to the FDA of an IND, which must become eﬀecve before human clinical studies may begin and must be updated annually; conducng adequate and well-controlled human clinical studies that generally follow the three- to four-phase design described above to establish the safety and eﬃcacy, or for BLA products, the safety, purity, and potency, of the product candidate for each proposed indicaon under an acve IND and approved by an independent IRB represenng each clinical site; preparaon of and submission to the FDA of a new drug applicaon, or NDA, or biologics license applicaon, or BLA, aer compleon of all pivotal clinical studies; potenal review of the product applicaon by an FDA advisory commiee, where appropriate and if applicable; sasfactory compleon of an FDA pre-approval inspecon of the manufacturing facilies where the proposed drug substance and drug product are produced to assess compliance with Good Manufacturing Pracces, or GMP; FDA inspecon of one or more clinical sites to assure compliance with GCP; and 19 • FDA review and approval of an NDA or BLA. Submission of an NDA or BLA to the FDA Assuming successful compleon of all required tesng in accordance with all applicable regulatory requirements, detailed invesgaonal new drug product informaon is submied to the FDA in the form of an NDA or BLA requesng approval to market the product for one or more indicaons. Under federal law, the submission of most NDAs and BLAs is subject to a signiﬁcant applicaon user fee, unless waived. Pursuant to Title 21 of the Code of Federal Regulaons, the FDA conducts a preliminary review of an NDA within 60 days of receipt. FDA procedures provide that the FDA will inform the sponsor by the 74th day aer the FDA’s receipt of submission to determine whether the applicaon is suﬃciently complete to permit substanve review. The FDA may request addional informaon rather than accept an NDA for ﬁling, in which case the applicaon must be resubmied with the requested addional informaon. The resubmied applicaon is also subject to review before it is accepted for ﬁling. Once the submission is accepted for ﬁling, the FDA begins an in-depth substanve review. Once an NDA or BLA has been accepted, the FDA’s goal is to review the applicaon within ten months aer it accepts the applicaon for ﬁling, or, if the applicaon relates to an unmet medical need in the treatment of a serious or life-threatening condion, six months aer the FDA accepts the applicaon for ﬁling. The review process can be signiﬁcantly extended by FDA requests for addional informaon or clariﬁcaon. The FDA’s Decision on an NDA or BLA The FDA may issue an approval leer if it ﬁnds the applicaon has adequate support for commercial markeng. An approval leer authorizes commercial markeng of the drug with speciﬁc prescribing informaon for speciﬁc indicaons. As a condion of NDA or BLA approval, the FDA may impose addional requirements, such as post-markeng studies and/or a Risk Evaluaon and Migaon Strategy, or REMS, to help ensure that the beneﬁts of the drug outweigh the potenal risks. A REMS can include medicaon guides, assessment plans, communicaon plans for healthcare professionals, and elements to assure safe use. The FDA may also issue a Complete Response Leer, which indicates that the review cycle of the applicaon is complete but the applicaon is not ready for approval. A Complete Response Leer may require addional clinical data and/or an addional pivotal Phase 3 clinical study(ies), and/or other signiﬁcant, expensive and me-consuming requirements related to clinical studies, preclinical studies or manufacturing. If the condions set forth in the Complete Response Leer are met, the FDA may approve the product for markeng. Expedited Review and Accelerated Approval Programs A sponsor may seek approval of its product candidate under programs designed to accelerate the FDA’s review and approval of NDAs and BLAs. For example, Fast Track Designaon may be granted to a drug intended for treatment of a serious or life-threatening disease or condion and data demonstrate its potenal to address unmet medical needs for the disease or condion. The key beneﬁts of fast-track designaon are the eligibility for priority review, rolling review (submission of porons of an applicaon before the complete markeng applicaon is submied), and accelerated approval, if relevant criteria are met. The FDA may grant the NDA or BLA a priority review designaon, which sets the target date for FDA acon on the applicaon at six months aer the FDA accepts the applicaon for ﬁling. Priority review is granted where there is evidence that the proposed product would be a signiﬁcant improvement in the safety or eﬀecveness of the treatment, diagnosis, or prevenon of a serious condion. Priority review designaon does not change the scienﬁc/medical standard for approval or the quality of evidence necessary to support approval. The FDA may approve an NDA or BLA under the accelerated approval program if the drug treats a serious condion, provides a meaningful advantage over available therapies, and demonstrates an eﬀect on either (1) a surrogate endpoint that is reasonably likely to predict clinical beneﬁt, or (2) on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an eﬀect on irreversible morbidity or mortality or other clinical beneﬁt, taking into account the severity, rarity, or prevalence of the condion and the availability or lack of alternave treatments. Post-markeng studies or compleon of ongoing studies aer markeng approval are generally required to verify the drug’s clinical beneﬁt in relaonship to the surrogate endpoint or ulmate outcome in relaonship to the clinical beneﬁt. The FDA may require, as appropriate, that such studies be underway prior to approval or within a speciﬁc me period aer the date of approval for a product that has been granted accelerated approval. The FDA also has authority for expedited procedures to withdraw approval of a product or indicaon that was inially approved under accelerated approval if the sponsor fails to conduct the required post-markeng studies or if such studies fail to verify the predicted clinical beneﬁt. In addion, as a condion for accelerated approval, the FDA currently also requires pre-approval of promoonal materials, which could adversely impact the ming of the commercial launch of the product. 20 In addion, the Food and Drug Administraon Safety and Innovaon Act, or FDASIA, established the Breakthrough Therapy designaon. A sponsor may seek FDA designaon of its product candidate as a breakthrough therapy if the drug is intended, alone or in combinaon with one or more other drugs, to treat a serious or life-threatening disease or condion and preliminary clinical evidence indicates that the drug may demonstrate substanal improvement over exisng therapies on one or more clinically signiﬁcant endpoints, such as substanal treatment eﬀects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will provide more intensive guidance on the drug development program and expedite its review. Furthermore, the FDA has made available expedited programs to sponsors of regenerave medicine therapies that have been granted designaon as a regenerave medicine advanced therapy, or RMAT. Regenerave medicine therapies include cell therapies, therapeuc ssue engineering products and human cell and ssue products. A sponsor may seek RMAT designaon if its regenerave medicine product is intended to treat, modify, reverse, or cure a serious or life-threatening condion and preliminary clinical evidence indicates that the regenerave medicine therapy has the potenal to address unmet medical needs for such condion. Advantages of the RMAT designaon include early interacons with the FDA to discuss the development plan for the product candidate, including potenal surrogate or intermediate endpoints, and eligibility for rolling and priority review. Products granted RMAT designaon may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical beneﬁt, or reliance upon data obtained from a meaningful number of sites, including through expansion to addional sites. RMAT-designated products that receive accelerated approval may, as appropriate, fulﬁll their post-approval requirements through the submission of clinical evidence, clinical studies, paent registries, or other sources of real-world evidence (such as electronic health records); through the collecon of larger conﬁrmatory data sets; or via post- approval monitoring of all paents treated with such therapy prior to approval of the therapy. Orphan Designaon and Exclusivity Under the Orphan Drug Act, the FDA may grant orphan drug designaon to drugs intended to treat a rare disease or condion that aﬀects fewer than 200,000 individuals in the U.S., or if it aﬀects more than 200,000 individuals in the U.S. and there is no reasonable expectaon that the cost of developing and making the drug for this type of disease or condion will be recovered from sales in the U.S. Orphan drug designaon must be requested before subming an NDA or BLA. Aer the FDA grants orphan drug designaon, the identy of the therapeuc agent and its potenal orphan use are publicly disclosed by the FDA. Orphan drug designaon entles a party to ﬁnancial incenves such as opportunies for grant funding towards clinical study costs, tax advantages, and user-fee waivers. Orphan drug designaon does not convey any advantage in, or shorten the duraon of, the regulatory review and approval process. In addion, the ﬁrst NDA or BLA applicant to receive orphan drug designaon for a parcular drug is entled to orphan drug exclusivity, which means the FDA may not approve any other applicaon to market the same drug for the same indicaon for a period of seven years in the U.S., except in limited circumstances. Orphan drug exclusivity does not prevent the FDA from approving a diﬀerent drug for the same disease or condion, or the same drug for a diﬀerent disease or condion. There is some uncertainty with respect to the FDA’s interpretaon of the scope of orphan drug exclusivity. Historically, exclusivity was speciﬁc to the orphan indicaon for which the drug was approved. As a result, the scope of exclusivity was interpreted as prevenng approval of a compeng product. However, in 2021, the federal court in Catalyst Pharmaceucals, Inc. v. Becerra, suggested that orphan drug exclusivity covers the full scope of the orphan- designated “disease or condion” regardless of whether a drug obtained approval for a narrower use. Pediatric Studies and Exclusivity NDAs and BLAs must contain data to assess the safety and eﬀecveness of an invesgaonal new drug product for the claimed indicaons in all relevant pediatric populaons in order to support dosing and administraon for each pediatric subpopulaon for which the drug is safe and eﬀecve. The FDA may, on its own iniave or at the request of the applicant, grant deferrals for submission of some or all pediatric data unl aer approval of the product for use in adults or full or paral waivers if certain criteria are met. Pediatric development plans can be discussed with the FDA at any me, but usually occur any me between the end-of-Phase 2 meeng and submission of the NDA or BLA. Unless otherwise required by regulaon, the requirements for pediatric data do not apply to any drug for an indicaon for which orphan designaon has been granted. Pediatric exclusivity is another type of non-patent exclusivity in the U.S. that may be granted if certain FDA requirements are met, such as FDA’s determinaon that informaon relang to the use of a new drug in the pediatric populaon may produce health beneﬁts, and the applicant agrees to perform and report on FDA-requested studies within a certain me frame. Pediatric exclusivity adds a period of six months of exclusivity to the end of all exisng markeng exclusivity and patents held by the sponsor for that acve moiety. This is not a patent term extension, but it eﬀecvely extends the regulatory period during which the FDA cannot accept or approve another applicaon relying on the NDA or BLA sponsor’s data. 21 Biosimilars and Exclusivity The Paent Protecon and Aﬀordable Care Act of 2010, or Aﬀordable Care Act, includes a subtle called the Biologics Price Compeon and Innovaon Act of 2009, or BPCI Act, which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-licensed reference biological product. A reference biologic is granted twelve years of exclusivity from the me of ﬁrst licensure of the reference product. The ﬁrst biologic product submied under the abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against other biologics submied under the abbreviated approval pathway for the lesser of (i) one year aer the ﬁrst commercial markeng, (ii) eighteen months aer approval if there is no legal challenge, (iii) eighteen months aer the resoluon in the applicant’s favor of a lawsuit challenging the biologics’ patents if an applicaon has been submied, or (iv) 42 months aer the applicaon has been approved if a lawsuit is ongoing within the 42-month period. The Inﬂaon Reducon Act of 2022, or the IRA, is intended to foster generic and biosimilar compeon and to lower drug and biologic costs. The IRA provides the Centers for Medicare & Medicaid Services, or CMS, with signiﬁcant new authories. CMS is able to directly negoate prescripon drug prices and to cap out-of-pocket costs. Each year, CMS will select and negoate a preset number of high-spend drugs and biologics covered under Medicare Parts B and D that lack generic or biosimilar compeon. Price negoaons began in 2023. Eﬀecve from 2023, the IRA provides a new “inﬂaon rebate” that covers Medicare paents and is intended to counter certain price increases in prescripon drugs. The inﬂaon rebate requires drug manufacturers to pay a rebate to the federal government if the price for a drug or biologic under Medicare Parts B or D increases faster than the rate of inﬂaon. To support biosimilar compeon, qualifying biosimilars may receive a Medicare Part B payment increase for a period of ﬁve years, beginning in October 2022. Separately, if a biologic drug for which no biosimilar exists delays a biosimilar’s market entry beyond two years, CMS will be authorized to subject the biologics manufacturer to price negoaons intended to ensure fair compeon. Notwithstanding these provisions, the IRA’s impact on compeon and commercializaon remains largely uncertain. Abbreviated New Drug Applicaons for Generic Drugs and New Chemical Enty Exclusivity The Drug Price Compeon and Patent Term Restoraon Act of 1984, or the Hatch-Waxman Amendments, authorized the FDA to approve generic drugs that are bioequivalent (i.e. idencal) to previously approved branded drugs. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug applicaon, or ANDA, to the FDA. In support of such applicaons, a generic manufacturer may rely on the preclinical and clinical tesng conducted for a drug product previously approved under an NDA, known as the reference listed drug, or RLD. Speciﬁcally, in order for an ANDA to be approved, the FDA must ﬁnd that the generic version is bioequivalent to the RLD with respect to the acve ingredients, the route of administraon, the dosage form, quality and performance characteriscs, the strength of the drug, and intended use. The FDCA provides a period of ﬁve years of non-patent exclusivity for a new drug containing a new chemical enty. In cases where such exclusivity has been granted, an ANDA may not be ﬁled with the FDA unl the expiraon of ﬁve years unless the submission is accompanied by a Paragraph IV cerﬁcaon, in which case the applicant may submit its applicaon four years following the original product approval. The FDCA also provides for a period of three years of exclusivity if an NDA or supplement includes reports of one or more new clinical invesgaons, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essenal to the approval of the applicaon. This three-year exclusivity period oen protects changes to a previously approved drug product, such as a new dosage form, route of administraon, combinaon or indicaon. When an ANDA applicant ﬁles its applicaon with the FDA, it must cerfy, among other things, that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable, which is called a Paragraph IV cerﬁcaon. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA applicaon will not be approved unl all the listed patents claiming the referenced product have expired. If the ANDA applicant has provided a Paragraph IV cerﬁcaon to the FDA, the applicant must also send noce of the Paragraph IV cerﬁcaon to the NDA and patent holders once the ANDA has been accepted for ﬁling by the FDA. The NDA and patent holders may then iniate a patent infringement lawsuit in response to the noce of the Paragraph IV cerﬁcaon. The ﬁling of a patent infringement lawsuit within 45 days aer the receipt of a Paragraph IV cerﬁcaon automacally prevents the FDA from approving the ANDA unl the earlier of 30 months aer the receipt of the Paragraph IV noce, expiraon of the patent, or a decision in the infringement case that is favorable to the ANDA applicant. Secon 505(b)(2) New Drug Applicaons As an alternave path to FDA approval for modiﬁcaons to formulaons or uses of products previously approved by the FDA pursuant to an NDA, an applicant may submit an NDA under Secon 505(b)(2) of the FDCA. Secon 505(b)(2) was enacted as part of the Hatch-Waxman Amendments and permits the ﬁling of an NDA where at least some of the informaon required for approval 22 comes from studies not conducted by, or for, the applicant, and for which the applicant has not obtained a right of reference. If the Secon 505(b)(2) applicant can establish that reliance on the FDA’s previous ﬁndings of safety and eﬀecveness is scienﬁcally and legally appropriate, it may eliminate the need to conduct certain preclinical studies or clinical trials of the new product. The FDA may also require companies to perform addional bridging studies or measurements, including clinical trials, to support the change from the previously approved reference drug. The FDA may then approve the new drug candidate for all, or some, of the label indicaons for which the reference drug has been approved, as well as for any new indicaon sought by the Secon 505(b)(2) applicant. To the extent that a Secon 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to cerfy to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. As a result, approval of a Secon 505(b)(2) NDA can be stalled unl all the listed patents claiming the referenced product have expired, unl any non-patent exclusivity (such as exclusivity for obtaining approval of a new chemical enty) listed in the Orange Book for the referenced product has expired and, in the case of a Paragraph IV cerﬁcaon and subsequent patent infringement suit, unl the earlier of 30 months, selement of the lawsuit, or a decision in the infringement case that is favorable to the Secon 505(b)(2) applicant. Patent Term Restoraon Some of our U.S. patents may be eligible for limited patent term extension under the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoraon term of up to ﬁve years as compensaon for patent term lost during product development and the FDA regulatory review process. However, patent term restoraon cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent term restoraon period is generally one-half the me between the eﬀecve date of an IND and the submission date of an NDA or BLA, plus the me between the submission date and the approval of that applicaon. Only one patent applicable to an approved product is eligible for the extension and the applicaon for the extension must be submied prior to the expiraon of the patent. The USPTO, in consultaon with the FDA, reviews and approves the applicaon for any patent term extension or restoraon. Thus, for each approved product, we may apply for restoraon of patent term for one of our related owned or licensed patents to add patent life beyond the original expiraon date, depending on the expected length of the clinical studies and other factors involved in the ﬁling of the relevant NDA or BLA. EU Regulaon In the EU and in Iceland, Norway and Liechtenstein, together the European Economic Area or EEA, aer compleon of all required clinical tesng, pharmaceucal products may only be placed on the market aer obtaining a Markeng Authorizaon, or MA. To obtain a MA, we must submit a markeng authorizaon applicaon, or MAA. The content of the MAA is similar to that of an NDA or BLA ﬁled in the U.S., with the excepon of, among other things, country-speciﬁc document requirements. Authorizaon Procedures Medicines can be authorized by using, among other things, a centralized or decentralized procedure. The centralized authorizaon procedure results in a single markeng authorizaon issued by the European Commission, or EC, following the scienﬁc assessment of the applicaon by the European Medicines Agency, or EMA, that is valid across the EEA. The centralized procedure is compulsory for speciﬁc medicinal products, including medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products, or ATMPs, and medicinal products with a new acve substance indicated for the treatment of certain diseases (for instance, AIDS, cancer, neurodegenerave disorders, diabetes, auto-immune and viral diseases). Medicines that fall outside the mandatory scope of the centralized procedure have three routes to authorizaon: (i) they can be authorized under the centralized procedure if they concern a signiﬁcant therapeuc, scienﬁc or technical innovaon, or if their authorizaon would be in the interest of public health; (ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorizaon in more than one EU country; or (iii) they can be authorized in a EU member state in accordance with that state’s naonal procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, naonal markeng authorizaon (mutual recognion procedure). All new MAAs must include a Risk Management Plan, or RMP, describing the risk management system that the Company will put in place and documenng measures to prevent or minimize the risks associated with the product. RMPs are connually modiﬁed and updated throughout the lifeme of the medicine as new informaon becomes available. We need to submit an updated RMP: (i) at the request of EMA or a naonal competent authority, or (ii) whenever the risk-management system is modiﬁed, especially as the result of new informaon being received that may lead to a signiﬁcant change to the beneﬁt-risk proﬁle or as a result of an important pharmacovigilance or risk-minimizaon milestone being reached. The regulatory authories may also impose speciﬁc obligaons as a condion of the MA. RMPs and Periodic Safety Update Reports, or PSURs, are rounely available to third pares requesng access, subject to limited redacons. 23 Special rules apply in part for ATMPs. ATMPs comprise gene therapy products, somac cell therapy products and ssue engineered products, which are genes, cells or ssues that have undergone substanal manipulaon and that are administered to human beings in order to cure, diagnose or prevent diseases or regenerate, repair or replace a human ssue. Pursuant to the ATMP Regulaon, the Commiee on Advanced Therapies, or CAT, is responsible in conjuncon with the CHMP for the evaluaon of ATMPs. The CHMP and CAT are also responsible for providing guidelines on ATMPs. These guidelines provide addional guidance on the factors that the EMA will consider in relaon to the development and evaluaon of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs. The manufacturing and control informaon that should be submied in a MAA; and post-approval measures required to monitor paents and evaluate the long- term eﬃcacy and potenal adverse reacons of ATMPs. Although such guidelines are not legally binding, compliance with them is oen necessary to gain and maintain approval for product candidates. In addion to the mandatory RMP, the holder of a MA for an ATMP must put in place and maintain a system to ensure that each individual product and its starng and raw materials, including all substances coming into contact with the cells or ssues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the relevant healthcare instuon where the product is used. A Pediatric Invesgaon Plan, or PIP, and/or a request for waiver (for example, because the relevant disease or condion occurs only in adults) or deferral (for example, unl enough informaon to demonstrate its eﬀecveness and safety in adults is available), is required for submission prior to subming an MAA. A PIP describes, among other things, proposed pediatric studies and their ming relave to clinical studies in adults and an MAA must comply with the PIP to be validated. MAA Review and Approval Timeframe and Accelerated Assessment Under the centralized procedure in the EU, the Commiee for Medicinal Products for Human Use, or CHMP, established at the EMA, is responsible for conducng the inial assessment of a drug. In principle, the maximum meframe for the evaluaon of an MAA by the CHMP is 210 days from receipt of a valid MAA. However, this meline excludes clock stops, when addional wrien or oral informaon is to be provided by the applicant in response to quesons asked by the CHMP, so the overall process typically takes a year or more. A favorable opinion on the applicaon by the CHMP will typically result in the granng of the markeng authorizaon within 67 days of receipt of the opinion. Accelerated evaluaon might be granted by the CHMP in exceponal cases, when a medicinal product is expected to be of a major public health interest, parcularly from the point of view of therapeuc innovaon. In this circumstance, and upon request by the applicant, the CHMP’s evaluaon me frame is reduced to 150 days, excluding me taken by an applicant to respond to quesons. MA Validity Period MAs have an inial duraon of ﬁve years. Aer ﬁve years, the authorizaon may subsequently be renewed on the basis of a reevaluaon of the risk- beneﬁt balance. Once renewed, the MA is valid for an unlimited period unless the EC or the naonal competent authority decides, on jusﬁed grounds relang to pharmacovigilance, to proceed with only one addional ﬁve-year renewal. Applicaons for renewal must be made to the EMA at least nine months before the ﬁve-year period expires. Conduct of Clinical Trials Clinical trials are studies intended to discover or verify the eﬀects of one or more invesgaonal medicines. The regulaon of clinical trials aims to promote the protecon of the rights, safety and well-being of trial parcipants and the credibility of the results of clinical trials. Regardless of where they are conducted, all clinical trials included in applicaons for markeng authorizaon for human medicines in the EU or EEA must have been carried out in accordance with EU regulaons (such as, among others, the Clinical Trials Regulaon (Regulaon (EU) No 536/2014) and the Clinical Trials Direcve (EC) No 2001/20/EC). This means that clinical trials conducted in the EU or EEA have to comply with EU clinical trial legislaon and that clinical trials conducted outside the EU or EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to internaonal good clinical pracce and the Declaraon of Helsinki. 24 Exceponal Circumstances/Condional Approval Orphan drugs or drugs with unmet medical needs may be eligible for EU approval under exceponal circumstances or with condional approval. Approval under exceponal circumstances is applicable to orphan products and is used when an applicant is unable to provide comprehensive data on the eﬃcacy and safety under normal condions of use because the indicaon for which the product is intended is encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, when the present state of scienﬁc knowledge does not allow comprehensive informaon to be provided, or when it is medically unethical to collect such informaon. A condional MA is applicable to orphan medicinal products, medicinal products for seriously debilitang or life-threatening diseases, or medicinal products to be used in emergency situaons in response to recognized public threats. Condional MAs can be granted for medicinal products where, although comprehensive clinical data referring to the safety and eﬃcacy of the medicinal product have not been supplied, a number of criteria are fulﬁlled: (i) the beneﬁt/risk balance of the product is posive, (ii) it is likely that the applicant will be in a posion to provide the comprehensive clinical data, (iii) unmet medical needs will be fulﬁlled by the grant of the MA and (iv) the beneﬁt to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that addional data are sll required. Condional MAs are valid for only one year and must be reviewed annually subject to certain speciﬁc obligaons. PRIME Program PRIME is a program launched by the EMA to enhance support for the development of medicines that target an unmet medical need. The program focuses on medicines that may oﬀer a major therapeuc advantage over exisng treatments, or beneﬁt paents without treatment opons. These medicines are considered priority medicines by EMA. To be accepted for PRIME, a medicine has to show its potenal to beneﬁt paents with unmet medical needs based on early clinical data. Through PRIME, the EMA oﬀers early and proacve support to medicine developers to opmize development plans and the generaon of robust data on a medicine’s beneﬁts and risks and enables accelerated assessment of medicines applicaons. PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designaon or eligibility will result in expedited review or approval. Orphan Designaon and Exclusivity As in the U.S., we may apply for designaon of a product as an orphan drug for the treatment of a speciﬁc indicaon in the EU before the applicaon for markeng authorizaon is made. The EMA’s Commiee for Orphan Medicinal Products, or COMP, grants orphan drug designaon to promote the development of products that are intended for the diagnosis, prevenon, or treatment of life-threatening or chronically debilitang condions aﬀecng not more than 5 in 10,000 persons in the EU Community and for which no sasfactory method of diagnosis, prevenon, or treatment has been authorized (or the product would be a signiﬁcant beneﬁt to those aﬀected). Addionally, designaon is granted for products intended for the diagnosis, prevenon, or treatment of a life-threatening, seriously debilitang, or serious and chronic condion when, without incenves, it is unlikely that sales of the drug in the EU would be suﬃcient to jusfy the necessary investment in developing the medicinal product. Orphan drug designaon entles a party to ﬁnancial incenves such as reducon of fees or fee waivers and 10 years of market exclusivity is granted following medicinal product approval. This period may be reduced to six years if the orphan drug designaon criteria are no longer met, including where it is shown that the product is suﬃciently proﬁtable not to jusfy maintenance of market exclusivity. The applicant will receive a fee reducon for the MAA if the orphan drug designaon has been granted, but not if the designaon is sll pending at the me the markeng authorizaon is submied, and sponsors must submit an annual report to EMA summarizing the status of development of the medicine. Orphan drug designaon does not convey any advantage in, or shorten the duraon of, the regulatory review and approval process. New Chemical Enty Exclusivity In the EU, new chemical enes, or NCEs, somemes referred to as new acve substances, qualify for eight years of data exclusivity upon the product’s ﬁrst MA in the EU and an addional two years of market exclusivity. This data exclusivity, if granted, prevents regulatory authories in the EU from referencing the innovator’s data to assess a generic (abbreviated) applicaon for eight years, aer which generic markeng authorizaon can be submied, and the innovator’s data may be referenced, but not approved for two years. The overall ten-year period will be extended to a maximum of eleven years if, during the ﬁrst eight of those ten years, the markeng authorizaon holder obtains an authorizaon for one or more new therapeuc indicaons which, during the scienﬁc evaluaon prior to their authorizaon, are held to bring a signiﬁcant clinical beneﬁt in comparison with exisng therapies. Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the EU’s regulatory authories to include an NCE. Even if a compound is considered to be a NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company could market a version of the medicinal product if such company can complete a full MAA with its own complete database of pharmaceucal tests, preclinical studies and clinical trials and obtain MA of its product. 25 Post-Approval Requirements Drugs manufactured or distributed pursuant to regulatory approvals are subject to pervasive and connuing regulaon by the regulatory authories, including, among other things, requirements relang to formal commitments for post approval clinical trials and studies, manufacturing, recordkeeping, periodic reporng, product sampling and distribuon, markeng, labeling, adversing and promoon and reporng of adverse experiences with the product. Aer approval, most changes to the approved product, such as adding new indicaons or other labeling claims are subject to prior regulatory authority review and approval. Drug manufacturers are subject to periodic unannounced inspecons by regulatory authories and country or state agencies for compliance with GMP and other requirements. Changes to the manufacturing process are strictly regulated, and, depending on the signiﬁcance of the change, may require prior regulatory approval before being implemented. Regulaons also require invesgaon and correcon of any deviaons from GMP and impose reporng and documentaon requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must connue to expend me, money, and eﬀort in the area of producon and quality control to maintain compliance with GMP and other aspects of regulatory compliance. Pharmaceucal Coverage, Pricing and Reimbursement In the U.S. and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend in part on the availability of coverage and reimbursement from third-party payors. Third-party payors include government authories, managed care providers, private health insurers and other organizaons. The process for determining whether a payor will provide coverage for a drug product may be separate from the process for seng the reimbursement rate that the payor will pay for the drug product. Third-party payors may limit coverage to speciﬁc drug products on an approved list, or formulary, which might not include all of the approved drugs for a parcular indicaon. Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Adequate third-party reimbursement may not be available to enable us to maintain price levels suﬃcient to realize an appropriate return on our investment in product development. In the EU, governments inﬂuence the price of pharmaceucal products through their pricing and reimbursement rules and control of naonal health care systems that fund a large part of the cost of those products to paents. Some jurisdicons operate posive and negave list systems under which products may only be marketed once a reimbursement price has been agreed to by the government. Other member states allow companies to ﬁx their own prices for medicines, but monitor and control company proﬁts, including volume-based arrangements, caps and reference pricing mechanisms. In addion, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country. Other Healthcare, Privacy, and Cybersecurity Laws and Compliance Requirements We are subject to various laws targeng, among other things, fraud and abuse in the healthcare industry, and privacy and protecon of personal informaon, including health informaon. These laws may impact, among other things, our proposed sales, markeng, and educaon programs. The laws that may aﬀect our ability to operate include: • • • • the federal An-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully solicing or receiving renumeraon in return for, and from knowingly and willfully oﬀering or paying remuneraon to induce, referrals of federal healthcare program paents and the purchase or recommendaon of an item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs; federal civil and criminal false claims laws and civil monetary penalty laws, which prohibit, among other things, individuals or enes from knowingly presenng, or causing to be presented to Medicare, Medicaid, or other third-party payers, claims for payment that are false or fraudulent; federal civil and criminal false claims laws and civil monetary penalty laws, which prohibit, among other things, individuals or enes from knowingly presenng, or causing to be presented to Medicare, Medicaid, or other third-party payers, claims for payment that are false or fraudulent; the EU General Data Protecon Regulaon, or GDPR, and the U.K. General Data Protecon Regulaon, or UK GDPR, which apply to processing of personal data in the context of the acvies of an enty established in the EEA/UK, and to processing by an enty not established in the EEA/UK where such processing is related to the oﬀering of goods or services to individuals who are in the EEA/UK, or the monitoring of the behavior of individuals who are in the EEA/UK, and imposes requirements and limitaons relang to the processing, storage, purpose of collecon, accuracy, security, sharing and transfer of personal data outside the EEA/UK, in parcular with respect to special categories of personal data like health data, and the noﬁcaon of supervisory authories about data breaches, accompanied by a strong sanconing mechanism—in addion, EU member states may also impose addional requirements in relaon to health, genec and biometric data through their naonal implemenng legislaon; 26 • • • the 21st Century Cures Act, or the Cures Act, which introduced a wide range of reforms, such as broadening the types of data required to support drug approval, extending protecons for generic compeon, accelerang approval of breakthrough therapies, expanding the orphan drug product program, requiring disclosures about compassionate care programs, and clarifying how manufacturers communicate about their products; the federal transparency laws, including the federal Physician Payment Sunshine Act, that requires drug manufacturers to disclose payments and other transfers of value provided to various healthcare professionals and teaching hospitals; and state and foreign law equivalents, or similar, of each of the above federal laws, such as transparency laws, an-kickback and false claims laws which may apply to items or services reimbursed by any third-party payer, including commercial insurers, and privacy and security of health informaon laws, including comprehensive privacy and security laws in California. Addional Regulaon The U.S. Foreign Corrupt Pracces Act or FCPA, to which we are subject, prohibits corporaons and individuals from engaging in certain acvies to obtain or retain business or to inﬂuence a person working in an oﬃcial capacity. It is illegal to pay, oﬀer to pay or authorize the payment of anything of value to any foreign government oﬃcial, government staﬀ member, polical party, or polical candidate in an aempt to obtain or retain business or to otherwise inﬂuence a person working in an oﬃcial capacity. Similar laws exist in other countries, such as the United Kingdom or in EU member states, that restrict improper payments to public and private pares. Many countries have laws prohibing these types of payments within the respecve country. In addion to these an-corrupon laws, we are subject to import and export control laws, tariﬀs, trade barriers, economic sancons, and regulatory limitaons on our ability to operate in certain foreign markets. In addion, federal, state, and foreign government bodies and agencies have adopted, are considering adopng, or may adopt laws and regulaons regarding the collecon, use, storage and disclosure of personally idenﬁable informaon or other informaon treated as conﬁdenal obtained from consumers and individuals. We are also subject to regulaon under the Occupaonal Safety and Health Act, the Environmental Protecon Act, the Toxic Substances Control Act, the Resource Conservaon and Recovery Act and other present and potenal federal, state, or local regulaons. These and other laws govern our use, handling and disposal of various biological and chemical substances used in, and waste generated by, our operaons. Complying with these requirements may have a signiﬁcant impact on our capital expenditures and results of operaons. Customers Our customers include collaboraon partners, drug wholesalers, and retail pharmacy distributors. For the year ended December 31, 2023, more than half of our total revenues were earned from our collaboraon partner KKC. Human Capital General Informaon As of December 31, 2023, we had 1,276 total employees, of which 876 are in research and development and 400 are in sales, general, and administrave. Further, 1,089 employees are based in the U.S., including at our facilies in Novato, California, Brisbane, California, Cambridge, Massachuses, and Woburn, Massachuses, and 187 employees are based at our internaonal locaons. The majority of new employees hired during the year ended December 31, 2023 were to support and extend our clinical and preclinical pipeline, our in-house manufacturing capacies for our GTMF, as well as our commercializaon acvies, with hires in commercial, clinical development and operaons, research, manufacturing, and general and administrave funcons. We believe our relaonship with our employees to be generally good. We have not experienced any material employment-related issues or interrupons of services due to labor disagreements and are not a party to any collecve bargaining agreements. We expect to connue to strategically add employees in 2024 with a focus on expanding our in-house manufacturing capacity in connecon with maintaining and operang our gene therapy manufacturing facility, increasing experse and bandwidth in clinical and preclinical research and development and commercializaon acvies and expanding our geographic reach in connecon with the global launches of our approved products. We connually evaluate our business need and opportunity and balances in-house experse and capacity with outsourced experse and capacity. Currently, we outsource substanal clinical trial work to clinical research organizaons and certain drug manufacturing to contract manufacturers. 27 Workforce Safety and Employee Wellbeing We maintain a safety culture grounded on the premise of eliminang workplace incidents, risks and hazards. Our health and safety management system includes several elements, such as incorporaon of Global Environmental, Health, Safety and Sustainability (EHSS) standards, site-speciﬁc standard operang procedures, incident and safety observaon reporng, hazard idenﬁcaon and risk assessments, job safety analyses, ergonomic assessments and industrial hygiene evaluaons. We have adopted a ﬂexible, hybrid working arrangement for our employees, which allows some of our employees to work remotely during certain days of the week. We provide our employees with wellness oﬀerings to support their physical and mental health including our “Caring For U” program, a global reimbursement program oﬀering employees up to $1,200 annually (in local currency) for wellness and caregiving acvies. Employee Retenon and Engagement The biotechnology industry is an extremely compeve labor market and we believe our company’s success depends on our ability to aract, develop, and retain key personnel. We invest in the growth and development of our employees through various training and development programs that build and strengthen employees’ leadership and professional skills, including leadership development programs for new leaders, six sigma cerﬁcaon, as well as a mentoring program. We also have a talent management framework and processes in place that includes regularly conducted acvies such as performance management, succession, and workforce planning in order to support our employees in their growth and development and to provide learning opportunies. We oﬀer on-demand career coaching services through an external network of professional execuve coaches. We encourage all employees to have an individual development plan to idenfy focus areas for learning and growth. To regularly assess and improve our employee retenon and engagement, we conduct an engagement survey approximately every 18 months, with "pulse" surveys in between, the results of which are discussed with our board of directors, at all hands employee meengs and in individual funcons. We take acons to address areas of employment concern and follow-up rounely to share with employees what we are doing. Diversity, Equity, Inclusion and Belonging We are commied to fostering a healthy, inclusive environment while nurturing a culture of belonging where all employees have equal opportunies. We strive to create an environment where everyone we work with, serve, and engage with feels valued, respected, and empowered. As of December 31, 2023, of the eight members of our board of directors, three directors were women, three directors self-idenﬁed as racially or ethnically diverse, and one director self-idenﬁed as LGBTQ+. As of December 31, 2023, women represented 56% of our global workforce and 44% of our leadership posions at the Vice President level or above. As of December 31, 2023, 46% of our U.S. workforce that self-reported idenﬁed as racially or ethnically diverse. We have included quesons in our engagement survey to measure employee percepon of our inclusive culture, with the results from such survey on inclusion and diversity included in our corporate goals. Our business units review diversity data related to hiring, promoons, and retenon on an ongoing basis in order to promote inclusivity and equal employment opportunies. We have also established a Diversity, Equity, Inclusion and Belonging, or DEIB Acon Team, comprised of employee representaves throughout our company. In 2023, we hosted oﬀsite DEIB workshops and retreats that brought together members of our DEIB Acon Team and the leaders of our Employee Resource Groups (ERGs). These sessions were designed to support team building, building our leadership skills, crically assessing, and enhancing our mul- year DEIB corporate roadmap, aligning our eﬀorts, and execung the roadmap's acon items. In our eﬀorts to promote diversity and inclusion, we have also established or supported several internal ERGs, including UltraProud, LanX, UltraAPAC, UltraMosaic, and Empower X Women in Biotech. 28 Beneﬁts and Compensaon We are dedicated to fostering a workplace environment that keeps our employees inspired, including providing a comprehensive beneﬁts program that supports the health care, family, and ﬁnancial needs of our employees. All of our full-me employees are eligible for cash bonuses and equity awards in addion to other beneﬁts including comprehensive health insurance, life and disability insurance, 401(k) matching, paid me oﬀ for volunteering, wellness programs, and tuion reimbursement. We benchmark and e compensaon to market data as well as to an employee’s experience, funcon and performance. Our compensaon structure includes performance-based elements, with the goal of recognizing and rewarding exceponal performance. We regularly review our compensaon policies and pracces in an eﬀort to idenfy and address any disparies or inequies. General Informaon Our Internet website address is www.ultragenyx.com. No poron of our website, or any other website that may be referenced, is incorporated by reference into this Annual Report. You are advised to read this Annual Report in conjuncon with other reports and documents that we ﬁle from me to me with the Securies and Exchange Commission, or the SEC. In parcular, please read our deﬁnive proxy statements, our Annual Reports on Form 10-K, our Quarterly Reports on Form 10-Q and any Current Reports on Form 8-K that we may ﬁle from me to me. The SEC maintains informaon for electronic ﬁlers (including Ultragenyx) at its website at www.sec.gov. We make our annual reports on Form 10-K, our quarterly reports on Form 10-Q, and our current reports on Form 8-K, and amendments to those reports, available on our internet website, free of charge, as soon as reasonably praccable aer such material is electronically ﬁled with, or furnished to, the SEC. 29 Item 1A. Risk Factors Invesng in our common stock involves a high degree of risk. You should carefully consider the following material risks, together with all the other informaon in this Annual Report, including our ﬁnancial statements and notes thereto, before deciding to invest in our common stock. The risks and uncertaines described below are not the only ones we face. Addional risk and uncertaines not presently known to us or that we presently deem less signiﬁcant may also impair our business operaons. If any of the following risks actually materialize, our operang results, ﬁnancial condion, and liquidity could be materially adversely aﬀected. As a result, the trading price of our common stock could decline and you could lose part or all of your investment. Our company’s business, ﬁnancial condion and operang results can be aﬀected by a number of factors, whether currently known or unknown, including but not limited to those described below, any one or more of which could, directly or indirectly, cause our actual ﬁnancial condion and operang results to vary materially from past, or from ancipated future, ﬁnancial condion and operang results. Any of these factors, in whole or in part, could materially and adversely aﬀect our business, prospects, ﬁnancial condion, operang results and stock price. Because of the following factors, as well as other factors aﬀecng our ﬁnancial condion and operang results, past ﬁnancial performance should not be considered to be a reliable indicator of future performance, and investors should not use historical trends to ancipate results or trends in future periods. Risk Factor Summary • • • • • • • • • • • • • • • • • • • • We have a history of operang losses and ancipate that we will connue to incur losses for the foreseeable future. We have limited experience in generang revenue from product sales. We may need to raise addional capital to fund our acvies. Clinical drug development is a lengthy, complex, and expensive process with uncertain outcomes. We may experience delays in commercializaon of our products and other adverse eﬀects if we do not achieve our projected development goals in the me frames we announce and expect. We may experience diﬃculty in enrolling paents. The regulatory approval processes of the FDA and comparable foreign authories are lengthy and inherently unpredictable. Fast Track Product, Breakthrough Therapy, Priority Review or RMAT designaons by the FDA, and analogous designaons by the EMA, for our product candidates may not lead to faster development or approval. Our product candidates may cause undesirable or serious side eﬀects. We face a multude of manufacturing risks, parcularly with respect to our gene therapy and mRNA product candidates. Our products remain subject to regulatory scruny even if we obtain regulatory approval. Product liability lawsuits against us could cause us to incur substanal liabilies. We may not realize the full commercial potenal of our product candidates if we are unable to source and develop eﬀecve biomarkers. We rely on third pares to conduct our nonclinical and clinical studies and perform other tasks for us. We are dependent on KKC for the clinical and commercial supply of Crysvita for all major markets and for the development and commercializaon of Crysvita in certain major markets. We rely on third pares to manufacture our products and product candidates. The loss of, or failure to supply by, any of any of our single-source suppliers for our drug substance and drug product could adversely aﬀect our business. The acons of distributors and specialty pharmacies could aﬀect our ability to sell or market products proﬁtably. Our revenue may be adversely aﬀected if the market opportunies for our products and product candidates are smaller than expected. Our competors may develop therapies that are similar, more advanced, or more eﬀecve than ours. 30 • • • • • • • • • • • • • • • • • • • • • • • • • • We may not successfully manage expansion of our company, including building an integrated commercial organizaon. Aer the transion of our commercializaon responsibilies for Crysvita in the U.S. and Canada, the success of Crysvita in those territories is dependent on the eﬀecveness of KKC’s commercializaon eﬀorts. Commercial success of our products depends on the degree of market acceptance. We face uncertainty related to insurance coverage and reimbursement status of our newly approved products. If we, or our third-party partners, are unable to maintain eﬀecve proprietary rights for our products or product candidates, we may not be able to compete eﬀecvely. Claims of intellectual property infringement may prevent or delay our development and commercializaon eﬀorts. We may not be successful in obtaining or maintaining necessary rights to our product candidates through acquisions and in-licenses. We may face compeon from biosimilars of our biologics product and product candidates or from generic versions of our small-molecule product and product candidates, which may result in a material decline in sales of aﬀected products. We could lose license rights that are important to our business if we fail to comply with our obligaons in the agreements under which we license intellectual property and other rights from third pares. We may become involved in lawsuits to protect or enforce our patents or the patents of our licensors, or be subject to claims that challenge the inventorship or ownership of our patents. Changes to patent laws in the U.S. and other jurisdicons could diminish the value of patents in general, thereby impairing our ability to protect our products. We may not be able to protect our intellectual property rights throughout the world. We have limited experience as a company operang our own manufacturing facility. Our success depends in part on our ability to retain our President and Chief Execuve Oﬃcer and other qualiﬁed personnel. Our revenue may be impacted if we fail to obtain or maintain orphan drug exclusivity for our products. Our operang results may be adversely impacted if our intangible assets become impaired. We may not be successful in idenfying, licensing, developing, or commercializing addional product candidates. We may fail to comply with laws and regulaons or changes in laws and regulaons could adversely aﬀect our business. We are exposed to risks related to internaonal expansion of our business outside of the U.S. Our business may be adversely aﬀected in the event of computer system failures or security breaches. We or our third-party partners may be adversely aﬀected by earthquakes or other serious natural disasters. We may incur various costs and expenses and risks related to acquision of companies or products or strategic transacons. The market price of our common stock is highly volale. Future sales and issuances of our common stock could dilute the percentage ownership of our current stockholders and result in a decline in stock price. Provisions in our amended and restated cerﬁcate of incorporaon and by-laws, as well as provisions of Delaware law, could make it more diﬃcult for a third party to acquire us or increase the cost of acquiring us or could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, oﬃcers or employees. We face general risks related to our ability to maintain eﬀecve internal controls over ﬁnancial reporng, addional tax liabilies related to our operaons, our ability to use our net operang loss carryforwards, costs of ligaon, stockholder acvism and increased scruny regarding our ESG pracces and disclosures. 31 Risks Related to Our Financial Condion and Capital Requirements We have a history of operang losses and ancipate that we will connue to incur losses for the foreseeable future. We are a biopharmaceucal company with a history of operang losses, and ancipate connuing to incur operang losses for the foreseeable future. Biopharmaceucal product development is a highly speculave undertaking and involves a substanal degree of risk. We have devoted substanally all of our ﬁnancial resources to idenfying, acquiring, and developing our products and product candidates, including conducng clinical studies, developing manufacturing processes, manufacturing product candidates for clinical studies, and providing selling, general and administrave support for these operaons. The amount of our future net losses will depend, in part, on non-recurring events, the success of our commercializaon eﬀorts, and the rate of our future expenditures. We ancipate that our expenses will increase substanally if and as we: • • • • • • • • • • • • • • • • • • connue our research and nonclinical and clinical development of our product candidates; expand the scope of our current clinical studies for our product candidates; advance our programs into more expensive clinical studies; iniate addional nonclinical, clinical, or other studies for our product candidates; pursue preclinical and clinical development for addional indicaons for exisng products and product candidates; change or add addional manufacturers or suppliers; expand upon our manufacturing-related facilies and capabilies, parcularly as we connue to ramp-up operaons at our GMP gene therapy manufacturing facility; seek regulatory and markeng approvals for our product candidates that successfully complete clinical studies; connue to establish Medical Aﬀairs ﬁeld teams to iniate relevant disease educaon; connue to establish a markeng and distribuon infrastructure and ﬁeld force to commercialize our products and any product candidates for which we may obtain markeng approval; connue to manage our internaonal subsidiaries and establish new ones; connue to operate as a public company and comply with legal, accounng and other regulatory requirements; seek to idenfy, assess, license, acquire, and/or develop other product candidates, technologies, and/or businesses; make milestone or other payments under any license or other agreements; seek to maintain, protect, and expand our intellectual property porolio; seek to aract and retain skilled personnel; create addional infrastructure, including facilies and systems, to support the growth of our operaons, our product development, and our commercializaon eﬀorts; and experience any delays or encounter issues with any of the above, including, but not limited to, failed studies, complex results, safety issues, inspecon outcomes, or other regulatory challenges that require longer follow-up of exisng studies, addional major studies, or addional supporve studies in order to pursue markeng approval. The net losses we incur may ﬂuctuate signiﬁcantly from quarter to quarter and year to year, such that a period-to-period comparison of our results of operaons may not be a good indicaon of our future performance. We have limited experience in generang revenue from product sales. Our ability to generate signiﬁcant revenue from product sales depends on our ability, alone or with strategic collaboraon partners, to successfully commercialize our products and to complete the development of, and obtain the regulatory and markeng approvals necessary to commercialize, our product candidates. Our ability to generate substanal future revenue from product sales, including named paent sales, depends heavily on our success in many areas, including, but not limited to: • • obtaining regulatory and markeng approvals with broad indicaons for product candidates for which we complete clinical studies; developing a sustainable and scalable manufacturing process for our products and any approved product candidates and establishing and maintaining supply and manufacturing relaonships with third pares that can conduct the processes 32 and provide adequate (in amount and quality) product supply to support market demand for our products and product candidates, if approved; launching and commercializing our products and product candidates for which we obtain regulatory and markeng approval, either directly or with a collaborator or distributor; obtaining market acceptance of our products and product candidates as viable treatment opons; obtaining adequate market share, reimbursement and pricing for our products and product candidates; our ability to sell our products and product candidates on a named paent basis or through an equivalent mechanism and the amount of revenue generated from such sales; our ability to ﬁnd paents so they can be diagnosed and begin receiving treatment; addressing any compeng technological and market developments; negoang favorable terms, including commercial rights, in any collaboraon, licensing, or other arrangements into which we may enter, any amendments thereto or extensions thereof; maintaining, protecng, and expanding our porolio of intellectual property rights, including patents, trade secrets, and know-how; and aracng, hiring, and retaining qualiﬁed personnel. • • • • • • • • • If the number of our addressable rare disease paents is not as signiﬁcant as we esmate, the indicaon approved by regulatory authories is narrower than we expect, or the reasonably accepted populaon for treatment is narrowed by compeon, physician choice, or treatment guidelines, or any other reasons, we may not generate signiﬁcant revenue from sales of our products, even if they receive regulatory approval. We may need to raise addional capital to fund our acvies. Such addional ﬁnancing may not be available on acceptable terms, if at all. Failure to obtain this necessary capital when needed may force us to delay, limit, or terminate our product development eﬀorts or other acvies. As of December 31, 2023, our available cash, cash equivalents, and marketable debt securies were $777.1 million. We expect we will need addional capital to connue to commercialize our products, and to develop and obtain regulatory approval for, and to commercialize, all of our product candidates. In addion, our operang plans may change as a result of many factors that may currently be unknown to us, and we may need to seek addional funds sooner than planned. Our future funding requirements will depend on many factors, including but not limited to: • • • • • • • • • • the scope, rate of progress, results, and cost of our clinical studies, nonclinical tesng, and other related acvies; the cost of manufacturing clinical and commercial supplies of our products and product candidates; the cost of creang addional infrastructure, including facilies and systems, such as systems in our GMP gene therapy manufacturing facility; the cost of operang and maintaining our gene therapy manufacturing facility; the number and characteriscs of the product candidates that we pursue; the cost, ming, and outcomes of regulatory approvals; the cost and ming of establishing and operang our internaonal subsidiaries; the cost and ming of establishing and operang ﬁeld forces, markeng, and distribuon capabilies; the cost and ming of other acvies needed to commercialize our products; and the terms and ming of any collaborave, licensing, acquision, and other arrangements that we may establish, including any required milestone, royalty, and reimbursements or other payments thereunder. 33 Any addional fundraising eﬀorts may divert our management’s aenon from their day-to-day acvies, which can adversely aﬀect our ability to develop our product candidates and commercialize our products. In addion, we cannot guarantee that future ﬁnancing will be available in suﬃcient amounts or on terms acceptable to us, if at all, parcularly in light of the current macroeconomic condions, including the general economic slowdown and potenal recessionary environment. The terms of any ﬁnancing may adversely aﬀect the holdings or the rights of our stockholders and the issuance of addional securies by us, whether equity or debt, or the possibility of such issuance, may cause the market price of our shares to decline. The sale of addional equity or converble securies would dilute all of our stockholders. If we incur debt, it could result in increased ﬁxed payment obligaons and we may be required to agree to certain restricve covenants, such as limitaons on our ability to incur addional debt, limitaons on our ability to acquire, sell, or license intellectual property rights, and other operang restricons that could adversely impact our ability to conduct our business. We have in the past sought and may in the future seek funds through a sale of future royalty payments similar to our transacons with Royalty Pharma and OMERS or through collaborave partnerships, strategic alliances, and licensing or other arrangements, such as our transacon with Daiichi Sankyo Co., Ltd., or Daiichi Sankyo, and we may be required to relinquish rights to some of our technologies or product candidates, future revenue streams, research programs, and other product candidates or otherwise agree to terms unfavorable to us, any of which may have a material adverse eﬀect on our business, operang results, and prospects. Even if we believe we have suﬃcient funds for our current or future operang plans, we may seek addional capital if market condions are favorable or if we have speciﬁc strategic consideraons. In addion, we may not be able to access a poron of our exisng cash, cash equivalents and investments due to market condions. If banks or ﬁnancial instuons enter receivership or become insolvent in the future, similar to what occurred at Silicon Valley Bank in March 2023, or if there is a concern that they may do so in response to ﬁnancial condions aﬀecng the banking system and ﬁnancial markets, our ability to access our exisng cash, cash equivalents and investments may be threatened and the value of our investments may be signiﬁcantly impaired. If we are unable to access our exisng cash, cash equivalents and investments and/or are unable to obtain funding on a mely basis, or at all, we may be required to signiﬁcantly curtail, delay, or disconnue one or more of our research or development programs or the commercializaon of our products and any approved product candidates or be unable to expand our operaons or otherwise capitalize on our business opportunies, as desired, which could materially aﬀect our business, ﬁnancial condion, and results of operaons. Risks Related to the Discovery and Development of Our Product Candidates Clinical drug development involves a lengthy, complex, and expensive process with uncertain outcomes and the potenal for substanal delays, and the results of earlier studies may not be predicve of future study results. Before obtaining markeng approval from regulatory authories for the sale of our product candidates, we must conduct extensive clinical studies to demonstrate the safety and eﬃcacy of the product candidates in humans. Clinical tesng is expensive, complex, me consuming, and uncertain as to outcome. We cannot guarantee that any clinical studies will be conducted as planned or completed on schedule, if at all. We have also had diﬃcules in recruing clinical site invesgators and clinical staﬀ for our studies, and may connue to experience such diﬃcules. Addionally, a failure of one or more clinical studies can occur at any stage of tesng, and our future clinical studies may not be successful. Product candidates that have shown promising results in early-stage clinical studies may sll suﬀer signiﬁcant setbacks or fail in subsequent clinical studies. The safety or eﬃcacy results generated to date in clinical studies do not ensure that later clinical studies will demonstrate similar results. Further, we have reported and expect to connue to report preliminary or interim data from our clinical trials. Preliminary or interim data from our clinical trials are subject to the risk that one or more of the clinical outcomes may materially change as paent enrollment connues and/or more paent data become available. Such data may show inial evidence of clinical beneﬁt, but as paents connue to be assessed and more paent data become available, there is a risk that any therapeuc eﬀects are no longer durable in paents and/or decrease over me or cease enrely. As a result, preliminary or interim data should be considered carefully and with cauon unl the ﬁnal data are available. Results from invesgator-sponsored studies or compassionate-use studies may not be conﬁrmed in company-sponsored studies or may negavely impact the prospects for our programs. Addionally, given the nature of the rare diseases we are seeking to treat, we oen devise newly-deﬁned endpoints to be tested in our studies, which can lead to subjecvity in interpreng study results and could result in regulatory agencies not agreeing with the validity of our endpoints, or our interpretaon of the clinical data, and therefore delaying or denying approval. Given the illness of the paents in our studies and the nature of their rare diseases, we have also been required to or have chosen to conduct certain studies on an open-label basis. We have in the past, and may in the future elect to review interim clinical data at mulple me points during the studies, which could introduce bias into the study results and potenally result in denial of approval. 34 In the biopharmaceucal industry, there is a high failure rate for drugs and biologics proceeding through clinical studies, and product candidates in later stages of clinical studies may fail to show the desired safety and eﬃcacy despite having progressed through nonclinical studies and inial clinical studies. A number of companies in the biopharmaceucal industry have suﬀered signiﬁcant setbacks in advanced clinical studies due to lack of eﬃcacy or adverse safety proﬁles, notwithstanding promising results in earlier studies. Scenarios that can prevent successful or mely compleon of clinical development include but are not limited to: • • • • • • • • • • • • • • • • • • • • • • delays or failures in generang suﬃcient preclinical, toxicology, or other in vivo or in vitro data to support the iniaon or connuaon of human clinical studies or ﬁlings for regulatory approval; failure to demonstrate a starng dose for our product candidates in the clinic that might be reasonably expected to result in a clinical beneﬁt; delays or failures in developing gene therapy, messenger RNA, or mRNA, DNA, small interfering RNA, or siRNA, or other novel and complex product candidates, which are expensive and diﬃcult to develop and manufacture; delays resulng from a shutdown, or uncertainty surrounding the potenal for future shutdowns of the U.S. government, including the FDA; delays or failures in reaching a consensus with regulatory agencies on study design; delays in reaching agreement on acceptable terms with contract research organizaons, or CROs, clinical study sites, and other clinical trial- related vendors; failure or delays in obtaining required regulatory agency approval and/or IRB or EC approval at each clinical study site or in certain countries; failure to correctly design clinical studies which may result in those studies failing to meet their endpoints or the expectaons of regulatory agencies; changes in clinical study design or development strategy resulng in delays related to obtaining approvals from IRBs or ECs and/or regulatory agencies to proceed with clinical studies; imposion of a clinical hold by regulatory agencies aer review of an IND applicaon or amendment, another equivalent applicaon or amendment, or an inspecon of our clinical study operaons or study sites; delays in recruing suitable paents to parcipate in our clinical studies; diﬃculty collaborang with paent groups and invesgators; failure by our CROs, other third pares, or us to adhere to clinical study requirements; failure to perform in accordance with the FDA’s and/or ICH’s good clinical pracces requirements or applicable regulatory guidelines in other countries; delays in paents’ compleon of studies or their returns for post-treatment follow-up; paents dropping out of a study; adverse events associated with the product candidate occurring that are viewed to outweigh its potenal beneﬁts; changes in regulatory requirements and guidance that require amending or subming new clinical protocols; greater than ancipated costs associated with clinical studies of our drug candidates, including as a result of inﬂaon; clinical studies of our drug candidates producing negave or inconclusive results, which may result in us deciding, or regulators requiring us, to conduct addional clinical or nonclinical studies or to abandon drug development programs; compeng clinical studies of potenal alternave product candidates or invesgator-sponsored studies of our product candidates; and delays in manufacturing, tesng, releasing, validang, or imporng/exporng suﬃcient stable quanes of our product candidates for use in clinical studies or the inability to do any of the foregoing. Any inability to successfully complete nonclinical and clinical development could result in addional costs to us or negavely impact our ability to generate revenue. In addion, if we make manufacturing or formulaon changes to our product candidates, we may need to conduct addional toxicology, comparability or other studies to bridge our modiﬁed product candidates to earlier versions. Clinical study delays could also shorten any periods during which our products have commercial exclusivity and may allow our competors to bring products to market before we do, which could negavely impact our ability to obtain orphan exclusivity and to successfully commercialize our product candidates and may harm our business and results of operaons. 35 If we do not achieve our projected development goals in the me frames we announce and expect, the commercializaon of our products may be delayed and the credibility of our management may be adversely aﬀected and, as a result, our stock price may decline. For planning purposes, we esmate the ming of the accomplishment of various scienﬁc, clinical, regulatory, and other product development goals, which we somemes refer to as milestones. These milestones may include the commencement or compleon of scienﬁc studies and clinical trials, the ming of paent dosing, the ming, type or clarity of data from clinical trials, the submission or acceptance of regulatory ﬁlings, and the potenal approval of such regulatory ﬁlings. We periodically make public announcements about the expected ming of some of these milestones. All of these milestones are based on a variety of assumpons, but the actual ming of these milestones can vary dramacally from our esmates. If we do not meet these publicly announced milestones, the commercializaon of our products may be delayed and the credibility of our management may be adversely aﬀected and, as a result, our stock price may decline. We may ﬁnd it diﬃcult to idenfy and enroll paents in our clinical studies due to a variety of factors, including the limited number of paents who have the diseases for which our product candidates are being studied and other unforeseen events. Diﬃculty in enrolling paents could delay or prevent clinical studies of our product candidates. Idenfying and qualifying paents to parcipate in clinical studies of our product candidates is crical to our success. The ming of our clinical studies depends in part on the speed at which we can recruit paents to parcipate in tesng our product candidates, and we may experience delays in our clinical studies if we encounter diﬃcules in enrollment. Each of the condions for which we plan to evaluate our current product candidates is a rare genec disease. Accordingly, there are limited paent pools from which to draw for clinical studies. For example, we esmate that approximately 6,000 paents worldwide suﬀer from GSDIa, for which DTX401 is being studied, and these all may not be treatable if they are immune to the AAV viral vector. In addion to the rarity of these diseases, the eligibility criteria of our clinical studies will further limit the pool of available study parcipants as we will require paents to have speciﬁc characteriscs that we can measure or to assure their disease is either severe enough or not too advanced to include them in a study. The process of ﬁnding and diagnosing paents is costly and me-consuming, especially since the rare diseases we are studying are commonly underdiagnosed. We also may not be able to idenfy, recruit, and enroll a suﬃcient number of appropriate paents to complete our clinical studies because of demographic criteria for prospecve paents, the perceived risks and beneﬁts of the product candidate under study, the proximity and availability of clinical study sites for prospecve paents, and the paent referral pracces of physicians. The availability and eﬃcacy of compeng therapies and clinical studies can also adversely impact enrollment. If paents are unwilling to parcipate in our studies for any reason (such as drug-related side eﬀects), the meline for and our success in recruing paents, conducng studies, and obtaining regulatory approval of potenal products may be delayed or impaired, the commercial prospects of our product candidates will be harmed, and our ability to generate product sales from any of these product candidates could be delayed or prevented. Delays in compleng our clinical studies will increase our costs, slow down our product candidate development and approval process, and jeopardize our ability to commence product sales and generate revenue. 36 The regulatory approval processes of the FDA and comparable foreign authories are lengthy, me consuming, and inherently unpredictable. Even if we achieve posive results in our pre-clinical and clinical studies, if we are ulmately unable to obtain mely regulatory approval for our product candidates, our business will be substanally harmed. Our future success is dependent on our ability to successfully commercialize our products and develop, obtain regulatory approval for, and then successfully commercialize one or more product candidates. We are not permied to market or promote any of our product candidates before we receive regulatory approval from the FDA or comparable foreign regulatory authories. We have only obtained regulatory approval for three products that we have developed, and it is possible that none of our exisng product candidates or any product candidates we may seek to develop in the future will ever obtain regulatory approval. Further, as the clinical trial requirements of regulatory authories and the criteria these regulators use to determine the safety and eﬃcacy of a product candidate vary substanally according to the type, complexity, novelty and intended use and market of the product candidates, the regulatory approval process for novel product candidates, such as our gene therapy product candidates, can be more expensive and take longer than for other product candidates, leading to fewer product approvals. To date, very few gene therapy products have received regulatory approval in the U.S. or Europe. The regulatory framework and oversight over development of gene therapy products has evolved and may connue to evolve in the future. Within the FDA, the Center for Biologics Evaluaon and Research, or CBER, regulates gene therapy products. Within the CBER, the review of gene therapy and related products is consolidated in the Oﬃce of Cellular, Tissue and Gene Therapies, and the FDA has established the Cellular, Tissue and Gene Therapies Advisory Commiee to advise CBER on its reviews. The CBER works closely with the Naonal Instutes of Health, or NIH. The FDA and the NIH have published guidance with respect to the development and submission of gene therapy protocols. For example, in January 2020, the FDA issued ﬁnal guidance to set forth the framework for the development, review and approval of gene therapies. The ﬁnal guidance pertains to the development of gene therapies for the treatment of speciﬁc disease categories, including rare diseases, and to manufacturing and long-term follow up issues relevant to gene therapy, among other topics. At the same me the FDA issued guidance describing the FDA’s approach for determining whether two gene therapy products were the same or diﬀerent for the purpose of assessing orphan drug exclusivity. Within the European Medicines Agency, or EMA, special rules apply to gene therapy and related products as they are considered advanced therapy medicinal products, or ATMPs. Pursuant to the ATMP Regulaon, the Commiee on Advanced Therapies, or CAT, is responsible in conjuncon with the Commiee for Medicinal Products for Human Use, or CHMP, for the evaluaon of ATMPs. The CHMP and CAT are also responsible for providing guidelines on ATMPs. These guidelines provide addional guidance on the factors that the EMA will consider in relaon to the development and evaluaon of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs. The manufacturing and control informaon that should be submied in a MAA; and post-approval measures required to monitor paents and evaluate the long-term eﬃcacy and potenal adverse reacons of ATMPs. Although such guidelines are not legally binding, compliance with them is oen necessary to gain and maintain approval for product candidates. In addion to the mandatory risk-management plan, or RMP, the holder of a markeng authorizaon for an ATMP must put in place and maintain a system to ensure that each individual product and its starng and raw materials, including all substances coming into contact with the cells or ssues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport, and delivery to the relevant healthcare instuon where the product is used. To obtain regulatory approval in the U.S. and other jurisdicons, we must comply with numerous and varying requirements regarding safety, eﬃcacy, chemistry, manufacturing and controls, clinical studies (including good clinical pracces), commercial sales, pricing, and distribuon of our product candidates, as described above in “Item 1. Business – Government Regulaon”. Even if we are successful in obtaining approval in one jurisdicon, we cannot ensure that we will obtain approval in any other jurisdicons. In addion, approval policies, regulaons, posions of the regulatory agencies on study design and/or endpoints, or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development, which may cause delays in the approval or the decision not to approve an applicaon. Communicaons with the regulatory agencies during the approval process are also unpredictable; favorable communicaons early in the process do not ensure that approval will be obtained and unfavorable communicaons early on do not guarantee that approval will be denied. Applicaons for our product candidates could fail to receive regulatory approval, or could be delayed in receiving regulatory approval, for many reasons, including but not limited to the following: • • • • • regulatory authories may disagree with the design, implementaon, or conduct of our clinical studies; regulatory authories may change their guidance or requirements for a development program for a product candidate; the populaon studied in the clinical program may not be suﬃciently broad or representave to assure eﬃcacy and safety in the full populaon for which we seek approval; regulatory authories may disagree with our interpretaon of data from nonclinical studies or clinical studies; the data collected from clinical studies of our product candidates may not be suﬃcient to support the submission of an NDA, or biologics license applicaon, or BLA, or other submission or to obtain regulatory approval; 37 • • • • • • we may be unable to demonstrate to regulatory authories that a product candidate’s risk-beneﬁt rao for its proposed indicaon is acceptable; regulatory authories may fail to approve the manufacturing processes, test procedures and speciﬁcaons, or facilies used to manufacture our clinical and commercial supplies; the U.S. government may be shut down, which could delay the FDA; the FDA may be delayed in responding to our applicaons or submissions due to compeng priories or limited resources, including as a result of the lack of FDA funding or personnel; failure of our nonclinical or clinical development to comply with an agreed upon Pediatric Invesgaonal Plan, or PIP, which details the designs and compleon melines for nonclinical and clinical studies and is a condion of markeng authorizaon in the EU; and the approval policies or regulaons of regulatory authories may signiﬁcantly change in a manner rendering our clinical data insuﬃcient for approval. Furthermore, the disease states we are evaluang oen do not have clear regulatory paths for approval and/or do not have validated outcome measures. In these circumstances, we work closely with the regulatory authories to deﬁne the approval path and may have to qualify outcome measures as part of our development programs. Addionally, many of the disease states we are targeng are highly heterogeneous in nature, which may impact our ability to determine the treatment beneﬁt of our potenal therapies. This lengthy and uncertain approval process, as well as the unpredictability of the clinical and nonclinical studies, may result in our failure to obtain regulatory approval to market any of our product candidates, or delayed regulatory approval. Fast Track, Breakthrough Therapy, Priority Review, or Regenerave Medicine Advanced Therapy, or RMAT, designaons by the FDA, or access to the Priority Medicine scheme, or PRIME, by the EMA, for our product candidates, if granted, may not lead to faster development or regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive markeng approval. As described in “Item 1. Business – Government Regulaon”, we seek Fast Track, Breakthrough Therapy designaon, RMAT designaon, PRIME scheme access or Priority Review designaon for our product candidates if supported by the results of clinical trials. Designaon as a Fast Track product, Breakthrough Therapy, RMAT, PRIME, or Priority Review product is within the discreon of the relevant regulatory agency. Accordingly, even if we believe one of our product candidates meets the criteria for designaon as a Fast Track product, Breakthrough Therapy, RMAT, PRIME, or Priority Review product, the agency may disagree and instead determine not to make such designaon. The receipt of such a designaon for a product candidate also may not result in a faster development process, review or approval compared to drugs considered for approval under convenonal regulatory procedures and does not assure that the product will ulmately be approved by the regulatory authority. In addion, regarding Fast Track products and Breakthrough Therapies, the FDA may later decide that the products no longer meet the condions for qualiﬁcaon as either a Fast Track product, RMAT, or a Breakthrough Therapy or, for Priority Review products, decide that period for FDA review or approval will not be shortened. Furthermore, with respect to PRIME designaon by the EMA, PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designaon or eligibility will result in expedited review or approval. The FDA Rare Pediatric Disease Priority Review Voucher Program, or PRV Voucher Program, awards Priority Review Vouchers, or PRVs, to sponsors of rare pediatric product applicaons that meet certain criteria. Under the program, a company that receives an approval for a product for a rare pediatric disease (as determined by the applicable regulaons) may qualify for a PRV that can be redeemed to receive Priority Review of a subsequent markeng applicaon for a diﬀerent product. PRVs may also be sold by the company to third pares. We received PRVs under the PRV Voucher Program in connecon with the approval of Mepsevii and Crysvita in 2018 and subsequently sold these two PRVs to third pares for an average amount of $105.3 million for each PRV. The current PRV Voucher Program is scheduled to sunset such that the FDA may only award a PRV for a product applicaon if a company receives the rare pediatric disease designaon from the FDA for the product candidate by September 30, 2024, and the FDA will cease awarding PRVs aer September 30, 2026. Extension of the current PRV Voucher Program is subject to approval by Congress and it is currently uncertain whether the program will be extended. If our qualifying product candidates are approved by the FDA aer the current approval deadlines, we will not be eligible to receive addional PRVs for our product candidates and accordingly, we would be unable to use such PRV for Priority Review for another one of our programs or to sell such PRV, which sale has the potenal to generate signiﬁcant proceeds. 38 Our product candidates may cause undesirable side eﬀects or have other properes that could delay or prevent their regulatory approval, limit the commercial proﬁle of an approved label, or result in signiﬁcant negave consequences following markeng approval, if any. Undesirable side eﬀects caused by our product candidates could cause us or regulatory authories to interrupt, delay, or halt clinical studies or further development, and could result in a more restricve label, the delay or denial of regulatory approval by the FDA or other comparable foreign authories, or a Risk Evaluaon and Migaon Strategy, or REMS, plan, which could include a medicaon guide outlining the risks of such side eﬀects for distribuon to paents, restricted distribuon, a communicaon plan for healthcare providers, and/or other elements to assure safe use. Our product candidates are in development and the safety proﬁle has not been established. Further, as one of the goals of Phase 1 and/or 2 clinical trials is to idenfy the highest dose of treatment that can be safely provided to study parcipants, adverse side eﬀects, including serious adverse eﬀects, have occurred in certain studies as a result of changes to the dosing regimen during such studies and may occur in future studies. Results of our studies or invesgator-sponsored trials could reveal a high and unacceptable severity and prevalence of these or other side eﬀects. In such an event, our studies could be suspended or terminated, and the FDA or comparable foreign regulatory authories could order us to cease further development of or deny or withdraw approval of our product candidates for any or all targeted indicaons. Addionally, notwithstanding our prior or future regulatory approvals for our product candidates, if we or others later idenfy undesirable side eﬀects caused by such products, a number of potenally signiﬁcant negave consequences could result, including but not limited to: • • • • • regulatory authories may withdraw approvals of such product; regulatory authories may require addional warnings on the product’s label or restrict the product’s approved use; we may be required to create a REMS plan; paents and physicians may elect not to use our products, or reimbursement authories may elect not to reimburse for them; and our reputaon may suﬀer. Any of these events could prevent us from achieving or maintaining market acceptance of the parcular product candidate, if approved. Serious adverse events in clinical trials involving gene therapy product candidates may damage public percepon of the safety of our product candidates, increase government regulaon, and adversely aﬀect our ability to obtain regulatory approvals for our product candidates or conduct our business. Gene therapy remains a novel technology. Public percepon may be inﬂuenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the public or the medical community. For example, certain gene therapy trials using AAV8 vectors (although at signiﬁcantly higher doses than those used in our gene therapy product candidates) and other vectors led to several well-publicized adverse events, including cases of leukemia and death. The risk of cancer or death remains a concern for gene therapy and we cannot assure you that it will not occur in any of our planned or future clinical studies. In addion, there is the potenal risk of delayed adverse events following exposure to gene therapy products due to persistent biological acvity of the genec material or other components of products used to carry the genec material. Serious adverse events in our clinical trials, or other clinical trials involving gene therapy products, parcularly AAV gene therapy products such as candidates based on the same capsid serotypes as our product candidates, or occurring during use of our competors’ products, even if not ulmately aributable to the relevant product candidates, and the resulng publicity, could result in increased government regulaon, unfavorable public percepon, potenal regulatory delays in the tesng or approval of our gene therapy product candidates, stricter labeling requirements for those gene therapy product candidates that are approved and a decrease in demand for any such gene therapy product candidates. Gene therapy and mRNA, DNA and siRNA product candidates are novel, complex, expensive and diﬃcult to manufacture. We could experience manufacturing problems that result in delays in developing and commercializing these programs or otherwise harm our business. The manufacturing process used to produce our gene therapy, mRNA, DNA and siRNA product candidates is novel, complex, and has not been validated for commercial use. Several factors could cause producon interrupons, including equipment malfuncons, malfuncons of internal informaon technology systems, regulatory inspecons, facility contaminaon, raw material shortages or contaminaon, natural disasters, geopolical instability, disrupon in ulity services, human error or disrupons in the operaons of our suppliers. Further, given that cGMP gene therapy, mRNA, DNA and siRNA manufacturing is a nascent industry, there are a small number of CMOs with the experience necessary to manufacture our gene therapy product candidates and we may 39 have diﬃculty ﬁnding or maintaining relaonships with such CMOs or hiring experts for internal manufacturing and accordingly, our producon capacity may be limited. Our gene therapy, mRNA, DNA and siRNA product candidates require processing steps that are more complex than those required for most small molecule drugs. Moreover, unlike small molecules, the physical and chemical properes of a biologic such as gene therapy, mRNA, DNA and siRNA product candidates generally cannot be fully characterized. As a result, assays of the ﬁnished product candidate may not be suﬃcient to ensure that the product candidate is consistent from lot to lot or will perform in the intended manner. Accordingly, we employ mulple steps to control the manufacturing process to assure that the process works reproducibly, and the product candidate is made strictly and consistently in compliance with the process. Problems with the manufacturing process, even minor deviaons from the normal process, could result in product defects or manufacturing failures that result in lot failures, noncompliance with regulatory requirements, product recalls, product liability claims or insuﬃcient inventory. We may encounter problems achieving adequate quanes and quality of clinical-grade materials that meet FDA, the EMA or other applicable standards or speciﬁcaons with consistent and acceptable producon yields and costs. In addion, FDA, the EMA and other foreign regulatory authories may require us to submit samples of any lot of any approved product together with the protocols showing the results of applicable tests at any me. Under some circumstances, FDA, the EMA or other foreign regulatory authories may require that we not distribute a lot unl the agency authorizes its release. Slight deviaons in the manufacturing process, including those aﬀecng quality aributes and stability, may result in unacceptable changes in the product that could result in lot failures or product recalls. Lot failures or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, ﬁnancial condion, results of operaons and prospects. Even if we obtain regulatory approval for our product candidates, our products remain subject to regulatory scruny. Our products and any product candidates that are approved in the future remain subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, distribuon, adversing, promoon, sampling, record-keeping, conduct of post-markeng studies, and submission of safety, eﬃcacy, and other post-market informaon, including both federal and state requirements in the U.S. and requirements of comparable foreign regulatory authories, as described above in “Item 1. Business – Government Regulaon.” Manufacturers and manufacturers’ facilies are required to comply with extensive FDA, and comparable foreign regulatory authority, requirements, including ensuring that quality control and manufacturing procedures conform to Good Manufacturing Pracces, or GMP, regulaons. As such, we and our contract manufacturers are subject to connual review and inspecon to assess compliance with GMP and adherence to commitments made in any NDA, BLA, MAA, or other comparable applicaon for approval in another jurisdicon. Although we are not involved in the day-to-day operaons of our contract manufacturers, we are ulmately responsible for ensuring that our products are manufactured in accordance with GMP regulaons. Regulatory authories may, at any me, audit or inspect a manufacturing facility involved with the preparaon of our products, product candidates or the associated quality systems for compliance with the regulaons applicable to the acvies being conducted. Due to the complexity of the processes used to manufacture our products and product candidates, we or any of our collaborators or contract manufacturers may be unable to comply with GMP regulaons in a cost-eﬀecve manner and may be unable to inially or connue to pass a federal, naonal or internaonal regulatory inspecon. If we, our collaborators, such as KKC or Regeneron, or any of our third-party manufacturers fail to maintain regulatory compliance, the FDA or other applicable regulatory authority can impose regulatory sancons including, among other things, warning or untled leers, ﬁnes, unancipated compliance expenses, the temporary or permanent suspension of a clinical study or commercial sales, recalls or seizures of product or the temporary or permanent closure of a facility or withdrawal of product approval, enforcement acons and criminal or civil prosecuon. If supply from one approved manufacturer is interrupted due to failure to maintain regulatory compliance, an alternave manufacturer would need to be qualiﬁed through an NDA or BLA supplement or MAA variaon, or equivalent foreign regulatory ﬁling, which could result in delays in product supply. The regulatory agencies may also require addional studies if a new manufacturer, material, tesng method or standard is relied upon for commercial producon. Switching manufacturers, materials, test methods or standards may involve substanal costs and may result in a delay in our desired clinical and commercial melines. Accordingly, we and others with whom we work are required connue to expend me, money, and eﬀort in all areas of regulatory compliance, including manufacturing, producon, and quality control. 40 Any regulatory approvals that we receive for our product candidates may be subject to limitaons on the approved indicated uses for which the product may be marketed or other condions of approval, or contain requirements for potenally costly post-markeng tesng, including Phase 4 clinical studies, and surveillance to monitor the safety and eﬃcacy of the product candidate. We could also be asked to conduct post-markeng clinical studies to verify the safety and eﬃcacy of our products in general or in speciﬁc paent subsets. If original markeng approval was obtained via the accelerated approval or condional markeng authorizaon pathways, we would be required to conduct a successful post-markeng clinical study to conﬁrm clinical beneﬁt for our products. An unsuccessful post-markeng study or failure to complete such a study could result in the withdrawal of markeng approval. We will be required to report certain adverse events and manufacturing problems, if any, to the FDA and comparable foreign regulatory authories. The holder of an approved NDA, BLA, MAA, or other comparable applicaon must submit new or supplemental applicaons and obtain approval for certain changes to the approved product, product labeling, or manufacturing process. If we fail to comply with applicable regulatory requirements, or there are safety or eﬃcacy problems with a product, a regulatory agency or enforcement authority may, among other things: • • • • • • • • issue warning or noce of violaon leers; impose civil or criminal penales; suspend or withdraw regulatory approval; suspend any of our ongoing clinical studies; refuse to approve pending applicaons or supplements to approved applicaons submied by us; impose restricons on our operaons, including closing our contract manufacturers’ facilies; seize or detain products, or require a product recall; or require entry into a consent decree. Any government invesgaon of alleged violaons of law could require us to expend signiﬁcant me and resources in response, and could generate negave publicity. Any failure to comply with ongoing regulatory requirements may signiﬁcantly and adversely aﬀect our ability to commercialize and generate revenue from our products. If regulatory sancons are applied or if regulatory approval is withdrawn, the value of our company and our operang results will be adversely aﬀected. Product liability lawsuits against us could cause us to incur substanal liabilies and could limit commercializaon of our approved products or product candidates. We face an inherent risk of product liability exposure related to the tesng of our approved products and product candidates in human clinical trials, as well as in connecon with commercializaon of our current and future products. If we cannot successfully defend ourselves against claims that any of our approved products or product candidates caused injuries, we could incur substanal liabilies. There can be no assurance that our product liability insurance, which provides coverage in the amount of $15.0 million in the aggregate, will be suﬃcient in light of our current or planned clinical programs. We may not be able to maintain insurance coverage at a reasonable cost or in suﬃcient amounts to protect us against losses due to liability, or losses may exceed the amount of insurance that we carry. A product liability claim or series of claims brought against us could cause our stock price to decline and, if judgments exceed our insurance coverage, could adversely aﬀect our results of operaons and business. In addion, regardless of merit or eventual outcome, product liability claims may result in impairment of our business reputaon, withdrawal of clinical study parcipants, costs due to related ligaon, distracon of management’s aenon from our primary business, iniaon of invesgaons by regulators, substanal monetary awards to paents or other claimants, the inability to commercialize our product candidates, and decreased demand for our product candidates, if approved for commercial sale. If we are unable to idenfy, source, and develop eﬀecve biomarkers, or our collaborators are unable to successfully develop and commercialize companion diagnoscs for our product candidates, or experience signiﬁcant delays in doing so, we may not realize the full commercial potenal of our product candidates. We are developing companion diagnosc tests to idenfy the right paents for certain of our product candidates and to monitor response to treatment. In certain cases, diagnosc tests may need to be developed as companion diagnoscs and regulatory approval obtained in order to commercialize some product candidates. We currently use and expect to connue to use biomarkers to idenfy the right paents for certain of our product candidates. We may also need to develop predicve biomarkers in the future. We can oﬀer no assurances that any current or future potenal biomarker will in fact prove predicve, be reliably measured, or be accepted as a measure of eﬃcacy by the FDA or other regulatory authories. In addion, our success may depend, in part, on the development and commercializaon of companion diagnoscs. We also expect the FDA will require the development 41 and regulatory approval of a companion diagnosc assay as a condion to approval of our gene therapy product candidates. There has been limited success to date industrywide in developing and commercializing these types of companion diagnoscs. Development and manufacturing of companion diagnoscs is complex and there are limited manufacturers with the necessary experse and capability. Even if we are able to successfully develop companion diagnoscs, we may not be able to manufacture the companion diagnoscs at a cost or in quanes or on melines necessary for use with our product candidates. To be successful, we need to address a number of scienﬁc, technical and logiscal challenges. We are currently working with a third party to develop companion diagnoscs; however, we have lile experience in the development and commercializaon of diagnoscs and may not ulmately be successful in developing and commercializing appropriate diagnoscs to pair with any of our product candidates that receive markeng approval. We rely on third pares for the automaon, characterizaon and validaon, of our bioanalycal assays, companion diagnoscs and the manufacture of its crical reagents. Companion diagnoscs are subject to regulaon by the FDA and similar regulatory authories outside the U.S. as medical devices and require regulatory clearance or approval prior to commercializaon. In the U.S., companion diagnoscs are cleared or approved through FDA’s 510(k) premarket noﬁcaon or premarket approval, or PMA, process. Changes in markeng approval policies during the development period, changes in or the enactment of addional statutes or regulaons, or changes in regulatory review for each submied 510(k) premarket noﬁcaon, PMA or equivalent applicaon types in jurisdicons outside the U.S., may cause delays in the approval, clearance or rejecon of an applicaon. Given our limited experience in developing and commercializing diagnoscs, we expect to rely in part or in whole on third pares for companion diagnosc design and commercializaon. We and our collaborators may encounter diﬃcules in developing and obtaining approval or clearance for the companion diagnoscs, including issues relang to selecvity/speciﬁcity, analycal validaon, reproducibility, or clinical validaon. Any delay or failure by us or our collaborators to develop or obtain regulatory approval of the companion diagnoscs could delay or prevent approval of our product candidates. Risks Related to our Reliance on Third Pares We rely on third pares to conduct our nonclinical and clinical studies and perform other tasks for us. If these third pares do not successfully carry out their contractual dues, meet expected deadlines, or comply with regulatory requirements, we may be exposed to sub-opmal quality and reputaonal harm, we may not be able to obtain regulatory approval for or commercialize our product candidates, and our business could be substanally harmed. We have relied upon and plan to connue to rely upon third pares, including CROs, collaborave partners, and independent invesgators to analyze, collect, monitor, and manage data for our ongoing nonclinical and clinical programs. We rely on third pares for execuon of our nonclinical and clinical studies, and for esmates regarding costs and eﬀorts completed, and we control only certain aspects of their acvies. We and our CROs and other vendors and partners are required to comply with GMP, GCP, and GLP, which are regulaons and guidelines enforced by the FDA, the Competent Authories of the Member States of the European Economic Area, and comparable foreign regulatory authories for all of our product candidates in development. Regulatory authories enforce these regulaons through periodic inspecons of study sponsors, principal invesgators, study sites, and other contractors. If we or any of our CROs or other vendors and partners, including the sites at which clinical studies are conducted, fail to comply with applicable regulaons, the data generated in our nonclinical and clinical studies may be deemed unreliable and the FDA, EMA, or comparable foreign regulatory authories may deny approval and/or require us to perform addional nonclinical and clinical studies before approving our markeng applicaons, which would delay the approval process. We cannot make assurances that upon inspecon by a given regulatory authority, such regulatory authority will determine that any of our clinical studies comply with GCP regulaons or that nonclinical studies comply with GLP regulaons. In addion, our clinical studies must be conducted with products produced under GMP regulaons. If the regulatory authories determine that we have failed to comply with GLP, GMP, or GCP regulaons, they may deny approval of our product candidates and/or we may be required to repeat clinical or nonclinical studies, which would delay the regulatory approval process. Our CROs and other vendors and partners are not our employees and we cannot control whether or not they devote suﬃcient me and resources to our on-going nonclinical and clinical programs, except for the limited remedies available to us under our agreements with such third pares. If our vendors and partners do not successfully carry out their contractual dues or obligaons or meet expected deadlines, if they need to be replaced, or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere to our protocols, regulatory requirements, or for other reasons, our clinical studies may be extended, delayed, or terminated, and we may not be able to obtain regulatory approval for or successfully commercialize our product candidates. CROs and other vendors and partners have also generated higher costs than ancipated as a result of changes in scope of work or otherwise. As a result, the commercial prospects for our product candidates could be harmed, our costs could increase, and our ability to generate revenue could be delayed. 42 If any of our relaonships with these third pares terminate, we may not be able to enter into arrangements with alternave vendors or do so on commercially reasonable terms. Switching or adding addional vendors involves addional cost and requires management me and focus. In addion, there is a natural transion period when a new vendor commences work. As a result, delays may occur, which can materially impact our ability to meet our desired clinical development melines. Our eﬀorts to manage our relaonships with our vendors and partners can provide no assurance that we will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, ﬁnancial condion, and business prospects. We also rely on third pares in other ways, including eﬀorts to support paent diagnosis and idenfy paents, to assist our ﬁnance and legal departments, and to provide other resources for our business. Use of these third pares could expose us to sub-opmal quality, missed deadlines, and non- compliance with applicable laws, all of which could result in reputaonal harm to us and negavely aﬀect our business. We are dependent on KKC for the clinical and commercial supply of Crysvita for all major markets and for the development and commercializaon of Crysvita in certain major markets, and KKC’s failure to provide an adequate supply of Crysvita or to commercialize Crysvita in those markets could result in a material adverse eﬀect on our business and operang results. Under our agreement with KKC, KKC has the sole right to commercialize Crysvita in Europe and, at certain speciﬁed mes, in the U.S., Canada, and Turkey, subject to certain rights retained. Our partnership with KKC may not be successful, and we may not realize the expected beneﬁts from such partnership, due to a number of important factors, including but not limited to the following: • • • • • • • • • • KKC has no obligaon under our agreement to use diligent eﬀorts to commercialize Crysvita in Europe. The ming and amount of any royalty payments that are made by KKC based on sales of Crysvita in Europe will depend on, among other things, the eﬀorts, allocaon of resources, and successful commercializaon of Crysvita by KKC in Europe; the ming and amount of any payments we may receive under our agreement with KKC will depend on, among other things, the eﬀorts, allocaon of resources, and successful commercializaon of Crysvita by KKC in the U.S. and Canada under our agreement; KKC may change the focus of its commercializaon eﬀorts or pursue higher priority programs; KKC may make decisions regarding the indicaons for our product candidates in countries where it has the sole right to commercialize the product candidates that limit commercializaon eﬀorts in those countries or in countries where we have the right to commercialize our product candidates; KKC may make decisions regarding market access and pricing in countries where it has the sole right to commercialize our product candidates which can negavely impact our commercializaon eﬀorts in countries where we have the right to commercialize our product candidates; KKC may fail to manufacture or supply suﬃcient drug product of Crysvita in compliance with applicable laws and regulaons or otherwise for our development and clinical use or commercial use, which could result in program delays or lost revenue; KKC may elect to develop and commercialize Crysvita indicaons with a larger market than XLH and at a lower price, thereby reducing the proﬁt margin on sales of Crysvita for any orphan indicaons, including XLH; if KKC were to breach or terminate the agreement with us, we would no longer have any rights to develop or commercialize Crysvita or such rights would be limited to non-terminated countries; KKC may terminate its agreement with us, adversely aﬀecng our potenal revenue from licensed products; and the ming and amounts of expense reimbursement that we may receive are uncertain, and the total expenses for which we are obligated to reimburse KKC may be greater than ancipated. We rely on third pares to manufacture our products and our product candidates and we are subject to a multude of manufacturing risks, any of which could substanally increase our costs and limit the supply of our product and product candidates. As we currently lack the resources and the full capability to manufacture all of our products and product candidates on a clinical or commercial scale, we rely on third pares to manufacture our products and product candidates. Although we oversee the contract manufacturers, we cannot control the manufacturing process of, and are substanally dependent on, our contract manufacturing partners for compliance with the regulatory requirements. See “- Even if we obtain regulatory approval for our product candidates, our products remain subject to regulatory scruny” risk factor above. Further, we depend on our manufacturers 43 to purchase from third-party suppliers the materials necessary to produce our products and product candidates. There are a limited number of suppliers for raw materials that we use to manufacture our drugs, placebos, or acve controls, and there may be a need to idenfy alternate suppliers to prevent or migate a possible disrupon of the manufacture of the materials necessary to produce our products and product candidates for our clinical studies, and, if approved, ulmately for commercial sale. We also do not have any control over the process or ming of the acquision of these raw materials by our manufacturers. We may also experience interrupons in supply of product if the product or raw material components fail to meet our quality control standards or the quality control standards of our suppliers. Further, manufacturers that produce our products and product candidates may not have experience producing our products and product candidates at commercial levels and may not produce our products and product candidates at the cost, quality, quanes, locaons, and ming needed to support proﬁtable commercializaon. We have not yet secured manufacturing capabilies for commercial quanes of all of our product candidates and may be unable to negoate binding agreements with manufacturers to support our commercializaon acvies on commercially reasonable terms. Even if our third- party product manufacturers develop acceptable manufacturing processes that provide the necessary quanes of our products and product candidates in a compliant and mely manner, the cost to us for the supply of our products and product candidates manufactured by such third pares may be high and could limit our proﬁtability. For instance, KKC is our sole supplier of commercial quanes of Crysvita. The supply price to us for commercial sales of Crysvita in Lan America and the transfer price for commercial sales of the product in the U.S. and Canada was 35% of net sales through December 31, 2022 and 30% thereaer, which is higher than the typical cost of sales for companies focused on rare diseases. The process of manufacturing our products and product candidates is complex, highly regulated, and subject to several risks, including but not limited to those listed below. • • The process of manufacturing our products and product candidates is extremely suscepble to product loss due to contaminaon, equipment failure or improper installaon or operaon of equipment, or vendor or operator error. Even minor deviaons from normal manufacturing processes for our products and any of our product candidates could result in reduced producon yields, product defects, and other supply disrupons. If microbial, viral, or other contaminaons are discovered in our products and product candidates or in the manufacturing facilies in which our products and product candidates are made, such manufacturing facilies may need to be closed for an extended period of me to invesgate and remedy the contaminaon. The manufacturing facilies in which our products and product candidates are made could be adversely aﬀected by equipment failures, labor shortages, raw material shortages, natural disasters, power failures, actual or threatened public health emergencies, and numerous other factors. Any adverse developments aﬀecng manufacturing operaons for our products and product candidates may result in shipment delays, inventory shortages, lot failures, withdrawals or recalls, or other interrupons in the supply of our products and product candidates. Due to their stage of development, small volume requirements, and infrequency of batch producon runs, we carry limited amounts of safety stock for our products and product candidates. We have, and may in the future, be required to take inventory write-oﬀs and incur other charges and expenses for products and product candidates that fail to meet speciﬁcaons, undertake costly remediaon eﬀorts, or seek more costly manufacturing alternaves. 44 The drug substance and drug product for our products and most of our product candidates are currently acquired from single-source suppliers. The loss of these suppliers, or their failure to supply us with the necessary drug substance or drug product, could materially and adversely aﬀect our business. We acquire most of the drug substances and drug products for our products and product candidates from single sources. If any single source supplier breaches an agreement with us, or terminates the agreement in response to an alleged breach by us or otherwise becomes unable or unwilling to fulﬁll its supply obligaons, we would not be able to manufacture and distribute the product or product candidate unl a qualiﬁed alternave supplier is idenﬁed, which could signiﬁcantly impair our ability to commercialize such product or delay the development of such product candidate. For example, the drug substance and drug product for Crysvita and Evkeeza are made, respecvely, by KKC pursuant to a license and collaboraon agreement and Regeneron pursuant to a supply agreement. The drug substance and drug product for Mepsevii are currently manufactured by Rentschler under a commercial supply and services agreement, accompanying purchase orders, and other agreements. Pharmaceucal-grade drug substance for Dojolvi is manufactured by IOI Oleo pursuant to a supply agreement, and the drug product for Dojolvi is prepared by Haupt Pharma AG, pursuant to a master services agreement. Single source suppliers are also used for our gene therapy programs. Haupt Pharma closed its Wolfrathshausen, Germany site, which produces the Dojolvi drug product, at the end of 2023. As such, we are in the process of qualifying and conducng transfer acvies to an alternave supplier. We cannot provide assurances that qualifying alternate sources, if available at all, for the Dojolvi drug product or for any of our other drug substances and drug products, and establishing relaonships with such sources would not result in signiﬁcant expense, supply disrupons or delay in the commercializaon of our products or the development of our product candidates. Addionally, we may not be able to enter into supply arrangements with an alternave supplier on commercially reasonable terms or at all. The terms of any new agreement may also be less favorable or more costly than the terms we have with our current supplier. A delay in the commercializaon of our products or the development of our product candidates or having to enter into a new agreement with a diﬀerent third- party on less favorable terms than we have with our current suppliers could have a material adverse impact upon on our business. The acons of distributors and specialty pharmacies could aﬀect our ability to sell or market products proﬁtably. Fluctuaons in buying or distribuon paerns by such distributors and specialty pharmacies could adversely aﬀect our revenues, ﬁnancial condion, or results of operaons. We rely on commercial distributors and specialty pharmacies for a considerable poron of our product sales and such sales are concentrated within a small number of distributors and specialty pharmacies. The ﬁnancial failure of any of these pares could adversely aﬀect our revenues, ﬁnancial condion or results of operaons. Our revenues, ﬁnancial condion or results of operaons may also be aﬀected by ﬂuctuaons in buying or distribuon paerns of such distributors and specialty pharmacies. These ﬂuctuaons may result from seasonality, pricing, wholesaler inventory objecves, or other factors. Risks Related to Commercializaon of Our Products and Product Candidates If the market opportunies for our products and product candidates are smaller than we believe they are, our revenue may be adversely aﬀected, and our business may suﬀer. Because the target paent populaons of our products and product candidates are small, and the addressable paent populaon potenally even smaller, we must be able to successfully idenfy paents and acquire a signiﬁcant market share to achieve proﬁtability and growth. We focus our research and product development on treatments for rare and ultrarare genec diseases. Given the small number of paents who have the diseases that we are targeng, it is crical to our ability to grow and become proﬁtable that we connue to successfully idenfy paents with these rare and ultrarare genec diseases. Some of our current products or clinical programs may also be most appropriate for paents with more severe forms of their disease. For instance, while adults make up the majority of the XLH paents, they oen have less severe disease that may reduce the penetraon of Crysvita in the adult populaon relave to the pediatric populaon. Given the overall rarity of the diseases we target, it is diﬃcult to project the prevalence of the more severe forms, or the other subsets of paents that may be most suitable to address with our products and product candidates, which may further limit the addressable paent populaon to a small subset. Our projecons of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potenal to beneﬁt from treatment with our products and product candidates, are based on our beliefs and esmates. These esmates have been derived from a variety of sources, including the scienﬁc literature, surveys of clinics, paent foundaons, or market research, and may prove to be incorrect. Further, new studies may change the esmated incidence or prevalence of these diseases. The number of paents may turn out to be lower than expected. The eﬀort to idenfy paents with diseases we seek to treat is in early stages, and we cannot accurately predict the number of paents for whom treatment might be possible. Addionally, the potenally addressable paent populaon for each of our products and product candidates may be limited or may not be amenable to treatment with our products and product candidates, and new paents may become increasingly diﬃcult to idenfy or access. Further, even if we obtain signiﬁcant market share for our products and product candidates, because the potenal target populaons are very small, we may never become or remain proﬁtable nor generate suﬃcient revenue growth to sustain our business. 45 We face intense compeon and rapid technological change and the possibility that our competors may develop therapies that are similar, more advanced, or more eﬀecve than ours, which may adversely aﬀect our ﬁnancial condion and our ability to successfully commercialize our product candidates. The biotechnology and pharmaceucal industries are intensely compeve and subject to rapid and signiﬁcant technological change. We are currently aware of various exisng treatments that may compete with our products and product candidates. See “Item 1. Business – Compeon” above. We have competors both in the U.S. and internaonally, including major mulnaonal pharmaceucal companies, specialty pharmaceucal companies, biotechnology companies, startups, academic research instuons, government agencies, and public and private research instuons. Many of our competors have substanally greater ﬁnancial, technical, and other resources, such as larger research and development staﬀ and experienced markeng and manufacturing organizaons. Addional mergers and acquisions in the biotechnology and pharmaceucal industries can oen result in even more resources being concentrated in our competors. As a result, these companies may obtain regulatory approval more rapidly than we are able to and may be more eﬀecve in selling and markeng their products as well. Smaller or early-stage companies may also prove to be signiﬁcant competors, parcularly through collaborave arrangements with large, established companies. Compeon may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competors may succeed in developing, acquiring, or licensing on an exclusive basis, products that are more eﬀecve or less costly than any product candidate that we may develop, or achieve earlier patent protecon, regulatory approval, product commercializaon, and market penetraon than we do. Addionally, technologies developed by our competors may render our potenal products and product candidates uneconomical or obsolete, and we may not be successful in markeng our products and product candidates against competors. We may not be able to eﬀecvely manage the expansion of our organizaon, including building an integrated commercial organizaon. If we are unable to expand our exisng commercial infrastructure or enter into agreements with third pares to market and sell our products and product candidates, as needed, we may be unable to increase our revenue. We expect to need addional managerial, operaonal, markeng, ﬁnancial, legal, and other resources to support our development and commercializaon plans and strategies. In order to successfully commercialize our products as well as any addional products that may result from our development programs or that we acquire or license from third pares, we are expanding our commercial infrastructure in, Europe, Lan America and the Asia-Paciﬁc region. This infrastructure consists of both oﬃce-based as well as ﬁeld teams with technical experse, and will be expanded as we approach the potenal approval dates of addional products that result from our development programs. Our management may need to divert a disproporonate amount of its aenon away from our day-to-day acvies and devote a substanal amount of me to managing these growth acvies. We may not be able to eﬀecvely manage the expansion of our operaons, which may result in weaknesses in our infrastructure, operaonal mistakes, loss of business opportunies, loss of employees, and reduced producvity among remaining employees. Our expected growth could require signiﬁcant capital expenditures and may divert ﬁnancial resources from other projects, such as the development of addional product candidates. If our management is unable to eﬀecvely manage our growth, our expenses may increase more than expected, our ability to generate and/or grow revenue could be reduced, and we may not be able to implement our business strategy. Our future ﬁnancial performance and our ability to commercialize product candidates and compete eﬀecvely will depend, in part, on our ability to eﬀecvely manage any future growth. We, as a company, have limited, recent experience selling and markeng our product and only some of our employees have prior experience promong other similar products while employed at other companies. As we increase the number and range of our commercialized products, we may experience addional complexies in our sales process and strategy and may encounter diﬃcules in allocang suﬃcient resources to sales and markeng of certain products. Further, as we launch addional products or as demand for our products change, our inial esmate of the size of the required ﬁeld force may be materially more or less than the size of the ﬁeld force actually required to eﬀecvely commercialize our product candidates. As such, we may be required to hire larger teams to adequately support the commercializaon of our products and product candidates or we may incur excess costs in an eﬀort to opmize the hiring of commercial personnel. With respect to certain geographical markets, we may enter into collaboraons with other enes to ulize their local markeng and distribuon capabilies, but we may be unable to enter into such agreements on favorable terms, if at all. If our future collaborators do not commit suﬃcient resources to commercialize our future products, if any, and we are unable to develop the necessary markeng capabilies on our own, we will be unable to generate suﬃcient product sales to sustain our business. We face compeon from companies that currently have extensive and well-funded markeng and sales operaons. Without a large internal team or the support of a third party to perform key commercial funcons, we may be unable to compete successfully against these more established companies. 46 Our exclusive rights to promote Crysvita in the U.S. and Canada transioned back to KKC and the success of Crysvita in those territories are dependent on the eﬀecveness of KKC’s commercializaon eﬀorts. Pursuant to the terms of our collaboraon and license agreement with KKC, or the collaboraon agreement, we had the sole right to promote Crysvita in the U.S. and Canada, or the proﬁt-share territory, for a speciﬁed period of me, with KKC increasingly parcipang in the promoon of the product unl the transion date of April 2023. At the transion date, commercializaon responsibilies for Crysvita in the proﬁt-share territory transioned to KKC, and KKC assumed responsibility for the commercializaon of the product in the territory. Aer the transion date, the commercial success of Crysvita in the proﬁt- share territory depends on, among other things, the eﬀorts and allocaon of resources of KKC, which we do not control. Failure by KKC to successfully market and sell Crysvita in the United States could have an adverse eﬀect on our ﬁnancial results. The commercial success of any current or future product will depend upon the degree of market acceptance by physicians, paents, third-party payors, and others in the medical community. Even with the requisite approvals from the FDA and comparable foreign regulatory authories, the commercial success of our current and future products will depend in part on the medical community, paents, and payors accepng our current and future products as medically useful, cost-eﬀecve, and safe. Any product that we bring to the market may not gain market acceptance by physicians, paents, payors, and others in the medical community. The degree of market acceptance of any of our current and future products will depend on a number of factors, including: • • • • • • • • • • the eﬃcacy of the product as demonstrated in clinical studies and potenal advantages over compeng treatments; the prevalence and severity of any side eﬀects, including any limitaons or warnings contained in a product’s approved labeling; the clinical indicaons for which approval is granted; relave convenience and ease of administraon; the cost of treatment, parcularly in relaon to compeng treatments; the willingness of the target paent populaon to try new therapies and of physicians to prescribe these therapies; the eﬀecveness of our ﬁeld forces and markeng eﬀorts; the strength of markeng and distribuon support and ming of market introducon of compeve products; publicity concerning our products or compeng products and treatments; and suﬃcient third-party insurance coverage and reimbursement. Even if a potenal product displays a favorable eﬃcacy and safety proﬁle in nonclinical and clinical studies, market acceptance of the product will not be fully known unl aer it is launched. Our eﬀorts to educate the medical community and payors on the beneﬁts of the product candidates require signiﬁcant resources and may never be successful. If our current and future products fail to achieve an adequate level of acceptance by physicians, paents, payors, and others in the medical community, we will not be able to generate suﬃcient revenue to become or remain proﬁtable. 47 The insurance coverage and reimbursement status of newly approved products is uncertain. Failure to obtain or maintain adequate coverage and reimbursement for new or current products could limit our ability to market those products and decrease our ability to generate revenue. Our target paent populaons are small, and accordingly the pricing, coverage, and reimbursement of our products and product candidates, if approved, must be adequate to support our commercial infrastructure. Our per-paent prices must be suﬃcient to recover our development and manufacturing costs and potenally achieve proﬁtability. We expect the cost of a single administraon of gene therapy products, such as those we are developing, to be substanal, when and if they achieve regulatory approval. Accordingly, the availability and adequacy of coverage and reimbursement by governmental and private payors are essenal for most paents to aﬀord expensive treatments such as ours, assuming approval. Sales of our products and product candidates, if approved, will depend substanally, both domescally and abroad, on the extent to which their costs will be paid for by health maintenance, managed care, pharmacy beneﬁt, and similar healthcare management organizaons, or reimbursed by government authories, private health insurers, and other payors. If coverage and reimbursement are not available, are available only to limited levels, or are not available on a mely basis, we may not be able to successfully commercialize our products and product candidates, if approved. For example, deteriorang economic condions and polical instability in certain Lan American countries and in Turkey connue to cause us to experience signiﬁcant delays in receiving approval for reimbursement for our products and consequently impact our product commercializaon melines in such regions. Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing suﬃcient to sustain our overall enterprise. In addion, we do not know the reimbursement rates unl we are ready to market the product and we actually negoate the rates. There is signiﬁcant uncertainty related to the insurance coverage and reimbursement of newly approved products. In the U.S., the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S. Department of Health and Human Services, decides whether and to what extent a new drug will be covered and reimbursed under Medicare. Private payors tend to follow the coverage reimbursement policies established by CMS to a substanal degree. It is diﬃcult to predict what CMS or private payors will decide with respect to reimbursement for products such as ours, especially our gene therapy product candidates as there is a limited body of established pracces and precedents for gene therapy products. Outside the U.S., internaonal operaons are generally subject to extensive governmental price controls and other market regulaons, and we believe the increasing emphasis on cost-containment iniaves in Europe, Canada, and other countries will put pressure on the pricing and usage of our products and product candidates. In many countries, the prices of medical products are subject to varying price control mechanisms as part of naonal health systems. Other countries allow companies to ﬁx their own prices for medicinal products, but monitor and control company proﬁts. Addional foreign price controls or other changes in pricing regulaon could restrict the amount that we are able to charge for our product candidates. Accordingly, in markets outside the U.S., the reimbursement for our products may be reduced compared with the U.S. and may be insuﬃcient to generate commercially reasonable revenue and proﬁts. The ming to complete the negoaon process in each country is highly uncertain, and in some countries outside of the United States, we expect the process to exceed several months. Even if a price can be negoated, countries frequently request or require reducons to the price and other concessions over me, including retrospecve “clawback” price reducons. Addionally, member states of the EU have regularly imposed new or addional cost containment measures for pharmaceucals such as volume discounts, cost caps, clawbacks and free products for a poron of the expected therapy period. For example, in France, we esmate clawback reserves on Dojolvi based on current regulaons, our esmate of pricing on approval of Dojolvi and other factors. However, if pricing is approved at levels lower than esmated, if at all, or if there are further changes in the regulatory framework, we may be required to pay back amounts higher than clawback reserves and reverse revenue that has been previously recorded. Moreover, increasing eﬀorts by governmental and third-party payors in the U.S. and abroad to cap or reduce healthcare costs may cause such organizaons to limit both coverage and the level of reimbursement for new products and, as a result, they may not cover or provide adequate payment for our products and product candidates. We expect to experience pricing pressures in connecon with the sale of any of our products and product candidates due to the trend toward managed healthcare, the increasing inﬂuence of health maintenance organizaons, addional legislave changes, including the impact from the Inﬂaon Reducon Act of 2022, and statements by elected oﬃcials. For example, proposals have been discussed to e U.S. drug prices to the cost in other countries, several states in the U.S. have introduced legislaon to require pharmaceucal companies to disclose their costs to jusfy the prices of their products. Drug pricing is also expected to remain a focus for the current Presidenal Administraon and Congress. The downward pressure on healthcare costs in general, and with respect to prescripon drugs, surgical procedures, and other treatments in parcular, has become very intense. As a result, increasingly high barriers are being erected to the entry of new products. 48 Risks Related to Our Intellectual Property If we are unable to obtain and maintain eﬀecve patent rights for our products, product candidates, or any future product candidates, we may not be able to compete eﬀecvely in our markets. We rely upon a combinaon of patents, trade secret protecon, and conﬁdenality agreements to protect the intellectual property related to our technologies, our products, and our product candidates. Our success depends in large part on our and our licensors’ ability to obtain and maintain patent and other intellectual property protecon in the U.S. and in other countries with respect to our proprietary technologies, our products, and our product candidates. We have sought to protect our proprietary posion by ﬁling patent applicaons in the U.S. and abroad related to our novel technologies, products and product candidates that are important to our business. This process is expensive and me consuming, and we may not be able to ﬁle and prosecute all necessary or desirable patent applicaons at a reasonable cost or in a mely manner. It is also possible that we will fail to idenfy patentable aspects of our research and development output before it is too late to obtain patent protecon. The patent posion of biotechnology and pharmaceucal companies generally is highly uncertain and involves complex legal and factual quesons for which legal principles remain unseled. The patent applicaons that we own or in-license may fail to result in issued patents with claims that cover our products or product candidates in the U.S. or in foreign countries. There is no assurance that all potenally relevant prior art relang to our patents and patent applicaons has been found, which can prevent a patent from issuing from a pending patent applicaon or provide the basis for third pares to challenge the validity of an issued patent. Third pares may challenge the validity, enforceability, or scope of any issued patents, which may result in such patents being narrowed, found unenforceable, or invalidated. Furthermore, even if the patents and patent applicaons we own or in-license are unchallenged, they may not adequately protect our intellectual property, provide exclusivity for our products or product candidates, or prevent others from designing around our claims. Any of these outcomes could impair our ability to prevent compeon from third pares. We, independently or together with our licensors, have ﬁled several patent applicaons covering various aspects of our products or product candidates. We cannot oﬀer any assurances about which, if any, patents will issue, the breadth of any such patent, or whether any issued patents will be found invalid and unenforceable or will be threatened by third pares. Any successful opposion to these patents could impair the exclusivity posion of our products or deprive us of rights necessary for the successful commercializaon of any product candidates that are approved. Further, if we encounter delays in regulatory approvals, the period of me during which we could market a product candidate under patent protecon could be reduced. Our current patents or applicaons covering methods of use and certain composions of maer do not provide complete patent protecon for our products and product candidates in all territories. For example, there are no issued patents covering the Crysvita composion of maer in Lan America, where we have rights to commercialize this product. Therefore, a competor could develop the same anbody or a similar anbody as well as other approaches that target FGF23 for potenal commercializaon in Lan America, subject to any intellectual property rights or regulatory exclusivies awarded to us. If we cannot obtain and maintain eﬀecve patent rights for our products or product candidates, we may not be able to compete eﬀecvely and our business and results of operaons would be harmed. We may not have suﬃcient patent terms to eﬀecvely protect our products and business. Patents have a limited lifespan. In the U.S., the natural expiraon of a patent is generally 20 years from its earliest non-provisional ﬁling date. Although various extensions may be available, the life of a patent, and the protecon it aﬀords, is limited. Even if patents covering our products or product candidates are obtained, once the patent life has expired for a product, we may be open to compeon from generic or biosimilar medicaons. Patent term extensions under the Hatch-Waxman Act in the U.S. and under supplementary protecon cerﬁcates in Europe may not be available to extend the patent exclusivity term for our products and product candidates, and we cannot provide any assurances that any such patent term extension will be obtained and, if so, for how long. Furthermore, we may not receive an extension if we fail to apply within applicable deadlines, fail to apply prior to expiraon of relevant patents, or otherwise fail to sasfy applicable requirements. Moreover, the length of the extension could be less than we request. If we do not have suﬃcient patent terms or regulatory exclusivity to protect our products, our business and results of operaons may be adversely aﬀected. 49 Patent law and rule changes could increase the uncertaines and costs surrounding the prosecuon of our patent applicaons and the enforcement or defense of our issued patents. Changes in either the patent laws or interpretaon of the patent laws in the U.S. and other countries may diminish the value of our patents or narrow the scope of our patent protecon. The laws of foreign countries may not protect our rights to the same extent as the laws of the U.S. Publicaons of discoveries in the scienﬁc literature oen lag behind the actual discoveries, and patent applicaons in the U.S. and other jurisdicons are typically not published unl 18 months aer ﬁling, or in some cases not at all. We therefore cannot be certain that we or our licensors were the ﬁrst to make the invenon claimed in our owned and in-licensed patents or pending applicaons, or that we or our licensor were the ﬁrst to ﬁle for patent protecon of such invenons. In 2011, the Leahy-Smith America Invents Act, or the Leahy-Smith Act, was signed into law and introduced signiﬁcant changes to the prosecuon of U.S. patent applicaons and to the procedures for challenging U.S. patents. The eﬀects of these changes sll remain unclear owing to the evolving nature of the law and the lengthy melines associated with court system review and interpretaon. However, the Leahy-Smith Act and its implementaon could increase the uncertaines and costs surrounding the prosecuon of our patent applicaons and the enforcement or defense of our issued patents, all of which could have a material adverse eﬀect on our business and ﬁnancial condion. Outside the U.S., there have been changes to patent laws in certain jurisdicons that could impair our ability to obtain, maintain, or enforce our patents in those territories. For instance, Europe’s new Unitary Patent system and Uniﬁed Patent Court (the “UPC”) may present uncertaines for our ability to protect and enforce our patent rights against competors in Europe. In 2012, as part of the European Patent Package (the “EU Patent Package”), regulaons were passed with the goal of providing a single pan-European Unitary Patent system and a new UPC, for ligaon involving European patents. Implementaon of the EU Patent Package occurred in June 2023. Under the UPC, all European patents, including those issued prior to raﬁcaon of the European Patent Package, will by default automacally fall under the jurisdicon of the UPC. The UPC will provide our competors with a new forum in which to seek central revocaon of our European patents and allow for the possibility of a competor to obtain pan-European injuncons. It will be several years before we will understand the scope of patent rights that will be recognized and the strength of patent remedies that will be provided by the UPC. Under the EU Patent Package, we will have the right to opt our patents out of the UPC over the ﬁrst seven years of the court’s existence, but doing so may preclude us from realizing the beneﬁts of the new uniﬁed court. If we are unable to maintain eﬀecve proprietary rights for our products, product candidates, or any future product candidates, we may not be able to compete eﬀecvely in our markets. In addion to the protecon aﬀorded by patents, we rely on trade secret protecon and conﬁdenality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are diﬃcult to enforce and any other elements of our products or product candidate discovery and development processes that involve proprietary know-how, informaon, or technology that is not covered by patents. However, trade secrets can be diﬃcult to protect. The conﬁdenality agreements entered into with our employees, consultants, scienﬁc advisors, contractors and other third pares that we rely on in connecon with the development, manufacture and commercializaon of our products may not be suﬃcient to protect our proprietary technology and processes, which increase the risk that such trade secrets may become known by our competors or may be inadvertently incorporated into the technology of others. The physical security of our premises and physical and electronic security of our informaon technology systems may not preserve the integrity and conﬁdenality of our data and trade secrets. These individuals, organizaons and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addion, our trade secrets may otherwise become known or be independently discovered by competors. The assignment agreements we enter into with our employees and consultants to assign their invenons to us, and the conﬁdenality agreements we enter into with our employees, consultants, advisors, and any third pares who have access to our proprietary know-how, informaon, or technology may not have been duly executed and we cannot assure that our trade secrets and other conﬁdenal proprietary informaon will not be disclosed or that competors will not otherwise gain access to our trade secrets or independently develop substanally equivalent informaon and techniques. Misappropriaon or unauthorized disclosure of our trade secrets could impair our compeve posion and may have a material adverse eﬀect on our business. Addionally, if the steps taken to maintain our trade secrets are deemed inadequate, we may have insuﬃcient recourse against third pares for misappropriang the trade secret. 50 Claims of intellectual property infringement may prevent or delay our development and commercializaon eﬀorts. Our commercial success depends in part on our avoiding infringement of the patents and proprietary rights of others. There have been many lawsuits and other proceedings involving patent and other intellectual property rights in the biotechnology and pharmaceucal industries, including patent infringement lawsuits, interferences, inter partes reviews, post grant reviews, opposions, and reexaminaon proceedings before the USPTO and corresponding foreign patent oﬃces. Numerous U.S. and foreign issued patents and pending patent applicaons, which are owned by other pares, exist in the ﬁelds in which we are developing product candidates. As the biotechnology and pharmaceucal industries expand and more patents are issued, the risk increases that our products or product candidates may be subject to claims of infringement of the patent rights of these other pares. Other pares may assert that we are employing their proprietary technology without authorizaon. There may be patents or patent applicaons with claims to materials, formulaons, methods of manufacture, or methods for treatment relevant to the use or manufacture of our products or product candidates. We have conducted freedom to operate analyses with respect only to our products and certain of our product candidates, and therefore we do not know whether there are any patents of other pares that would impair our ability to commercialize all of our product candidates. We also cannot guarantee that any of our analyses are complete and thorough, nor can we be sure that we have idenﬁed each and every patent and pending applicaon in the U.S. and abroad that is relevant or necessary to the commercializaon of our products or product candidates. Because patent applicaons can take many years to issue, there may be currently pending patent applicaons that may later result in issued patents that are relevant to our products or product candidates. We are aware of certain U.S. and foreign patents owned by third pares that a court might construe to be valid and relevant to one or more of our gene therapy product candidates, certain methods that may be used in their manufacture or delivery, or certain formulaons comprising one or more of our gene therapy candidates. Regarding our an-sclerosn anbody product candidate, setrusumab, we are aware of ligaon involving patents owned by a third-party, OssiFi-Mab LLC (OMab), relang to methods of using sclerosn antagonists in combinaon with anresorpve drugs to increase bone growth, bone formaon, and/or bone density. Speciﬁcally, in the U.S., OMab has asserted certain patents expiring in 2027 or 2028 against Amgen based on Amgen’s commercializaon of an an-sclerosn anbody, Evenity®, for the treatment of osteoporosis in postmenopausal women at high risk for fracture; Amgen denies infringement and asserts the OMab patents are invalid. In Europe, OMab was granted two patents with related subject maer; the ﬁrst patent has been revoked while the second has been opposed by Amgen, UCB, and two anonymous pares. There is a risk that one or more third pares may choose to engage in ligaon with us to enforce or to otherwise assert their patent rights against us. Even if we believe such claims are without merit, a court of competent jurisdicon could hold that one or more of these patents is valid, enforceable, and infringed, in which case the owners of any such patents may be able to block our ability to commercialize a product candidate unless we obtain a license under the applicable patents, or unl such patents expire. However, such a license may not be available on commercially reasonable terms or at all. Pares making claims against us may obtain injuncve or other equitable relief, which could eﬀecvely block our ability to connue commercializaon of our products, or block our ability to develop and commercialize one or more of our product candidates. Defense of these claims, regardless of their merit, would involve substanal ligaon expense and would be a substanal diversion of employee resources from our business. In the event of a successful claim of infringement against us, we may have to pay substanal damages, including treble damages and aorneys’ fees for willful infringement, pay royales, redesign our infringing products, or obtain one or more licenses from third pares, which may be impossible or require substanal me and monetary expenditure. We may not be successful in obtaining or maintaining necessary rights to our product candidates through acquisions and in-licenses. Because our programs may require the use of proprietary rights held by third pares, the growth of our business will likely depend in part on our ability to acquire, in-license, or use these proprietary rights. We may be unable to acquire or in-license any composions, methods of use, processes, or other third-party intellectual property rights from third pares that we idenfy as necessary for our product candidates. The licensing and acquision of third-party intellectual property rights is a compeve area, and a number of more established companies are also pursuing strategies to license or acquire third-party intellectual property rights that we may consider aracve. These established companies may have a compeve advantage over us due to their size, cash resources, and greater clinical development and commercializaon capabilies. In addion, companies that perceive us to be a competor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third-party intellectual property rights on terms that would allow us to make an appropriate return on our investment. 51 We somemes collaborate with U.S. and foreign academic instuons to accelerate our preclinical research or development under wrien agreements with these instuons. Typically, these instuons provide us an opon to negoate a license to any of the instuon’s rights in technology resulng from the collaboraon. Regardless of such opon, we may be unable to negoate a license within the speciﬁed meframe or under terms that are acceptable to us. If we are unable to do so, the instuon may oﬀer the intellectual property rights to other pares, potenally blocking our ability to pursue our program. If we are unable to successfully obtain rights to required third-party intellectual property rights or maintain the exisng intellectual property rights we have, we may have to abandon development of the corresponding program. We may face compeon from biosimilars, which may have a material adverse impact on the future commercial prospects of our biological products and product candidates. Even if we are successful in achieving regulatory approval to commercialize a product candidate faster than our competors, we may face compeon from biosimilars with respect to our biological products (Crysvita, Mepsevii and Evkeeza) and our biological product candidates. In the U.S., the Biologics Price Compeon and Innovaon Act of 2009, or BPCI Act, was included in the Aﬀordable Care Act and created an abbreviated approval pathway for biological products that are demonstrated to be “highly similar,” or biosimilar, to or “interchangeable” with an FDA-approved biological product. The BPCI Act prohibits the FDA from approving a biosimilar or interchangeable product that references a brand biological product unl 12 years aer the licensure of the reference product, but permits submission of an applicaon for a biosimilar or interchangeable product to the FDA four years aer the reference product was ﬁrst licensed. The BPCI Act does not prevent another company from developing a product that is highly similar to the innovave product, generang its own data, and seeking approval. The law is complex and is sll being interpreted and implemented by the FDA. Moreover, aspects of the law are sll being evaluated and interpreted by courts. As a result, its ulmate impact, implementaon and meaning are subject to uncertainty. Modiﬁcaon of the BPCI Act, or changes to the interpretaon or implementaon of the BPCI Act, could have a material adverse eﬀect on the future commercial prospects for our biological products and product candidates. In Europe, the European Commission has granted markeng authorizaons for several biosimilars pursuant to a set of general and product class- speciﬁc guidelines for biosimilar approvals issued over the past few years. In Europe, a competor may reference data supporng approval of an innovave biological product, but will not be able to get on the market unl 10 years aer the me of approval of the innovave product. This 10-year markeng exclusivity period will be extended to 11 years if, during the ﬁrst eight of those 10 years, the markeng authorizaon holder obtains an approval for one or more new therapeuc indicaons that bring signiﬁcant clinical beneﬁts compared with exisng therapies. In addion, companies may be developing biosimilars in other countries that could compete with our products. If competors are able to obtain markeng approval for biosimilars referencing our products, our products may become subject to compeon from such biosimilars, with the aendant compeve pressure and consequences. Competors could enter the market with generic versions of Dojolvi or our small-molecule product candidates, which may result in a material decline in sales of aﬀected products. Under the Hatch-Waxman Act, a pharmaceucal manufacturer may ﬁle an abbreviated new drug applicaon, or ANDA, seeking approval of a generic copy of an approved innovator product. Under the Hatch-Waxman Act, a manufacturer may also submit an NDA under secon 505(b)(2) that references the FDA’s ﬁnding of safety and eﬀecveness of a previously approved drug. A 505(b)(2) NDA product may be for a new or improved version of the original innovator product. Innovave small molecule drugs may be eligible for certain periods of regulatory exclusivity (e.g., ﬁve years for new chemical enes, three years for changes to an approved drug requiring a new clinical study, and seven years for orphan drugs), which preclude FDA approval (or in some circumstances, FDA ﬁling and review of) an ANDA or 505(b)(2) NDA relying on the FDA’s ﬁnding of safety and eﬀecveness for the innovave drug. In addion to the beneﬁts of regulatory exclusivity, an innovator NDA holder may have patents claiming the acve ingredient, product formulaon or an approved use of the drug, which would be listed with the product in the “Orange Book.” If there are patents listed in the Orange Book, a generic applicant that seeks to market its product before expiraon of the patents must include in the ANDA or 505(b)(2) what is known as a “Paragraph IV cerﬁcaon,” challenging the validity or enforceability of, or claiming non-infringement of, the listed patent or patents. Noce of the cerﬁcaon must be given to the innovator, too, and if within 45 days of receiving noce the innovator sues to enforce its patents, approval of the ANDA is stayed for 30 months, or as lengthened or shortened by the court. Accordingly, competors could ﬁle ANDAs for generic versions of our small-molecule product, Dojolvi, or 505(b)(2) NDAs that reference Dojolvi. For the patents listed for Dojolvi in the Orange Book, those ANDAs and 505(b)(2) NDAs would be required to include a cerﬁcaon as to each listed patent indicang whether the ANDA applicant does or does not intend to challenge the patent. We cannot predict how any generic competor would address such patents, whether we would sue on any such patents, or the outcome of any such suit. 52 There have been a number of recent regulatory and legislave iniaves designed to encourage generic compeon for small-molecule pharmaceucal products. For instance, in December 2019, the Creang and Restoring Equal Access to Equivalent Samples Act, or the CREATES Act, was enacted, which provides a legislavely deﬁned private right of acon under which eligible product developers can bring suit against companies who refuse to sell suﬃcient quanes of their branded products on commercially reasonable, market-based terms to support such eligible product developers’ markeng applicaons. It is our policy to evaluate requests for samples of our branded products, and to provide samples in response to bona ﬁde, CREATES Act- compliant requests from qualiﬁed third pares, including generic manufacturers. We have received requests for samples of Dojolvi, and when appropriate, we have sold samples of Dojolvi to eligible product developers in compliance with the requirements of the CREATES Act. We may not be successful in securing or maintaining proprietary patent protecon for products and technologies we develop or license. Moreover, if any patents that are granted and listed in the Orange Book are successfully challenged by way of a Paragraph IV cerﬁcaon and subsequent ligaon, the aﬀected product could more immediately face generic compeon and its sales would likely decline materially. For instance, if competors develop generic version of Dojolvi and are able to enter the market, our sales of Dojolvi could materially decline which could have an adverse impact on our ﬁnancial results. The patent protecon and patent prosecuon for some of our products and product candidates is dependent on third pares. While we normally seek and gain the right to fully prosecute the patents relang to our products or product candidates, there may be mes when patents relang to our products or product candidates are controlled by our licensors. This is the case with our license agreements with KKC and Regeneron, who are primarily responsible for the prosecuon of certain patents and patent applicaons covering Crysvita and Evkeeza, respecvely. In addion, we have in-licensed various patents and patent applicaons owned by the University of Pennsylvania relang to our DTX301, DTX401 and/or UX701 product candidates. Some of these patents and patent applicaons are licensed or sublicensed by REGENX and sublicensed to us. We do not have the right to control the prosecuon of these patent applicaons, or the maintenance of any of these patents. In addion, under our agreement with REGENX, we do not have the ﬁrst right to enforce the licensed patents, and our enforcement rights are subject to certain limitaons that may adversely impact our ability to use the licensed patents to exclude others from commercializing compeve products. Moreover, REGENX and the University of Pennsylvania may have interests which diﬀer from ours in determining whether to enforce and the manner in which to enforce such patents. If KKC, Regeneron, the University of Pennsylvania, REGENX, or any of our future licensing partners fail to appropriately prosecute, maintain, and enforce patent protecon for the patents covering any of our products or product candidates, our ability to develop and commercialize those products or product candidates may be adversely aﬀected and we may not be able to prevent competors from making, using, and selling compeng products. In addion, even where we now have the right to control patent prosecuon of patents and patent applicaons we have licensed from third pares, we may sll be adversely aﬀected or prejudiced by acons or inacons of our licensors and their counsel that took place prior to us assuming control over patent prosecuon. If we fail to comply with our obligaons in the agreements under which we license intellectual property and other rights from third pares or otherwise experience disrupons to our business relaonships with our licensors, we could lose license rights that are important to our business. We are a party to a number of intellectual property license agreements that are important to our business and expect to enter into addional license agreements in the future. Our exisng license agreements impose, and we expect that future license agreements will impose, various diligence, milestone payment, royalty, and other obligaons on us. If we fail to comply with our obligaons under these agreements, or we are subject to a bankruptcy, we may be required to make certain payments to the licensor, we may lose the exclusivity of our license, or the licensor may have the right to terminate the license, in which event we would not be able to develop or market products covered by the license. Addionally, the milestone and other payments associated with these licenses will make it less proﬁtable for us to develop our product candidates. In certain cases, we control the prosecuon of patents resulng from licensed technology. In the event we breach any of our obligaons related to such prosecuon, we may incur signiﬁcant liability to our licensing partners. Licensing of intellectual property is of crical importance to our business and involves complex legal, business, and scienﬁc issues. Disputes may arise regarding intellectual property subject to a licensing agreement, including but not limited to: • • • the scope of rights granted under the license agreement and other interpretaon-related issues; the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement; the sublicensing of patent and other rights; 53 • • • our diligence obligaons under the license agreement and what acvies sasfy those diligence obligaons; the ownership of invenons and know-how resulng from the joint creaon or use of intellectual property by our licensors and us and our collaborators; and the priority of invenon of patented technology. If disputes over intellectual property and other rights that we have licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the aﬀected product candidates. We may become involved in lawsuits to protect or enforce our patents or the patents of our licensors, or be subject to claims that challenge the inventorship or ownership of our patents or other intellectual property, which could be expensive, me consuming, and result in unfavorable outcomes. Competors may infringe our patents or the patents of our licensors. If we or one of our licensing partners were to iniate legal proceedings against a third party to enforce a patent covering our products or one of our product candidates, the defendant could counterclaim that the patent covering our product or product candidate is invalid and/or unenforceable. In patent ligaon in the U.S., defendant counterclaims alleging invalidity and/or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness, or non-enablement. Grounds for an unenforceability asseron could be an allegaon that someone connected with prosecuon of the patent withheld relevant informaon from the USPTO, or made a misleading statement, during prosecuon. The outcome following legal asserons of invalidity and unenforceability is unpredictable. Interference proceedings or derivaon proceedings now available under the Leahy-Smith Act provoked by third pares or brought by us or declared or instuted by the USPTO may be necessary to determine the priority of invenons with respect to our patents or patent applicaons or those of our licensors. An unfavorable outcome could require us to cease using the related technology or to aempt to license rights to it from the prevailing party. Our business could be harmed if the prevailing party does not oﬀer us a license on commercially reasonable terms. In addion, the validity of our patents could be challenged in the USPTO by one of the new post grant proceedings (i.e., inter partes review or post grant review) now available under the Leahy-Smith Act. Our defense of ligaon, interference proceedings, or post grant proceedings under the Leahy-Smith Act may fail and, even if successful, may result in substanal costs and distract our management and other employees. We may in the future also be subject to claims that former employees, collaborators, or other third pares have an interest in our patents as an inventor or co-inventor. In addion, we may have ownership disputes arise from conﬂicng obligaons of consultants or others who are involved in developing our product candidates. Ligaon may be necessary to defend against these and other claims challenging inventorship or ownership. If we fail to successfully defend against such ligaon or claims, in addion to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Even if we are successful in defending against such ligaon and claims, such proceedings could result in substanal costs and distract our management and other employees. Because of the substanal amount of discovery required in connecon with intellectual property ligaon, there is a risk that some of our conﬁdenal informaon could be compromised by disclosure during ligaon. There could also be public announcements of the results of hearings, moons, or other interim proceedings or developments related to such ligaon or claims. If securies analysts or investors perceive these results to be negave, it could have a material adverse eﬀect on the price of our common stock. We may be subject to claims that our employees, consultants, or independent contractors have wrongfully used or disclosed conﬁdenal informaon of third pares or that our employees have wrongfully used or disclosed alleged trade secrets of their former employers. We employ certain individuals who were previously employed at universies or other biotechnology or pharmaceucal companies, including our competors or potenal competors. Our eﬀorts to vet our employees, consultants, and independent contractors and prevent their use of the proprietary informaon or know-how of others in their work for us may not be successful, and we may in the future be subject to claims that our employees, consultants, or independent contractors have wrongfully used or disclosed conﬁdenal informaon of third pares. If we fail in defending any such claims, in addion to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could adversely impact our business. Even if we are successful in defending against such claims, ligaon could result in substanal costs and distract management and other employees. 54 Changes to patent laws in the U.S. and other jurisdicons could diminish the value of patents in general, thereby impairing our ability to protect our products. As is the case with other biotechnology and pharmaceucal companies, our success is heavily dependent on intellectual property, parcularly patents. Obtaining and enforcing patents in the biotechnology and pharmaceucal industries involves both technological and legal complexity. Therefore, obtaining and enforcing such patents is costly, me consuming, and inherently uncertain. In recent years, the U.S. Supreme Court has ruled on several patent cases, and in some instances, narrowed the scope of patent protecon available. In addion, there have been recent proposals for changes to U.S. laws that, if adopted, could impact our ability to obtain or maintain patent protecon for our proprietary technologies. Depending on future acons by U.S. courts, U.S. Congress, the USPTO, and the relevant law making bodies in other countries, the laws and regulaons governing patents could change in unpredictable ways that could weaken our ability to obtain new patents, shorten the term of our exisng patents and patents that we might obtain in the future, or impair the validity or enforceability of our patents that may be asserted against our competors or other third pares. Any of these outcomes could have a material adverse eﬀect on our business. For example, with respect to patent term adjustment (PTA), the Federal Circuit’s recent holding in In re Cellect, LLC, 81 F.4th 1216 (Fed. Cir. 2023), that the obviousness-type double patenng analysis for a patent that has received PTA must be based on the expiraon date of the patent aer the PTA has been added, may negavely impact the validity and/or term of certain of our owned or in-licensed U.S. patents. We may not be able to protect our intellectual property rights throughout the world. Filing, prosecung, and defending patents on our products or product candidates in all countries throughout the world would be prohibively expensive, and our intellectual property rights in some countries outside the U.S. can be less extensive than those in the U.S. In addion, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the U.S. Further, licensing partners such as KKC and Regeneron may not prosecute patents in certain jurisdicons in which we may obtain commercial rights, thereby precluding the possibility of later obtaining patent protecon in these countries. Consequently, we may not be able to prevent third pares from praccing our invenons in all countries outside the U.S., or from selling or imporng products made using our invenons in and into the U.S. or other jurisdicons. Competors may use our technologies in jurisdicons where we have not obtained patent protecon to develop their own products and may also export infringing products to territories where we have patent protecon, but enforcement is not as strong as that in the U.S. These products may compete with our products, and our patents or other intellectual property rights may not be eﬀecve or suﬃcient to prevent them from compeng. Many companies have encountered signiﬁcant problems in protecng and defending intellectual property rights in foreign jurisdicons. The legal systems of certain countries, parcularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protecon, parcularly those relang to biotechnology products, which could make it diﬃcult for us to stop the infringement of our patents or markeng of compeng products in violaon of our proprietary rights generally. Proceedings to enforce our patent rights in foreign jurisdicons, whether or not successful, could result in substanal costs and divert our eﬀorts and aenon from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applicaons at risk of not issuing, and could provoke third pares to assert claims against us. We may not prevail in any lawsuits that we iniate and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our eﬀorts to enforce our intellectual property rights around the world may be inadequate to obtain a signiﬁcant commercial advantage from the intellectual property that we develop or license. Risks Related to Our Business Operaons We have limited experience as a company operang our own manufacturing facility and may experience unexpected costs or challenges. We completed construcon of our gene therapy manufacturing facility in Bedford, Massachuses in 2023. Prior to construcon of this facility, we did not previously have experience as a company in operang our own manufacturing facility and at this point, we cannot assure that the facility will be fully ulized at all mes, parcularly as we have only recently commenced our manufacturing operaons. Our limited experience may contribute to unacceptable or inconsistent product quality success rates and yields, and we may be unable to maintain adequate quality control, quality assurance, and qualiﬁed personnel. We have incurred and will connue to incur signiﬁcant expenses and costs to operate the facility, which may be subject to signiﬁcant impairment if our gene therapy programs are unsuccessful. Before we can begin to commercially manufacture any of our product candidates at the facility, we must obtain regulatory approval from the FDA for our manufacturing processes and for the facility. In order to obtain approval, we will need to ensure that all of our processes, quality systems, methods, equipment, policies and procedures are 55 compliant with cGMP. Unl recently, few gene therapy products manufactured by a cGMP gene therapy manufacturing facility in the U.S. had received approval from the FDA; therefore, the me frame required for us to obtain such approval is uncertain. The cGMP requirements govern quality control of the manufacturing process and documentaon policies and procedures. In complying with cGMP, we will be obligated to spend me, money and eﬀort on producon, record keeping and quality control to assure that the product meets applicable speciﬁcaons and other requirements. If we fail to comply with these requirements, we would be subject to possible regulatory acon and may not be permied to sell any products that we may develop. As we seek to opmize and operate our manufacturing process at the facility, we will likely face technical and scienﬁc challenges, considerable capital costs and potenal diﬃculty in recruing and hiring experienced, qualiﬁed personnel at the facility which could result in delays in our producon or diﬃcules in maintaining compliance with applicable regulatory requirements. We may also experience unexpected technical, regulatory, safety, quality or operaonal issues during manufacturing campaigns. As we expand our commercial footprint to mulple geographies, we may establish mulple manufacturing facilies, which may lead to regulatory delays or prove costly. Even if we are successful, we cannot assure that such addional capacity will be required or that our investment will be recouped. Further, our manufacturing capabilies could be aﬀected by cost-overruns, unexpected delays, equipment failures, lack of capacity, labor shortages, natural disasters, power failures, program failures, actual or threatened public health emergencies, and numerous other factors that could prevent us from realizing the intended beneﬁts of our manufacturing strategy. Our future success depends in part on our ability to retain our Founder, President, and Chief Execuve Oﬃcer and to aract, retain, and movate other qualiﬁed personnel. We are dependent on Emil D. Kakkis, M.D., Ph.D., our Founder, President, and Chief Execuve Oﬃcer, the loss of whose services may adversely impact the achievement of our objecves. Dr. Kakkis could leave our employment at any me, as he is an “at will” employee. Recruing and retaining other qualiﬁed employees, consultants, and advisors for our business, including scienﬁc and technical personnel, will also be crical to our success. There is currently a shortage of skilled personnel in our industry, which is likely to connue. As a result, compeon for skilled personnel is intense and the turnover rate can be high. In addion, failure to succeed in preclinical or clinical studies may make it more challenging to recruit and retain qualiﬁed personnel. Over the last several years, we have also experienced certain execuve leadership changes. Leadership transions are inherently diﬃcult to manage, cause uncertainty and disrupon and could increase the likelihood of turnover of other key oﬃcers and employees. The inability to recruit and retain qualiﬁed personnel, or the loss of the services of Dr. Kakkis or any of other member of our execuve leadership team or other key employee, may impede the progress of our research, development, and commercializaon objecves. If we fail to obtain or maintain orphan drug exclusivity for our products, our competors may sell products to treat the same condions and our revenue will be reduced. Our business strategy focuses on the development of drugs that are eligible for FDA and EU orphan drug designaon. In the U.S., orphan drug designaon entles a party to ﬁnancial incenves such as opportunies for grant funding towards clinical study costs, tax advantages, and user-fee waivers. In addion, if a product receives the ﬁrst FDA approval for the indicaon for which it has orphan designaon, the product is entled to orphan drug exclusivity, which means the FDA may not approve any other applicaon to market the same drug for the same indicaon for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity or where the manufacturer is unable to assure suﬃcient product quanty. In the EU, orphan drug designaon entles a party to ﬁnancial incenves such as reducon of fees or fee waivers and ten years of market exclusivity following drug or biological product approval. This period may be reduced to six years if the orphan drug designaon criteria are no longer met, including where it is shown that the product is suﬃciently proﬁtable not to jusfy maintenance of market exclusivity. Because the extent and scope of patent protecon for our products may in some cases be limited, orphan drug designaon is especially important for our products for which orphan drug designaon may be available. For eligible drugs, we plan to rely on the exclusivity period under the Orphan Drug Act to maintain a compeve posion. If we do not obtain orphan drug exclusivity for our drug products and biologic products that do not have broad patent protecon, our competors may then sell the same drug to treat the same condion sooner than if we had obtained orphan drug exclusivity, and our revenue will be reduced. 56 Even though we have orphan drug designaon for UX111, UX143, DTX301, DTX401 and UX701 in the U.S. and Europe and for GTX 102 in the U.S., we may not be the ﬁrst to obtain markeng approval for any parcular orphan indicaon due to the uncertaines associated with developing pharmaceucal products. Further, even if we obtain orphan drug exclusivity for a product, that exclusivity may not eﬀecvely protect the product from compeon because diﬀerent drugs with diﬀerent acve moiees can be approved for the same condion or the same drug can be approved for a diﬀerent indicaon unless there are other exclusivies such as new chemical enty exclusivity prevenng such approval. Even aer an orphan drug is approved, the FDA or EMA can subsequently approve the same drug with the same acve moiety for the same condion if the FDA or EMA concludes that the later drug is safer, more eﬀecve, or makes a major contribuon to paent care. Orphan drug designaon neither shortens the development me or regulatory review me of a drug nor gives the drug any advantage in the regulatory review or approval process. Our operang results would be adversely impacted if our intangible assets become impaired. We have recorded on our Consolidated Balance Sheets intangible assets for in-process research and development, or IPR&D, related to DTX301 and DTX401 as a result of the accounng for our acquision of Dimension Therapeucs. We also recorded an intangible asset related to our license from Regeneron for Evkeeza. We test the intangible assets for impairment annually during the fourth quarter and more frequently if events or changes in circumstances indicate that it is more likely than not that the asset is impaired. If the associated research and development eﬀort is abandoned, the related assets will be wrien-oﬀ and we will record a noncash impairment loss on our Consolidated Statement of Operaons. We have not recorded any impairments related to our intangible assets through December 31, 2023. We may not be successful in our eﬀorts to idenfy, license, discover, develop, or commercialize addional product candidates. The success of our business depends upon our ability to idenfy, license, discover, develop, or commercialize addional product candidates in addion to the connued clinical tesng, potenal approval, and commercializaon of our exisng product candidates. Research programs to idenfy and develop new product candidates require substanal technical, ﬁnancial, and human resources. We may focus our eﬀorts and resources on potenal programs or product candidates that ulmately prove to be unsuccessful. Our research programs or licensing eﬀorts may fail to yield addional product candidates for clinical development and commercializaon for a number of reasons, including but not limited to the following: • • • • • • • • • • our research or business development methodology or search criteria and process may be unsuccessful in idenfying potenal product candidates; we may not be able or willing to assemble suﬃcient technical, ﬁnancial or human resources to acquire or discover addional product candidates; we may face compeon in obtaining and/or developing addional product candidates; our product candidates may not succeed in research, discovery, preclinical or clinical tesng; our potenal product candidates may be shown to have harmful side eﬀects or may have other characteriscs that may make the products unmarketable or unlikely to receive markeng approval; competors may develop alternaves that render our product candidates obsolete or less aracve; product candidates we develop may be covered by third pares’ patents or other exclusive rights; the market for a product candidate may change during our program so that such a product may become unreasonable to connue to develop; a product candidate may not be capable of being produced in commercial quanes at an acceptable cost or at all; and a product candidate may not be accepted as safe and eﬀecve by regulatory authories, paents, the medical community, or payors. If any of these events occur, we may be forced to abandon our development eﬀorts for a program or programs, or we may not be able to idenfy, license, discover, develop, or commercialize addional product candidates, which would have a material adverse eﬀect on our business and could potenally cause us to cease operaons. We may expend our limited resources to pursue a parcular product, product candidate or indicaon and fail to capitalize on products, product candidates or indicaons that may be more proﬁtable or for which there is a greater likelihood of success. Because we have limited ﬁnancial and managerial resources, we focus our sales, markeng and research programs on certain products, product candidates or for speciﬁc indicaons. As a result, we may forego or delay pursuit of opportunies with other 57 products or product candidates or other indicaons that later prove to have greater commercial potenal. Our resource allocaon decisions may cause us to fail to capitalize on viable commercial products or proﬁtable market opportunies. Our spending on current and future research and development programs and product candidates may not yield any commercially viable products. If we do not accurately evaluate the commercial potenal or target market for a parcular product or product candidate, we may relinquish valuable rights through collaboraon, licensing, or other royalty arrangements in cases in which it would have been advantageous for us to retain sole development and commercializaon rights or we may allocate internal resources to a product candidate in a therapeuc area in which it would have been more advantageous to enter into a partnering arrangement. Changes to healthcare and FDA laws, regulaons, and policies may have a material adverse eﬀect on our business and results of operaons. As described above in “Item 1. Business - Government Regulaon” and in the Risk Factor above entled “ – The insurance coverage and reimbursement status of newly approved products is uncertain” there have been and connue to be a number of legislave iniaves to contain healthcare costs and to modify the regulaon of drug and biologic products. We expect that addional state and federal healthcare reform measures and regulaons will be adopted in the future, including proposals to reduce the exclusivity protecons provided to already approved biological products and to provide biosimilar and interchangeable biologic products an easier path to approval. Any of these measures and regulaons could limit the amounts that federal and state governments will pay for healthcare products and services, result in reduced demand for our product candidates or addional pricing pressures and aﬀect our product development, tesng, markeng approvals and post-market acvies. Failure to comply with laws and regulaons could harm our business and our reputaon. Our business is subject to regulaon by various federal, state, local and foreign governmental agencies, including agencies responsible for monitoring and enforcing employment and labor laws, workplace safety, privacy and security laws and regulaons, and tax laws and regulaons. In certain jurisdicons, these regulatory requirements may be more stringent than those in the U.S., and in other circumstances these requirements may be more stringent in the U.S. In parcular, our operaons are directly, and indirectly through our customers, subject to various federal and state fraud and abuse laws, including, without limitaon, the federal An-Kickback Statute, the federal False Claims Act, and physician sunshine laws and regulaons; and paent and non-paent privacy regulaons, including the GDPR and the California Consumer Privacy Act, or CCPA, including amendments from the California Privacy Rights Act, or CPRA, as described above in “Item 1. Business – Government Regulaon”. Because of the breadth of these laws and the narrowness of the statutory excepons and safe harbors available, it is possible that some of our business acvies could be subject to challenge under one or more of such laws. For instance, one of our programs for sponsored genec tesng to help paents receive an accurate diagnosis was previously the subject of review by applicable governmental authories of compliance with various fraud and abuse laws. We seled the maer with the governmental authories for an immaterial selement amount and without any admission of legal liability. We cannot assure that our other operaons or programs will not be subject to review by governmental authories or found to violate such laws. The GDPR imposes a number of strict obligaons and restricons on the ability to process personal data of individuals, in parcular with respect to special categories of personal data like health data (e.g., reliance on a legal basis, informaon to individuals, noﬁcaon to relevant naonal data protecon authories in case of personal data breach and implementaon of appropriate security measures). EU member states may also impose addional requirements in relaon to special categories of personal data through their naonal legislaon. In addion, the GDPR imposes speciﬁc restricons on the transfer of personal data to countries outside of the EEA that are not considered by the European Commission as providing an adequate level of protecon (including the U.S.). Appropriate safeguards are required to enable such transfers (e.g., reliance on standard contractual clauses and transfer risk assessments). There are also several compliance requirements under the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Informaon Technology for Economic and Clinical Health Act, or HITECH, and implemenng regulaons that create requirements relang to the privacy and security of protected health informaon. Those requirements are also applicable, in many instances, to business associates of covered enes. In some cases, depending on our business operaons and contractual agreements, including through the conduct of clinical trials, we are subject to HIPAA requirements. Also, we may be subject to addional federal, state and local privacy laws and regulaons in the U.S., including new and recently enacted laws (such as CCPA and CPRA), that may apply to us and/or our service providers now or in the future and that require that we take measures to be transparent regarding, honor rights with respect to, and protect the privacy and security of certain informaon we gather and use in our business, including personal informaon, parcularly personal informaon that is not otherwise subject to HIPAA. 58 If our operaons are found to be in violaon of any of the laws described above or any other governmental regulaons that apply to us, we may be subject to penales, including civil and criminal penales, damages, ﬁnes, exclusion from parcipaon in government health care programs, such as Medicare and Medicaid, imprisonment, disgorgement of proﬁts, and the curtailment or restructuring of our operaons. If any governmental sancons, ﬁnes, or penales are imposed, or if we do not prevail in any possible civil or criminal ligaon, our business, operang results, ﬁnancial condion and our reputaon could be harmed. In addion, responding to any acon will likely result in a signiﬁcant diversion of management’s aenon and resources and an increase in professional fees. Our research and development acvies, including our process and analycal development acvies in our quality control laboratory, and our and our third-party manufacturers’ and suppliers’ acvies, including acvies related to the build-out and operaon of our gene therapy manufacturing facility, involve the controlled storage, use, and disposal of hazardous materials, including the components of our product candidates, such as viruses, and other hazardous compounds, which subjects us to laws and regulaons governing such acvies. In some cases, these hazardous materials and various wastes resulng from their use are stored at our or our manufacturers’ facilies pending their use and disposal. We cannot eliminate the risk of contaminaon, which could cause an interrupon of our commercializaon eﬀorts, research and development eﬀorts, and business operaons or environmental damage that could result in costly clean-up and liabilies under applicable laws and regulaons governing the use, storage, handling, and disposal of these materials and speciﬁed waste products. We cannot guarantee that the safety procedures ulized by us and our third-party manufacturers for handling and disposing of these materials comply with the standards prescribed by these laws and regulaons, or eliminate the risk of accidental contaminaon or injury from these materials. In such an event, we may be held liable for any resulng damages—and such liability could exceed our resources—and state or federal or other applicable authories may curtail our use of certain materials and/or interrupt our business operaons. Furthermore, environmental laws and regulaons are complex, change frequently, and have tended to become more stringent. We cannot predict the impact of such changes and cannot be certain of our future compliance. Addionally, as we and our employees increasingly use social media tools as a means of communicaon with the public, there is a risk that the use of social media by us or our employees to communicate about our products or business may cause to be found in violaon of applicable laws, despite our aempts to monitor such social media communicaons through company policies and guidelines. In addion, our employees may knowingly or inadvertently make use of social media in ways that may not comply with our company policies or other legal or contractual requirements, which may give rise to liability, lead to the loss of trade secrets or other intellectual property, cause reputaonal harm or result in public exposure of personal informaon of our employees, clinical trial paents, customers, and others. Internaonal expansion of our business exposes us to business, regulatory, polical, operaonal, ﬁnancial, and economic risks associated with doing business outside of the U.S. Our business strategy includes internaonal expansion. We currently conduct clinical studies and regulatory acvies and we also commercialize products outside of the U.S. Doing business internaonally involves a number of risks, including but not limited to: • • • • • • • • • mulple, conﬂicng, and changing laws and regulaons such as privacy and data regulaons, transparency regulaons, tax laws, export and import restricons, employment laws, regulatory requirements, and other governmental approvals, permits, and licenses; introducon of new health authority requirements and/or changes in health authority expectaons; failure by us to obtain and maintain regulatory approvals for the use of our products in various countries; addional potenally relevant third-party patent rights; complexies and diﬃcules in obtaining protecon for, and enforcing, our intellectual property; diﬃcules in staﬃng and managing foreign operaons; complexies associated with managing mulple payor reimbursement regimes, government payors, or paent self-pay systems; limits on our ability to penetrate internaonal markets; ﬁnancial risks, such as longer payment cycles, addional or more burdensome regulatory requirements of ﬁnancial instuons outside of the U.S., diﬃculty collecng accounts receivable, the impact of local and regional ﬁnancial crises on demand and payment for our products, and exposure to foreign currency exchange rate ﬂuctuaons; 59 • • • • natural disasters and geopolical and economic instability, including wars, terrorism, polical unrest (including, for example the conﬂict between Russia and Ukraine, the conﬂict between Israel and the surrounding areas, and the rising tensions between China and Taiwan), results of certain elecons and votes, actual or threatened public health emergencies and outbreak of disease, rising inﬂaon, the potenal recessionary environment, the potenal shutdown of the U.S. federal government, boycos and resulng staﬃng shortages, adopon or expansion of government trade restricons, and other business restricons; certain expenses including, among others, expenses for travel, translaon, and insurance; regulatory and compliance risks that relate to maintaining accurate informaon and control over commercial operaons and acvies that may fall within the purview of the U.S. Foreign Corrupt Pracces Act, or FCPA, its books and records provisions, or its an-bribery provisions, including those under the U.K. Bribery Act and similar foreign laws and regulaons; and regulatory and compliance risks relang to doing business with any enty that is subject to sancons administered by the Oﬃce of Foreign Assets Control of the U.S. Department of the Treasury. Any of these factors could signiﬁcantly harm our future internaonal expansion and operaons and, consequently, our results of operaons. Our business and operaons may be materially adversely aﬀected in the event of computer system failures or security breaches. Cybersecurity incidents, including phishing aacks and aempts to misappropriate or compromise conﬁdenal or proprietary informaon or sabotage enterprise IT systems are becoming increasingly frequent and more sophiscated. The informaon and data processed and stored in our technology systems, and those of our strategic partners, CROs, contract manufacturers, suppliers, distributors or other third pares for which we depend to operate our business, may be vulnerable to loss, damage, denial-of-service, unauthorized access or misappropriaon. Data security breaches can occur as a result of malware, hacking, business email compromise, ransomware aacks, phishing or other cyberaacks directed by third pares. We, and certain of the third pares for which we depend on to operate our business, have experienced cybersecurity incidents, including third party unauthorized access to and misappropriaon of ﬁnancial informaon, and may experience similar incidents in the future. Further, risks of unauthorized access and cyber-aacks have increased as most of our personnel, and the personnel of many third-pares with which we do business, have adopted hybrid working arrangements following the COVID-19 pandemic. Improper or inadvertent behavior by employees, contractors and others with permied access to our systems, pose a risk that sensive data may be exposed to unauthorized persons or to the public. A system failure or security breach that interrupts our operaons or the operaons at one of our third- party vendors or partners could result in intellectual property and other proprietary or conﬁdenal informaon being lost or stolen or a material disrupon of our drug development programs and commercial operaons. For example, the loss of clinical trial data from ongoing or planned clinical trials could result in delays in our regulatory approval eﬀorts and signiﬁcantly increase our costs to recover or reproduce the data. To the extent that any disrupon or security breach results in a loss of or damage to our data or applicaons, loss of trade secrets or inappropriate disclosure of conﬁdenal or proprietary informaon, including protected health informaon, or personal informaon of employees or former employees, access to our clinical data, or disrupon of the manufacturing process, we could incur liability and the further development of our drug candidates could be delayed. Further, we could incur signiﬁcant costs to invesgate and migate such cybersecurity incidents. A security breach that results in the unauthorized access, use or disclosure of personal informaon also requires us to nofy individuals, governmental authories, credit reporng agencies, or other pares, as applicable, pursuant to privacy and security laws and regulaons or other obligaons. Such a security breach could harm our reputaon, erode conﬁdence in our informaon security measures, and lead to regulatory scruny and result in penales, ﬁnes, indemniﬁcaon claims, ligaon and potenal civil or criminal liability. 60 We or the third pares upon whom we depend may be adversely aﬀected by earthquakes or other natural disasters and our business connuity and disaster recovery plans may not adequately protect us from a serious disaster. Our corporate headquarters and one of our laboratories are located in the San Francisco Bay Area, and our collaboraon partner for Crysvita, KKC, is located in Japan, which have both in the past experienced severe earthquakes and other natural disasters. We do not carry earthquake insurance. Earthquakes or other natural disasters could severely disrupt our operaons or those of our collaborators, and have a material adverse eﬀect on our business, results of operaons, ﬁnancial condion, and prospects. We have also experienced power outages as a result of wildﬁres in the San Francisco Bay Area which are likely to connue to occur in the future. If a natural disaster, power outage, or other event occurred that prevented us from using all or a signiﬁcant poron of our headquarters, that damaged crical infrastructure (such as the manufacturing facilies of our third-party contract manufacturers) or that otherwise disrupted operaons, it may be diﬃcult or, in certain cases, impossible for us to connue our business for a substanal period of me. The disaster recovery and business connuity plans we have in place currently are limited and may be inadequate in the event of a serious disaster or similar event. We may incur substanal expenses as a result of the limited nature of our disaster recovery and business connuity plans, which, parcularly when taken together with our lack of earthquake insurance, could have a material adverse eﬀect on our business. We may acquire companies or products or engage in strategic transacons, which could divert our management’s aenon and cause us to incur various costs and expenses, or result in ﬂuctuaons with respect to the value of such investment, which could impact our operang results. We may acquire or invest in businesses or products that we believe could complement or expand our business or otherwise oﬀer growth opportunies. For example, we acquired Dimension in November 2017 and GeneTx in July 2022. The pursuit of potenal acquisions or investments may divert the aenon of management and may cause us to incur various costs and expenses in idenfying, invesgang, and pursuing them, whether or not they are consummated. We may not be able to idenfy desirable acquisions or investments or be successful in compleng or realizing ancipated beneﬁts from such transacons. We may experience diﬃcules in assimilang the personnel, operaons and products of the acquired companies, management’s aenon may be diverted from other business concerns and we may potenally lose key employees of the acquired company. If we are unable to successfully or mely integrate the operaons of acquired companies with our business, we may incur unancipated liabilies and be unable to realize the revenue growth, synergies and other ancipated beneﬁts resulng from the acquision, and our business, results of operaons and ﬁnancial condion could be materially and adversely aﬀected. The value of our investments in other companies or businesses may also ﬂuctuate signiﬁcantly and impact our operang results quarter to quarter or year to year. We purchased 7,825,797 shares of common stock of Solid in October 2020. Our investment in Solid is being accounted for at fair value, as the fair value is readily determinable. As a result, increases or decreases in the stock price of equity investments have resulted in and will result in accompanying changes in the fair value of our investments, and cause substanal volality in, our operang results for the reporng period. As the fair value of our investment in Solid is dependent on the stock price of Solid, which has recently seen wide ﬂuctuaons, the value of our investments and the impact on our operang results may similarly ﬂuctuate signiﬁcantly from quarter to quarter and year to year such that period-to-period comparisons may not be a good indicaon of the future value of the investments and our future operang results. Risks Related to Ownership of Our Common Stock The market price of our common stock may be highly volale. The market price of our common stock has been, and is likely to connue to be, volale, including for reasons unrelated to changes in our business. Our stock price could be subject to wide ﬂuctuaons in response to a variety of factors, including but not limited to the following: • • • • • • adverse results or delays in preclinical or clinical studies; any inability to obtain addional funding; any delay in ﬁling an IND, NDA, BLA, MAA, or other regulatory submission for any of our product candidates and any adverse development or perceived adverse development with respect to the applicable regulatory agency’s review of that IND, NDA, BLA, MAA, or other regulatory submission; the percepon of limited market sizes or pricing for our products and product candidates; decisions by our collaboraon partners with respect to the indicaons for our products and product candidates in countries where they have the right to commercialize the products and product candidates; decisions by our collaboraon partners regarding market access and pricing in countries where they have the right to commercialize our products and product candidates; 61 • • • • • • • • • • • • • • • • • • • • • • • failure to successfully develop and commercialize our products and product candidates; the level of revenue we receive from our commercialized products or from named paent sales; post-markeng safety issues; failure to maintain our exisng strategic collaboraons or enter into new collaboraons; failure by us or our licensors and strategic collaboraon partners to prosecute, maintain, or enforce our intellectual property rights; changes in laws or regulaons applicable to our products; any inability to obtain adequate product supply for our products and product candidates or the inability to do so at acceptable prices; adverse regulatory decisions; introducon of new products, services, or technologies by our competors; changes in or failure to meet or exceed ﬁnancial projecons or other guidance we may provide to the public; changes in or failure to meet or exceed the ﬁnancial projecons or other expectaons of the investment community; the percepon of the pharmaceucal industry or our company by the public, legislatures, regulators, and the investment community; the percepon of the pharmaceucal industry’s approach to drug pricing; announcements of signiﬁcant acquisions, strategic partnerships, joint ventures, or capital commitments by us, our strategic collaboraon partners, or our competors; the integraon and performance of any businesses we have acquired or may acquire; disputes or other developments relang to proprietary rights, including patents, ligaon maers, and our ability to obtain patent protecon for our technologies; addions or departures of key scienﬁc or management personnel; signiﬁcant invesgaons, regulatory proceedings or lawsuits, including patent or stockholder ligaon; securies or industry analysts’ reports regarding our stock, or their failure to issue such reports; changes in the market valuaons of similar companies; general market, macroeconomic condions or geopolical developments, rising inﬂaon, and the potenal recessionary environment; sales of our common stock by us or our stockholders in the future; and trading volume of our common stock. In addion, biotechnology and biopharmaceucal companies in parcular have experienced extreme price and volume ﬂuctuaons that have oen been unrelated or disproporonate to the operang performance of these companies. Broad market and industry factors may negavely aﬀect the market price of our common stock, regardless of our actual operang performance. Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incenve plans, could result in addional diluon of the percentage ownership of our stockholders and could cause our stock price to fall. We will need addional capital in the future to connue our planned operaons. To the extent we raise addional capital by issuing equity securies, our stockholders may experience substanal diluon. We may sell common stock, converble securies, or other equity securies in one or more transacons at prices and in a manner we determine from me to me. If we sell common stock, converble securies, or other equity securies in more than one transacon, investors may be materially diluted by subsequent sales. These sales may also result in material diluon to our exisng stockholders, and new investors could gain rights superior to our exisng stockholders. In June 2023, we adopted our 2023 Incenve Plan, or the 2023 Plan, which replaced our 2014 Incenve Plan, following stockholder approval of the plan. Pursuant to our 2023 Plan, our management is authorized to grant stock opons and other equity-based awards to our employees, directors, and consultants. At December 31, 2023, there were 5,359,901 shares available for future grants under the 2023 Plan. 62 Pursuant to our 2014 Employee Stock Purchase Plan, which was amended and restated in June 2023, or the A&R ESPP, eligible employees can acquire shares of our common stock at a discount to the prevailing market price. At December 31, 2023, there were 6,609,795 shares available for issuance under the A&R ESPP. Our board of directors has adopted an Employment Inducement Plan, which was amended in June 2023, or the Inducement Plan, with a maximum of 850,000 shares available for grant under the plan. At December 31, 2023, there were 130,996 shares available for issuance under the Inducement Plan. If our board of directors elects to increase the number of shares available for future grant under the 2023 Plan, the A&R ESPP, or the Inducement Plan, our stockholders may experience addional diluon, which could cause our stock price to fall. Provisions in our amended and restated cerﬁcate of incorporaon and by-laws, as well as provisions of Delaware law, could make it more diﬃcult for a third party to acquire us or increase the cost of acquiring us, even if doing so would beneﬁt our stockholders, or remove our current management. Our amended and restated cerﬁcate of incorporaon, amended and restated by-laws, and Delaware law contain provisions that may have the eﬀect of delaying or prevenng a change in control of us or changes in our management. Our amended and restated cerﬁcate of incorporaon and by-laws include provisions that: • • • • • • • • • authorize “blank check” preferred stock, which could be issued by our board of directors without stockholder approval and may contain vong, liquidaon, dividend, and other rights superior to our common stock; create a classiﬁed board of directors whose members serve staggered three-year terms; specify that special meengs of our stockholders can be called only by our board of directors or the chairperson of our board of directors; prohibit stockholder acon by wrien consent; establish an advance noce procedure for stockholder approvals to be brought before an annual meeng of our stockholders, including proposed nominaons of persons for elecon to our board of directors; provide that our directors may be removed only for cause; provide that vacancies on our board of directors may be ﬁlled only by a resoluon adopted by the board of directors; expressly authorize our board of directors to modify, alter or repeal our amended and restated by-laws; and require holders of 75% of our outstanding common stock to amend speciﬁed provisions of our amended and restated cerﬁcate of incorporaon and amended and restated by-laws. These provisions, alone or together, could delay, deter, or prevent hosle takeovers and changes in control or changes in our management. In addion, because we are incorporated in Delaware, we are governed by the provisions of Secon 203 of the Delaware General Corporaon Law, which limits the ability of stockholders owning in excess of 15% of our outstanding vong stock to merge or combine with us. Further, no stockholder is permied to cumulate votes at any elecon of directors because this right is not included in our amended and restated cerﬁcate of incorporaon. Any provision of our amended and restated cerﬁcate of incorporaon or amended and restated by-laws or Delaware law that has the eﬀect of delaying or deterring a change in control could limit the opportunity for our stockholders to receive a premium for their shares of our common stock, and could also aﬀect the price that some investors are willing to pay for our common stock. 63 Our amended and restated cerﬁcate of incorporaon provides that the Court of Chancery of the State of Delaware is the sole and exclusive forum for substanally all disputes between us and our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, oﬃcers or employees. Our amended and restated cerﬁcate of incorporaon provides that the Court of Chancery of the State of Delaware is the sole and exclusive forum for (1) any derivave acon or proceeding brought on our behalf, (2) any acon asserng a claim of breach of ﬁduciary duty owed by any of our directors, oﬃcers, or other employees to us or to our stockholders, (3) any acon asserng a claim against us arising under the Delaware General Corporaon Law or under our amended and restated cerﬁcate of incorporaon or bylaws, or (4) any acon against us asserng a claim governed by the internal aﬀairs doctrine. The choice of forum provision may limit a stockholder’s ability to bring a claim in a judicial forum that it ﬁnds favorable for disputes with us or our directors, oﬃcers, or other employees, which may discourage such lawsuits against us and our directors, oﬃcers, and other employees. Alternavely, if a court were to ﬁnd the choice of forum provision contained in our amended and restated cerﬁcate of incorporaon to be inapplicable or unenforceable in an acon, we may incur addional costs associated with resolving such acon in other jurisdicons, which could harm our business, operang results and ﬁnancial condion. General Risk Factors If we are unable to maintain eﬀecve internal control over ﬁnancial reporng, investors may lose conﬁdence in the accuracy and completeness of our ﬁnancial reports and the market price of our stock may decrease. The Sarbanes-Oxley Act requires, among other things, that we maintain eﬀecve internal controls for ﬁnancial reporng and disclosure controls and procedures. In parcular, we are required to perform system and process evaluaon and tesng of our internal controls over ﬁnancial reporng to allow management to report on the eﬀecveness of our internal controls over ﬁnancial reporng, as required by Secon 404(a) of the Sarbanes-Oxley Act. Secon 404(b) of the Sarbanes-Oxley Act also requires our independent auditors to aest to, and report on, this management assessment. Ensuring that we have adequate internal controls in place so that we can produce accurate ﬁnancial statements on a mely basis is a costly and me-consuming eﬀort that will need to be evaluated frequently. If we are not able to comply with the requirements of Secon 404 or if we or our independent registered public accounng ﬁrm are unable to aest to the eﬀecveness of our internal control over ﬁnancial reporng, investors may lose conﬁdence in the accuracy and completeness of our ﬁnancial reports, the market price of our stock could decline and we could be subject to sancons or invesgaons by Nasdaq, the SEC, or other regulatory authories, which would require addional ﬁnancial and management resources. We may incur addional tax liabilies related to our operaons. We have a mulnaonal tax structure and are subject to income tax in the U.S. and various foreign jurisdicons. Our eﬀecve tax rate is inﬂuenced by many factors including changes in our operang structure, changes in the mix of our earnings among countries, our allocaon of proﬁts and losses among our subsidiaries, our intercompany transfer pricing agreements and rules relang to transfer pricing, the availability of U.S. research and development tax credits, and future changes in tax laws and regulaons in the U.S. and foreign countries. Signiﬁcant judgment is required in determining our tax liabilies including management’s judgment for uncertain tax posions. The Internal Revenue Service, other domesc taxing authories, or foreign taxing authories may disagree with our interpretaon of tax laws as applied to our operaons. Our reported eﬀecve tax rate and aer-tax cash ﬂows may be materially and adversely aﬀected by tax assessments in excess of amounts accrued for our ﬁnancial statements. This could materially increase our future eﬀecve tax rate thereby reducing net income and adversely impacng our results of operaons for future periods. Our ability to use our net operang loss carryforwards and certain other tax aributes may be limited. We have incurred substanal losses during our history. To the extent that we connue to generate taxable losses, unused taxable losses will, subject to certain limitaons, carry forward to oﬀset future taxable income, if any, unl such unused losses expire. Under Secons 382 and 383 of the Internal Revenue Code of 1986, as amended, or the IRC, if a corporaon undergoes an “ownership change,” generally deﬁned as a greater than 50% change (by value) in its equity ownership over a three-year period, the corporaon’s ability to use its pre-change net operang loss carryforwards, or NOL carryforwards, and other pre-change tax aributes (such as research tax credits) to oﬀset its post-change income may be limited. An analysis to determine limitaons upon our NOL carryforwards and other pre-change tax aributes for ownership changes that have occurred previously has been performed, resulng in a permanent decrease of federal and state NOL carryforwards in the amount of $7.2 million and a permanent decrease in federal research tax credit carryforwards in the amount of $0.2 million. As a result of these decreases and others that may occur as a result of future ownership changes, our ability to use our pre-change NOL carryforwards and other tax aribute carryforwards to oﬀset U.S. federal taxable income and tax liabilies is limited and may become subject to even greater limitaons, which could potenally accelerate or permanently increase future federal tax liabilies for us. In addion, there may be 64 periods during which the use of state income tax NOL carryforwards and other state tax aribute carryforwards (such as state research tax credits) are suspended or otherwise limited, which could potenally accelerate or permanently increase future state tax liabilies for us. Ligaon may substanally increase our costs and harm our business. We have been, and may in the future become, party to lawsuits including, without limitaon, acons, claims and proceedings in the ordinary course of business relang to our directors, oﬃcers, stockholders, intellectual property, and employment maers and policies, which will cause us to incur legal fees and other costs related thereto, including potenal expenses for the reimbursement of legal fees of oﬃcers and directors under indemniﬁcaon obligaons. The expense of defending against such claims or ligaon may be signiﬁcant and there can be no assurance that we will be successful in any defense. Further, the amount of me that may be required to resolve such claims or lawsuits is unpredictable, and these acons may divert management’s aenon from the day-to-day operaons of our business, which could adversely aﬀect our business, results of operaons, and cash ﬂows. Ligaon is subject to inherent uncertaines, and an adverse result in such maers that may arise from me to me could have a material adverse eﬀect on our business, results of operaons, and ﬁnancial condion. Our business and operaons could be negavely aﬀected if we become subject to stockholder acvism or hosle bids, which could cause us to incur signiﬁcant expense, hinder execuon of our business strategy and impact our stock price. Stockholder acvism, which takes many forms and arises in a variety of situaons, has been increasingly prevalent. Stock price declines may also increase our vulnerability to unsolicited approaches. If we become the subject of certain forms of stockholder acvism, such as proxy contests or hosle bids, the aenon of our management and our board of directors may be diverted from execuon of our strategy. Such stockholder acvism could give rise to perceived uncertaines as to our future strategy, adversely aﬀect our relaonships with business partners and make it more diﬃcult to aract and retain qualiﬁed personnel. Also, we may incur substanal costs, including signiﬁcant legal fees and other expenses, related to acvist stockholder maers. Our stock price could be subject to signiﬁcant ﬂuctuaon or otherwise be adversely aﬀected by the events, risks and uncertaines of any stockholder acvism. Increased scruny regarding ESG pracces and disclosures could result in addional costs and adversely impact our business and reputaon. Companies across all industries are facing increasing scruny relang to their Environmental, Social and Governance, or “ESG,” pracces and disclosures and instuonal and individual investors are increasingly using ESG screening criteria in making investment decisions. Investors who are focused on ESG maers may seek enhanced ESG disclosures or to implement policies adverse to our business, and there can be no assurances that stockholders will not advocate, via proxy contests, media campaigns or other public or private means, for us to make corporate governance changes or engage in certain corporate acons. Our disclosures on these maers or a failure to sasfy evolving stakeholder expectaons for ESG pracces and reporng may potenally harm our reputaon and impact employee retenon and access to capital. In addion, our failure, or perceived failure, to pursue or fulﬁll our goals, targets, and objecves or to sasfy various reporng standards within the melines we announce, or at all, could expose us to government enforcement acons and private ligaon. Our ability to achieve any goal or objecve, including with respect to environmental and diversity iniaves and compliance with ESG reporng standards, is subject to numerous risks, many of which are outside of our control. Examples of such risks include the availability and cost of technologies and products that meet sustainability and ethical supply chain standards, evolving regulatory requirements aﬀecng ESG standards or disclosures, our ability to recruit, develop, and retain diverse talent in our labor markets, and our ability to develop reporng processes and controls that comply with evolving standards for idenfying, measuring and reporng ESG metrics. As ESG best-pracces, reporng standards, and disclosure requirements connue to develop, we may incur increasing costs related to maintaining or achieving our ESG goals in addion to ESG monitoring and reporng. 65 Item 1B. Unresolved Staﬀ Comments None. Item 1C: Cybersecurity In the ordinary course of our business, we collect, use, store, and transmit digitally large amounts of conﬁdenal, ﬁnancial, sensive, proprietary, personal, and health-related informaon. The secure maintenance of this informaon and our informaon technology systems is important to our operaons and business strategy. To this end, we have implemented processes designed to assess, idenfy, and manage risks from potenal unauthorized occurrences on or through our informaon technology systems that may result in adverse eﬀects on the conﬁdenality, integrity, and availability of these systems and the data residing therein. These processes are managed and monitored by a dedicated informaon technology team, including a Senior Director of Informaon Security, and is led by our Senior Vice President, Chief Informaon Oﬃcer, or “CIO”. Our processes include mechanisms, controls, technologies, and systems designed to prevent or migate data loss, the, misuse, or other security incidents or vulnerabilies aﬀecng the data and maintain a stable informaon technology environment. For example, we conduct penetraon and vulnerability tesng, data recovery tesng, security audits, and ongoing risk assessments, including due diligence on and audits of our key technology vendors, and other contractors and suppliers. We also conduct regular employee trainings on cyber and informaon security, among other topics. In addion, we consult with outside advisors and experts, when appropriate, to assist with assessing, idenfying, and managing cybersecurity risks, including to ancipate future threats and trends, and their impact on the Company’s risk environment. Our CIO, together with our Senior Director of Informaon Security and other members of the IT leadership team, are responsible for assessing and managing cybersecurity risks. Our CIO has ten years of experience managing informaon technology and cybersecurity. Our Senior Director of Informaon Security has over 26 years of experience managing informaon technology and cybersecurity maers and is cerﬁed as a Cerﬁed Informaon Systems Security Professional (CISSP). We consider cybersecurity, along with other signiﬁcant risks that we face, within our overall enterprise risk management framework. During the year ended December 31, 2023, we did not idenfy risks from known cybersecurity threats, including as a result of any prior cybersecurity incidents, that have materially aﬀected us, but we face certain ongoing cybersecurity risks or threats that, if realized, are reasonably likely to materially aﬀect us. Addional informaon on cybersecurity risks we face is discussed in Part I, Item 1A, “Risk Factors,” under the heading “Our business and operaons may be materially adversely aﬀected in the event of computer system failures or security breaches.” The Board of Directors, as a whole and at the commiee level, has oversight for the most signiﬁcant risks facing us and for our processes to idenfy, priorize, assess, manage, and migate those risks. The Audit Commiee, which is comprised solely of independent directors, has been designated by our Board to oversee cybersecurity risks. The Audit Commiee receives regular updates on cybersecurity and informaon technology maers and related risk exposures from our CIO. The Board also receives updates from the Audit Commiee on cybersecurity risks on at least an annual basis. Item 2. Properes Our primary operaons are conducted at the leased facilies summarized in the below table. In 2023, we completed the construcon of our gene therapy manufacturing facility located in Bedford, Massachuses. We believe our facilies are adequate and suitable for our current needs and that we will be able to obtain new or addional leased space in the future when necessary. Property Locaon Novato, California Novato, California Brisbane, California Somerville, Massachuses Woburn, Massachuses Woburn, Massachuses Bedford, Massachuses Use Headquarters and oﬃce Laboratory and oﬃce Oﬃce Laboratory and oﬃce Laboratory and oﬃce Laboratory and oﬃce Manufacturing facility 66 Lease Expiraon Date December 2024 October 2028 June 2026 October 2029 April 2025 October 2026 Owned property Item 3. Legal Proceedings We are not currently a party to any material legal proceedings. We may, however, in the ordinary course of business face various claims brought by third pares or government regulators and we may, from me to me, make claims or take legal acons to assert our rights, including claims relang to our directors, oﬃcers, stockholders, intellectual property rights, employment maers and the safety or eﬃcacy of our products. Any of these claims could subject us to costly ligaon and, while we generally believe that we have adequate insurance to cover many diﬀerent types of liabilies, our insurance carriers may deny coverage, may be inadequately capitalized to pay on valid claims, or our policy limits may be inadequate to fully sasfy any damage awards or selements. If this were to happen, the payment of any such awards could have a material adverse eﬀect on our consolidated operaons, cash ﬂows and ﬁnancial posion. Addionally, any such claims, whether or not successful, could damage our reputaon and business. Item 4. Mine Safety Disclosures Not applicable. 67 Item 5. Market for Registrant’s Common Equity, Related Stockholder Maers and Issuer Purchases of Equity Securies Our common stock has been traded on The Nasdaq Global Select Market since January 31, 2014 under the symbol “RARE”. As of February 15, 2024, we had 8 holders of record of our common stock. Certain shares are held in “street” name and, accordingly, the number of beneﬁcial owners of such shares is not known or included in the foregoing number. PART II STOCK PRICE PERFORMANCE GRAPH The following stock performance graph compares our total stock return with the total return for (i) the Nasdaq Composite Index and (ii) the Nasdaq Biotechnology Index for the period from December 31, 2018 through December 31, 2023. The ﬁgures represented below assume an investment of $100 in our common stock at the closing price of $43.48 on December 31, 2018 and in the Nasdaq Composite Index, or IXIC, and the Nasdaq Biotechnology Index, or NBI, on December 31, 2018 and the reinvestment of dividends into shares of common stock. The comparisons in the table are required by the SEC and are not intended to forecast or be indicave of the possible future performance of our common stock. This graph shall not be deemed “solicing material” or be deemed “ﬁled” for purposes of Secon 18 of the Securies Exchange Act of 1934, as amended, or the Exchange Act, or otherwise subject to the liabilies under that secon, and shall not be deemed to be incorporated by reference into any of our ﬁlings under the Securies Act of 1933, as amended, or the Securies Act, whether made before or aer the date hereof and irrespecve of any general incorporaon language in any such ﬁling. $100 Investment in Stock or Index Ultragenyx Pharmaceucal Inc. NASDAQ Composite Index NASDAQ Biotechnology Index Ticker RARE ^IXIC ^NBI December 31, 2018 December 31, 2019 December 31, 2020 December 31, 2021 December 31, 2022 December 31, 2023 $ $ $ 100.00 $ 98.23 $ 318.38 $ 193.40 $ 106.55 $ 109.98 100.00 $ 135.23 $ 194.24 $ 235.78 $ 157.74 $ 226.24 100.00 $ 124.41 $ 156.36 $ 155.37 $ 138.42 $ 143.60 Dividend Policy We have never declared or paid cash dividends on our common stock. We currently intend to retain all available funds and any future earnings, if any, to fund the development, operaon, and expansion of our business, and we do not ancipate paying any cash dividends on our common stock in the foreseeable future. Any future determinaon to pay dividends will be made at the discreon of our board of directors or any authorized commiee thereof. Unregistered Sales of Equity Securies None. Issuer’s Purchases of Equity Securies None. Item 6. Reserved 68 Item 7. Management’s Discussion and Analysis of Financial Condion and Results of Operaons MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS You should read the following discussion and analysis of our ﬁnancial condion and results of operaons together with our Consolidated Financial Statements and related notes included elsewhere in this Annual Report. This discussion and analysis generally covers our ﬁnancial condion and results of operaons for the year ended December 31, 2023, including year- over-year comparisons versus the year ended December 31, 2022. Our Annual Report on Form 10-K for the year ended December 31, 2022 includes a discussion and analysis of our ﬁnancial condion and results of operaons for the year ended December 31, 2021 in "Part II, Item 7. Management’s Discussion and Analysis of Financial Condion and Results of Operaons.” Overview Ultragenyx Pharmaceucal Inc., we or the Company, are a biopharmaceucal company commied to bringing novel products to paents for the treatment of serious rare and ultrarare genec diseases. We have built a diverse porolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treang the underlying disease. Our strategy is predicated upon me- and cost-eﬃcient drug development, with the goal of delivering safe and eﬀecve therapies to paents with the utmost urgency. Approved Therapies and Clinical Product Candidates Our current approved therapies and clinical-stage pipeline consist of four product categories: biologics, small molecules, AAV gene therapy, and nucleic acid product candidates. We have four commercially approved products, consisng of Crysvita® (burosumab) for the treatment of X-linked hypophosphatemia, or XLH, and tumor-induced osteomalacia, or TIO, Mepsevii® (vestronidase alfa) for the treatment of mucopolysaccharidosis VII, or MPSVII or Sly Syndrome, Dojolvi® (triheptanoin) for the treatment of long-chain fay acid oxidaon disorders, or LC-FAOD, and Evkeeza® (evinacumab) for the treatment of homozygous familial hypercholesterolemia, or HoFH. Please see “Item 1. Business” above for a descripon of our approved products and our clinical stage pipeline products. Financial Operaons Overview We are a biopharmaceucal company with a limited operang history. To date, we have invested substanally all of our eﬀorts and ﬁnancial resources in idenfying, acquiring, and developing our products and product candidates, including conducng clinical studies and providing selling, general and administrave support for these operaons. To date, we have funded our operaons primarily from the sale of our equity securies, revenues from our commercial products, the sale of certain future royales, and strategic collaboraon arrangements. We have incurred net losses in each year since incepon. Our net losses were $606.6 million and $707.4 million for the years ended December 31, 2023 and 2022, respecvely. Substanally all of our net losses have resulted from costs incurred in connecon with our research and development programs and from selling, general and administrave costs associated with our operaons. For the year ended December 31, 2023, our total revenues increased to $434.2 million, compared to $363.3 million for the same period in 2022. The increase in revenue was driven by higher demand for our approved products. As of December 31, 2023, we had $777.1 million in available cash, cash equivalents and marketable debt securies. Crical Accounng Policies and Signiﬁcant Judgments and Esmates Our management’s discussion and analysis of our ﬁnancial condion and results of operaons is based on our Consolidated Financial Statements, which have been prepared in accordance with U.S. generally accepted accounng principles, or GAAP. The preparaon of these Consolidated Financial Statements requires us to make esmates and assumpons that aﬀect the reported amounts of assets and liabilies and the disclosure of conngent assets and liabilies at the date of the ﬁnancial statements, as well as the reported expenses incurred during the reporng periods. Our esmates are based on our historical experience and on various other factors that we believe are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilies that are not readily apparent from other sources. Actual results may diﬀer from these esmates under diﬀerent assumpons or condions. We periodically review our esmates as a result of changes in circumstances, facts and experience. The eﬀects of material revisions in esmates are reﬂected in the ﬁnancial statements prospecvely from the date of the change in esmate. Our signiﬁcant accounng policies are more fully described in Note 2 to our ﬁnancial statements included elsewhere in this Annual Report. 69 We deﬁne our crical accounng policies as those GAAP accounng principles that require us to make subjecve esmates and judgments about maers that are uncertain and are likely to have a material impact on our ﬁnancial condion and results of operaons as well as the speciﬁc manner in which we apply those principles. We believe the crical accounng policies used in the preparaon of our ﬁnancial statements that require signiﬁcant esmates and judgments are as follows: Accrued Research and Development, and Research and Development Expenses As part of the process of preparing consolidated ﬁnancial statements, we are required to esmate and accrue expenses, the largest of which is related to accrued research and development expenses. This process involves reviewing contracts and purchase orders, idenfying services that have been performed on our behalf, and esmang the level of service performed and the associated cost incurred for the service when we have not yet been invoiced or otherwise noﬁed of the actual costs. We record accruals for esmated costs of research, preclinical and clinical studies, and manufacturing development. These costs are a signiﬁcant component of our research and development expenses. A substanal poron of our ongoing research and development acvies is conducted by third-party service providers. We accrue the costs incurred under our agreements with these third pares based on actual work completed in accordance with agreements established with these third pares. We determine the actual costs through discussions with internal personnel and external service providers as to the progress or stage of compleon of the services and the agreed-upon fee to be paid for such services. We make signiﬁcant judgments and esmates in determining the accrual balance in each reporng period. As actual costs become known, we adjust our accruals. Although we do not expect our esmates to be materially diﬀerent from amounts actually incurred, our understanding of the status and ming of services performed relave to the actual status and ming of services performed may vary and could result in us reporng amounts that are too high or too low in any parcular period. Our accrual is dependent, in part, upon the receipt of mely and accurate reporng from clinical research organizaons and other third-party vendors. Research and development costs are expensed as incurred and consist of salaries and beneﬁts, stock-based compensaon, lab supplies, materials and facility costs, as well as fees paid to other nonemployees and enes that conduct certain research and development acvies on our behalf. Amounts incurred in connecon with collaboraon and license agreements are also included in research and development expense. Payments made prior to the receipt of goods or services to be used in research and development are capitalized unl the goods or services are received. To date, there have been no material diﬀerences from our accrued esmated expenses to the actual clinical trial expenses; however, due to the nature of esmates, we cannot assure you that we will not make changes to our esmates in the future as we become aware of addional informaon about the status or conduct of our clinical studies and other research acvies. Revenue Recognion Product Sales We sell our approved products through a limited number of distributors. Under ASC 606, revenue from product sales is recognized at the point in me when control is transferred to these distributors. We also recognize revenue from sales of certain products on a “named paent” basis, which are allowed in certain countries prior to the commercial approval of the product. Prior to recognizing revenue, we make esmates of the transacon price, including any variable consideraon that is subject to a constraint. Amounts of variable consideraon are included in the transacon price to the extent that it is probable that a signiﬁcant reversal in the amount of cumulave revenue recognized will not occur and when the uncertainty associated with the variable consideraon is subsequently resolved. Product sales are recorded net of esmated government-mandated rebates and chargebacks, esmated product returns, and other deducons. Provisions for returns and other adjustments are provided for in the period the related revenue is recorded, as esmated by management. These reserves are based on esmates of the amounts earned or to be claimed on the related sales and are reviewed periodically and adjusted as necessary. Our esmates of government mandated rebates, chargebacks, esmated product returns, and other deducons depends on the idenﬁcaon of key customer contract terms and condions, negoated pricing, as well as esmates of sales volumes to diﬀerent classes of payors. If actual results vary, we may need to adjust these esmates, which could have a material eﬀect on earnings in the period of the adjustment. Collaboraon, License and Royalty Revenue We have certain license and collaboraon agreements that are within the scope of Accounng Standards Codiﬁcaon, or ASC, 808, Collaborave Agreements, which provides guidance on the presentaon and disclosure of collaborave arrangements. Generally, the classiﬁcaon of the transacons under the collaborave arrangements is determined based on the nature of contractual terms of the arrangement, along with the nature of the operaons of the parcipants. We record our share of collaboraon revenue, net of transfer pricing related to net sales in the period in which such sales occur, if we are considered as an 70 agent in the arrangement. We are considered an agent when the collaboraon partner controls the product before transfer to the customers and has the ability to direct the use of and obtain substanally all of the remaining beneﬁts from the product. Funding received related to research and development services and commercializaon costs is generally classiﬁed as a reducon of research and development expenses and selling, general and administrave expenses, respecvely, in the Consolidated Statement of Operaons, because the provision of such services for collaborave partners are not considered to be part of our ongoing major or central operaons. We also record royalty revenues under certain of our license or collaboraon agreements in exchange for license of intellectual property. We ulize certain informaon from our collaboraon partners to record collaboraon revenue, including revenue from the sale of the product, associated reserves on revenue, and costs incurred for development and sales acvies. For the periods covered in the ﬁnancial statements presented, there have been no material changes to prior period esmates of revenues and expenses. We sold the right to receive certain royalty payments from net sales of Crysvita in certain territories to RPI Finance Trust, or RPI, an aﬃliate of Royalty Pharma, and to OCM LS23 Holdings LP, an investment vehicle for Ontario Municipal Employees Rerement System, or OMERS, as further described in “Liabilies for Sales of Future Royales” below. We record the royalty revenue from the net sales of Crysvita in the applicable territories on a prospecve basis as non-cash royalty revenue in the Consolidated Statements of Operaons over the term of the applicable arrangement. The terms of our collaboraon and license agreements may contain mulple performance obligaons, which may include licenses and research and development acvies. We evaluate these agreements under ASC 606, Revenue from Contracts with Customers, or ASC 606, to determine the disnct performance obligaons. We analogize to ASC 606 for the accounng for disnct performance obligaons for which there is a customer relaonship. Prior to recognizing revenue, we make esmates of the transacon price, including variable consideraon that is subject to a constraint. Amounts of variable consideraon are included in the transacon price to the extent that it is probable that a signiﬁcant reversal in the amount of cumulave revenue recognized will not occur and when the uncertainty associated with the variable consideraon is subsequently resolved. Total consideraon may include nonrefundable upfront license fees, payments for research and development acvies, reimbursement of certain third-party costs, payments based upon the achievement of speciﬁed milestones, and royalty payments based on product sales derived from the collaboraon. If there are mulple disnct performance obligaons, we allocate the transacon price to each disnct performance obligaon based on our relave standalone selling price. The standalone selling price is generally determined based on the prices charged to customers or using expected cost-plus margin. We esmate the eﬀorts needed to complete the performance obligaons and recognize revenue by measuring the progress towards complete sasfacon of the performance obligaons using input measures. Inventory We expense costs associated with the manufacture of our products prior to regulatory approval. Typically, capitalizaon of such costs begins when we have received the regulatory approval of the product. Prior to the approval of our products by the U.S. Food and Drug Administraon, or FDA, manufacturing and related costs are expensed. As of December 31, 2023, we do not hold a material amount of previously expensed inventory for our approved products. Inventory that is manufactured aer regulatory approval is valued at the lower of cost and net realizable value and cost is determined using the average-cost method. We periodically review our inventories for excess amounts or obsolescence and write down obsolete or otherwise unmarketable inventory to the esmated net realizable value. Liabilies for Sales of Future Royales In December 2019, we entered into a Royalty Purchase Agreement with RPI. Pursuant to the agreement, RPI paid us $320.0 million in consideraon for our right to receive royalty payments on the net sales of Crysvita in the European Union, or the EU, the United Kingdom, and Switzerland, eﬀecve January 1, 2020, under the terms of our Collaboraon and License Agreement with Kyowa Kirin Co., Ltd., or KKC. The agreement with RPI will automacally terminate, and the payment of royales to RPI will cease, in the event aggregate royalty payments received by RPI are equal to or greater than the capped amount of $608.0 million prior to December 31, 2030, or in the event aggregate royalty payments received by RPI are less than $608.0 million prior to December 31, 2030, when aggregate royalty payments received by RPI are equal to $800.0 million. In July 2022, we entered into a Royalty Purchase Agreement with OMERS. Pursuant to the agreement, OMERS paid $500.0 million to us in consideraon for the right to receive 30% of the future royalty payments due to us from KKC based on net sales of Crysvita in the U.S. and Canada under the terms of the KKC Collaboraon Agreement. The calculaon of royalty payments to OMERS 71 is based on net sales of Crysvita beginning in April 2023 and connuing unl expiraon, which is the earlier of the date on which aggregate payments received by OMERS equals $725.0 million or the date the ﬁnal royalty payment is made to us under the KKC Collaboraon Agreement. Proceeds from these transacons were recorded as liabilies (speciﬁcally, liabilies for sales of future royales on the Consolidated Balance Sheets). We are amorzing $320.0 million and $500.0 million, net of transacon costs of $5.8 million and $9.1 million for RPI and OMERS, respecvely, using the eﬀecve interest method over the esmated life of the applicable arrangement. In order to determine the amorzaon of the liabilies, we are required to esmate the total amount of future royalty payments to be received by us and paid to RPI and OMERS, subject to the capped amount, over the life of the arrangements. The excess of future esmated royalty payments (subject to the capped amount) to RPI and OMERS, in excess of the net proceeds received of $314.2 million and $491.0 million, respecvely, is recorded as non-cash interest expense over the life of the arrangements. Consequently, we esmate an imputed interest on the unamorzed poron of the liabilies and record interest expense relang to the transacons. We record the royalty revenue arising from the net sales of Crysvita in the applicable territories as non-cash royalty revenue in the Consolidated Statements of Operaons over the term of the arrangements. We periodically assess the expected royalty payments using a combinaon of historical results, internal projecons and forecasts from external sources. To the extent such payments are greater or less than our inial esmates or the ming of such payments is materially diﬀerent than its original esmates, we will prospecvely adjust the amorzaon of the liabilies and the eﬀecve interest rate. Our eﬀecve annual interest rates were 6.2% and 7.8%, for RPI and OMERS, respecvely, as of December 31, 2023. There are a number of factors that could materially aﬀect the amount and ming of royalty payments from KKC in the applicable territories, most of which are not within our control. Such factors include, but are not limited to, the success of KKC’s sales and promoon of Crysvita, changing standards of care, macroeconomic and inﬂaonary pressures, the introducon of compeng products, pricing for reimbursement in various territories, manufacturing or other delays, intellectual property maers, adverse events that result in governmental health authority imposed restricons on the use of Crysvita, signiﬁcant changes in foreign exchange rates as the royalty payments are made in U.S. dollars, or USD, while signiﬁcant porons of the underlying sales of Crysvita are made in currencies other than USD, and other events or circumstances that could result in reduced royalty payments from sales of Crysvita, all of which would result in a reducon of non-cash royalty revenue and the non-cash interest expense over the life of the arrangement. Conversely, if sales of Crysvita in the relevant territories are more than expected, the non-cash royalty revenue and the non-cash interest expense recorded by us would be greater over the term of the arrangements. Stock-Based Compensaon Stock-based compensaon costs related to equity awards granted to employees are measured at the date of grant based on the esmated fair value of the award, net of esmated forfeitures. We esmate the grant date fair value of opons, and the resulng stock-based compensaon expense, using the Black-Scholes opon-pricing model. The grant date fair value of the stock-based awards is recognized on a straight-line basis over the requisite service period, which is generally the vesng period of the respecve awards. We expect to connue to grant equity awards in the future, and to the extent that we do, our actual stock-based compensaon expense will likely increase. The Black-Scholes opon-pricing model requires the use of certain subjecve assumpons which determine the esmated fair value of stock-based awards. • • Expected Term — The expected term represents the period that the stock-based awards are expected to be outstanding and is determined using the simpliﬁed method (based on the midpoint between the vesng date and the end of the contractual term). Expected Volality— The expected volality is based on historical volality over the look-back period corresponding to the expected term. Strike price for opons, including performance stock opons, or PSOs, is equal to the closing market value of our common stock on the date of grant. In addion to the assumpons used in the Black-Scholes opon-pricing model, we also esmate a forfeiture rate to calculate the stock-based compensaon for our awards. We will connue to use judgment in evaluang the expected volality, expected terms, and forfeiture rates ulized for our stock-based compensaon calculaons on a prospecve basis and will revise in subsequent periods, if actual forfeitures diﬀer from those esmates. 72 For restricted stock units, or RSUs, and performance stock units, or PSUs, the fair value is based on the market value of our common stock on the date of grant, except for certain PSUs with a market vesng condion, for which fair value is esmated using a Monte Carlo simulaon model. Stock-based compensaon expense for RSUs is recognized on a straight-line basis over the requisite service period. PSUs are subject to vest only if certain speciﬁed criteria are achieved and the employees’ connued service with the Company. For certain PSUs, the number of PSUs that may vest are also subject to the achievement of certain speciﬁed criteria, including both performance condions and market condions. Compensaon expense for PSUs is recognized only aer the achievement of the speciﬁed criteria is considered probable and recognized on a straight-line basis between the grant date and the expected vest date, with a catch-up for previously unrecognized expense, if any, recognized in the period the achievement criteria is deemed probable. For the years ended December 31, 2023, 2022, and 2021 stock-based compensaon expense was $135.2 million, $130.4 million, and $105.0 million, respecvely. As of December 31, 2023, we had $219.8 million of total unrecognized stock-based compensaon costs, net of esmated forfeitures, which we expect to recognize over a weighted-average period of 2.2 years. Income Taxes We use the liability method of accounng for income taxes. Under this method, deferred tax assets and liabilies are determined based on the diﬀerences between the ﬁnancial reporng and the tax bases of assets and liabilies and are measured using the enacted tax rates and laws that will be in eﬀect when the diﬀerences are expected to reverse. We assess the likelihood that the resulng deferred tax assets will be realized. A valuaon allowance is provided when it is more likely than not that some poron or all of a deferred tax asset will not be realized. In conjuncon with the acquision of Dimension Therapeucs, or Dimension, in 2017, we recorded a deferred tax liability reﬂecng the tax impact of the diﬀerence between the book basis and tax basis of acquired IPR&D. Such deferred income tax liability was not used to oﬀset deferred tax assets when analyzing our valuaon allowance as the acquired IPR&D is considered to have an indeﬁnite life unl we complete or abandon development of the acquired IPR&D. We recognize beneﬁts of uncertain tax posions if it is more likely than not that such posions will be sustained upon examinaon based solely on their technical merits, as the largest amount of beneﬁt that is more likely than not to be realized upon the ulmate selement. Our policy is to recognize interest and penales related to the underpayment of income taxes as a component of income tax expense or beneﬁt. To date, there have been no interest or penales charged in relaon to the unrecognized tax beneﬁts. As of December 31, 2023, our total gross deferred tax assets were $1,041.8 million. Due to our lack of earnings history and uncertaines surrounding our ability to generate future taxable income, the net deferred tax assets have been fully oﬀset by a valuaon allowance. The deferred tax assets were primarily comprised of federal and state tax net operang losses and tax credit carryforwards. Ulizaon of the net operang loss and tax credit carryforwards may be subject to an annual limitaon due to historical or future ownership percentage change rules provided by the Internal Revenue Code of 1986, and similar state provisions. The annual limitaon may result in the expiraon of certain net operang loss and tax credit carryforwards before their ulizaon. 73 Results of Operaons Comparison of Years Ended December 31, 2023 and 2022 Revenues (dollars in thousands) Product sales: Crysvita Mepsevii Dojolvi Evkeeza Total product sales Crysvita royalty revenue Collaboraon and license revenue: Crysvita collaboraon revenue in Proﬁt-Share Territory Daiichi Sankyo Total collaboraon and license revenue Total revenues * not meaningful Year Ended December 31, 2022 2023 Dollar Change Percent Change $ $ 75,697 $ 30,441 70,633 3,642 180,413 182,652 42,678 $ 20,637 55,612 — 118,927 21,692 69,705 1,479 71,184 434,249 $ 215,024 7,686 222,710 363,329 $ 33,019 9,804 15,021 3,642 61,486 160,960 (145,319 ) (6,207 ) (151,526 ) 70,920 77% 48% 27% * 52% 742% -68% -81% -68% 20% Our product sales increased $61.5 million for the year ended December 31, 2023, compared to the same period in 2022. The increase was primarily due to an increase in demand for Crysvita in Lan America resulng from an increase in the number of paents on therapy, connued increase in demand for our other approved products, and increases in revenue under our named paent programs. Our Crysvita collaboraon revenue in the Proﬁt-Share Territory and royalty revenue increased by a net $15.6 million for the year ended December 31, 2023, compared to the same period in 2022; this increase in Crysvita revenue is primarily due to an increase in the number of paents on therapy. We transioned commercial responsibilies to KKC in the Proﬁt-Share Territory in April 2023. Post transion, we recognize our revenue share for Crysvita sales in the Proﬁt-Share Territory as royalty revenue, which was recorded as collaboraon revenue prior to the transion. Our revenue from the Daiichi Sankyo arrangement decreased by $6.2 million for the year ended December 31, 2023, compared to the same period in 2022. The decrease was due to the compleon of the technology transfer and the technology transfer period as of March 31, 2023. Cost of Sales (dollars in thousands) Cost of sales Year Ended December 31, 2022 2023 Dollar Change $ 45,209 $ 28,320 $ 16,889 Percent Change 60% Cost of sales increased by $16.9 million for the year ended December 31, 2023, compared to the same period in 2022. The increase in cost of sales was due to increased demand for our approved products, parally oﬀset by a decrease in the Crysvita transfer price on sales of the product in Lan America from 35% prior to December 31, 2022, to 30% in 2023. Research and Development Expenses (dollars in thousands) Research and development expenses include internal and external costs incurred for research and development of our programs and program candidates and expenses related to certain technology that we acquire or license through business development transacons. These expenses consist primarily of clinical studies performed by contract research organizaons, manufacturing of drug substance and drug product performed by contract manufacturing organizaons and at our gene therapy manufacturing facility, materials and supplies, fees from collaborave and other arrangements including milestones, licenses and other fees, personnel costs including salaries, beneﬁts and stock-based compensaon, and overhead allocaons consisng of various support and infrastructure costs. Clinical programs include study conduct and manufacturing costs related to clinical program candidates. Translaonal research includes costs for preclinical study work and costs related to preclinical programs prior to IND ﬁling. Upfront license, acquision, and milestone fees include any signiﬁcant expenses related to strategic licensing agreements. Approved products include costs for disease monitoring programs for post-markeng clinical studies, medical aﬀairs acvies to support scienﬁc discovery eﬀorts on 74 exisng programs, and regulatory costs for unapproved regions. Infrastructure costs include direct costs related to laboratory, IT, and equipment depreciaon costs, and overhead allocaons for human resources, IT, and other allocable costs. The following table provides a breakout of our research and development expenses by major program type and business acvies: Clinical programs: Gene therapy programs Biologic and nucleic acid programs Translaonal research Upfront license, acquision, and milestone fees Approved products Infrastructure Stock-based compensaon Other research and development Total research and development expenses Year Ended December 31, 2022 2023 Dollar Change Percent Change $ $ 168,705 $ 108,914 71,820 9,000 53,478 78,929 74,531 83,072 648,449 $ 153,754 $ 97,268 81,431 75,033 75,683 71,657 74,464 76,499 705,789 $ 14,951 11,646 (9,611 ) (66,033 ) (22,205 ) 7,272 67 6,573 (57,340 ) 10% 12% -12% -88% -29% 10% 0% 9% -8% Total research and development expenses decreased $57.3 million for the year ended December 31, 2023 compared to the same period in 2022. The change in research and development expenses was due to: • • • • • • • for gene therapy programs, an increase of $15.0 million, primarily related to the addion of the development costs for the UX111 program acquired from Abeona Therapeucs in May 2022, and an increase in producon materials purchases for internal manufacturing, parally oﬀset by decreases in external clinical manufacturing expenses for DTX401; for biologic and nucleic acid programs, an increase of $11.6 million, primarily related to the connued clinical progress of the UX143 and GTX102 programs and associated clinical development and manufacturing expenses, parally oﬀset by a reducon in development expense on UX053 for the treatment of Glycogen Storage Disease Type III; for translaonal research, a decrease of $9.6 million, primarily related to decreases in manufacturing and headcount expense for IND-stage projects; for upfront license, acquision, and milestone fees, a decrease of $66.0 million, due to $9.0 million related to payment for achievement of a clinical enrollment milestone for the UX143 program recognized during the year ended December 31, 2023, as compared to $75.0 million recognized from the GeneTx acquision for the year ended December 31, 2022; for approved products, a decrease of $22.2 million, primarily due to transion of Crysvita commercializaon responsibilies in North America to KKC and realized cost eﬃciencies for Dojolvi, parally oﬀset by reimbursement of Regeneron collaboraon expenses and increased personnel and launch costs for Evkeeza; for infrastructure, an increase of $7.3 million, primarily related to increased expenses for support of our clinical and research program pipeline, expansion of laboratory space, depreciaon of laboratory-related leasehold improvements and equipment, and IT-related expenses; and for other research and development expenses, an increase of $6.6 million, primarily related to increased staﬃng and material costs to support internal manufacturing and increased administrave and general support. We expect our annual research and development expenses to connue to moderate in the future as we advance our product candidates through clinical development. The ming and amount of expenses incurred will depend largely upon the outcomes of current or future clinical studies for our product candidates as well as the related regulatory requirements, manufacturing costs, and any costs associated with the advancement of our preclinical programs. Selling, General and Administrave Expenses (dollars in thousands) Selling, general and administrave $ 309,799 $ 278,139 $ 31,660 Year Ended December 31, 2022 2023 Dollar Change Percent Change 11% Selling, general and administrave expenses increased $31.7 million for the year ended December 31, 2023, compared to the same period in 2022. The increases in selling, general and administrave expenses were primarily due to increases in commercializaon costs, and professional services costs, as well as a one-me legal selement of $6.2 million for the year ended December 31, 2023. 75 We expect selling, general and administrave expenses to connue to moderate in the future as we connue to support our approved products and mulple clinical-stage product candidates, with expected decreases in commercial acvies due to transion of Crysvita commercial responsibilies to our partner in the Proﬁt-Share Territory. Interest Income (dollars in thousands) Interest income Year Ended December 31, 2022 2023 Dollar Change $ 26,688 $ 11,074 $ 15,614 Percent Change 141% Interest income increased $15.6 million for the year ended December 31, 2023 compared to the same period in 2022, primarily due to increases in interest rates. Change in Fair Value of Equity Investments (dollars in thousands) Change in fair value of equity investments $ 397 $ (19,299 ) $ 19,696 Year Ended December 31, 2022 2023 Dollar Change Percent Change (102%) For the year ended December 31, 2023, we recorded a net increase in the fair value of our equity investments of $0.4 million due to an increase in the fair value of our investments in Solid Biosciences Inc., or Solid, common stock for the period. For the year ended December 31, 2022, we recorded a net decrease in the fair value of our equity investments of $19.3 million. The fair value of our investments in Arcturus Therapeucs Holdings Inc., or Arcturus, and Solid common stock decreased by $8.4 million and $10.9 million, respecvely, for the period. The change in fair value of Arcturus included a realized gain on the sale of all our remaining shares of common stock for net proceeds of $10.1 million. As of December 31, 2022, we had sold all our remaining equity investments in Arcturus. Non-cash Interest Expense on Liabilies for Sales of Future Royales (dollars in thousands) Non-cash interest expense on liabilies for sales of future royales Year Ended December 31, 2022 2023 Dollar Change Percent Change $ 66,004 $ 43,015 $ 22,989 53% Our non-cash interest expense on liabilies for sales of future royales increased by $23.0 million for the year ended December 31, 2023, compared to the same period in 2022. This was primarily due to the paral sale of North American Crysvita royales to OMERS in July 2022, with a full year of interest expense in 2023. To the extent the royalty payments are greater or less than our inial esmates or the ming of such payments is materially diﬀerent than our original esmates, we prospecvely adjust the eﬀecve interest rate. Other Expense (dollars in thousands) Other expense Year Ended December 31, 2022 2023 Dollar Change $ (337 ) $ (1,566 ) $ 1,229 Percent Change (78%) Other expense decreased $1.2 million for the year ended December 31, 2023, compared to the same period in 2022. These changes were primarily due to ﬂuctuaons in foreign exchange rates. Beneﬁt from (provision for) income taxes Beneﬁt from (provision for) income taxes $ 1,825 $ (5,696 ) $ 7,521 Year Ended December 31, 2022 2023 Dollar Change Percent Change (132%) For the year ended December 31, 2023, we recognized an income tax beneﬁt of $4.8 million aributable to modiﬁcaons in our state apporonment methodology. We realized no beneﬁt for current year losses due to a full valuaon allowance against the U.S. net deferred tax assets. The beneﬁt was oﬀset by an income tax expense of $3.0 million from foreign jurisdicons. Beginning in 2022, the Tax Cuts and Jobs Act of 2017 eliminated the right to deduct research and development expenditures for tax purposes in the period the expenses were incurred and instead requires all U.S. and foreign research and development expenditures to be amorzed over ﬁve and ﬁeen tax years, respecvely. Due to this required capitalizaon of research and 76 development expenditures and the signiﬁcant taxable income generated as a result of our sale of royales in July 2022, we recorded a one-me discrete tax expense of $6.1 million for the year ended December 31, 2022. The discrete tax expense is for state taxes we ancipate paying as a result of statutory limitaons on our ability to oﬀset expected taxable income with net operang loss carry forwards in certain states. We realized no beneﬁt for current year losses due to a full valuaon allowance against the U.S. net deferred tax assets. Liquidity and Capital Resources To date, we have funded our operaons primarily from the sale of our equity securies, revenue from our commercial products, the sale of certain future royales, and strategic collaboraon arrangements. As of December 31, 2023, we had $777.1 million in available cash, cash equivalents, and marketable debt securies. We believe that our exisng capital resources will be suﬃcient to fund our projected operang requirements for at least the next twelve months. Our cash, cash equivalents, and marketable debt securies are held in a variety of deposit accounts, interest-bearing accounts, corporate bond securies, commercial paper, U.S government securies, asset-backed securies, and money market funds. Cash in excess of immediate requirements is invested with a view toward liquidity and capital preservaon, and we seek to minimize the potenal eﬀects of concentraon and credit risk. In October 2023, we completed an underwrien public oﬀering in which 9,833,334 shares of common stock were sold, including the exercise in full by the underwriters of their opon to purchase an addional 1,500,000 shares, at a public oﬀering price of $30.00 per share. In connecon with the oﬀering, we sold to certain investors pre-funded warrants, in lieu of common stock, to purchase 1,666,722 shares of common stock at a purchase price of $29.999 per pre- funded warrant, which equals the public oﬀering price per share of common stock less the $0.001 exercise price per share of each pre-funded warrant. The total proceeds that we received from the oﬀering were $326.5 million, net of underwring discounts and commissions. In May 2021, we entered into an Open Market Sale Agreement with Jeﬀeries LLC, or Jeﬀeries, pursuant to which we may oﬀer and sell shares of our common stock having an aggregate oﬀering proceeds up to $350.0 million, from me to me, in at-the-market, or ATM, oﬀerings through Jeﬀeries. There were 1,175,584 shares sold under this arrangement for the year ended December 31, 2023, for net proceeds of $53.3 million. No shares were sold under this arrangement for the year ended December 31, 2022. As of December 31, 2023, net proceeds from shares sold under the arrangement were $132.2 million. The following table summarizes our cash ﬂows for the periods indicated (in thousands): Cash used in operang acvies Cash provided by (used in) invesng acvies Cash provided by ﬁnancing acvies Eﬀect of exchange rate changes on cash Net increase (decrease) in cash, cash equivalents, and restricted cash Year Ended December 31, 2022 2023 (474,806 ) $ 168,000 388,142 462 (380,465 ) (291,652 ) 501,208 (1,075 ) 81,798 $ (171,984 ) $ $ Cash Used in Operang Acvies Our primary use of cash is to fund operang expenses, which consist primarily of research and development and commercial expenditures. Due to our signiﬁcant research and development expenditures, we have generated signiﬁcant operang losses since our incepon. Cash used to fund operang expenses is aﬀected by the ming of when we pay these expenses, as reﬂected in the change in our outstanding accounts payable and accrued expenses. Cash used in operang acvies for the year ended December 31, 2023 was $474.8 million and primarily reﬂected a net loss of $606.6 million, parally oﬀset by non-cash items of $146.9 million, net, which consisted primarily of non-cash collaboraon royalty revenues, interest expense related to the sale of future royales to RPI and OMERS, net of amounts capitalized, stock-based compensaon, amorzaon of discounts on marketable debt securies, and depreciaon and amorzaon. The change in operang assets and liabilies also reﬂected a net use of cash of $15.1 million, primarily due to an increase in accounts receivable primarily related to an increase in sales of our approved products, parally oﬀset by a net decrease in other assets primarily in prepaid manufacturing. 77 Cash used in operang acvies for the year ended December 31, 2022 was $380.5 million and reﬂected a net loss of $707.4 million parally oﬀset by non-cash items of $266.7 million, net, which consisted primarily of non-cash collaboraon royalty revenues, interest expense related to the sale of future royales to RPI and OMERS, net of amounts capitalized, stock-based compensaon, acquired in-process research and development relang to our acquision of GeneTx, the change in fair value of equity investments, primarily for the net change in fair value of equity investments from Arcturus and Solid, and depreciaon and amorzaon. The change in operang assets and liabilies also reﬂected net cash provided of $60.2 million, primarily due to an increase in accounts payable, accrued, and other liabilies, primarily due to ming of payments and receipt of invoices, as well as an increase in manufacturing accruals related to manufacturing and clinical expenses, an increase in accrued bonus due to an increase in headcount, and an increase in accrued development costs owed to a collaboraon partner, parally oﬀset by an increase in accounts receivable primarily related to an increase in sales of our approved products. Cash Provided by (Used in) Invesng Acvies Cash provided by invesng acvies for the year ended December 31, 2023 was $168.0 million and was primarily related to $219.8 million from net acvies in marketable debt securies, oﬀset by purchases of property, plant, and equipment of $44.3 million, primarily related to the ﬁt-out of our gene therapy manufacturing facility. Cash used in invesng acvies for the year ended December 31, 2022 was $291.7 million and was primarily related to purchases of property, plant, and equipment of $116.1 million, primarily related to the construcon of our gene therapy manufacturing facility, the acquision of GeneTx for $75.0 million, net of cash acquired, $79.8 million from net acvies in marketable debt securies, and the payment to Regeneron for intangible assets of $30.0 million, oﬀset by proceeds from the sale of Arcturus common stock of $10.1 million. Cash Provided by Financing Acvies Cash provided by ﬁnancing acvies for the year ended December 31, 2023 was $388.1 million and was primarily comprised of $326.5 million in net proceeds from the sale of common stock in our October 2023 underwrien public oﬀering and $53.3 million in net proceeds from the issuance of common stock from our ATM. Cash provided by ﬁnancing acvies for the year ended December 31, 2022 was $501.2 million and was primarily comprised of $491.0 million in net proceeds from the paral sale of future North America Crysvita royales to OMERS and $10.8 million in net proceeds from the issuance of common stock upon the exercise of stock opons, net of taxes withheld from the vesng of restricted stock units. Funding Requirements We ancipate that, excluding non-recurring items, we will connue to generate annual losses for the foreseeable future as we connue the development of, and seek regulatory approvals for, our product candidates, and connue with commercializaon of approved products. We may require addional capital to fund our operaons, to complete our ongoing and planned clinical studies, to commercialize our products, to connue invesng in early- stage research capabilies to promote our pipeline growth, to connue to acquire or invest in businesses or products that complement or expand our business, including future milestone payments thereunder, and to further develop our general infrastructure and such funding may not be available to us on acceptable terms or at all. If we are unable to raise addional capital in suﬃcient amounts or on terms acceptable to us, we may be required to delay, limit, reduce the scope of, or terminate one or more of our clinical studies, research and development programs, future commercializaon eﬀorts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves. Our future funding requirements will depend on many factors, including the following: • • • • • the scope, rate of progress, results and cost of our clinical studies, nonclinical tesng, and other related acvies; the cost of manufacturing clinical supplies, and establishing commercial supplies, of our product candidates, products that we have begun to commercialize, and any products that we may develop in the future; the cost of operang our GMP gene therapy manufacturing facility; the number and characteriscs of product candidates that we pursue; the cost, ming, and outcomes of regulatory interacons and approvals; 78 • • • the cost and ming of establishing our commercial infrastructure, and distribuon capabilies; the impact of macroeconomic condions, including the general economic slowdown, inﬂaonary pressure, high interest rates, a potenal U.S. federal government shutdown, and potenal recessionary environment on our business operaons and operang results, as described in “Part I, Item IA. Risk Factors " and the terms and ming of any collaborave, licensing, markeng, distribuon, acquision and other arrangements that we may establish, including any required upfront milestone, royalty, reimbursements or other payments thereunder. We expect to sasfy future cash needs through exisng capital balances, revenue from our commercial products, and a combinaon of public or private equity oﬀerings, debt ﬁnancings, collaboraons, strategic alliances, licensing arrangements, and other markeng and distribuon arrangements. Please see “Risk Factors—Risks Related to Our Financial Condion and Capital Requirements.” Contractual Obligaons and Commitments Material contractual obligaons arising in the normal course of business primarily consist of operang and ﬁnance leases and manufacturing and service contract obligaons. See Note 9 to the Consolidated Financial Statements for amounts outstanding for operang and ﬁnance leases on December 31, 2023. Manufacturing and service contract obligaons primarily relate to manufacturing of inventory for our approved products, the majority of which are due in the next 12 months. See Note 15 to the Consolidated Financial Statements for these contractual obligaons. The terms of certain of our licenses, royales, development and collaboraon agreements, as well as other research and development acvies, require us to pay potenal future milestone payments based on product development success. The amount and ming of such obligaons are unknown or uncertain. These potenal obligaons are further described in Note 8 to the Consolidated Financial Statements. Recent Accounng Pronouncements None. Item 7A. Quantave and Qualitave Disclosures about Market Risk Interest Rate Risk Our exposure to market risk for changes in interest rates relates primarily to interest earned on our cash equivalents and marketable debt securies. The primary objecve of our investment acvies is to preserve our capital to fund operaons. A secondary objecve is to maximize income from our investments without assuming signiﬁcant risk. Our investment policy provides for investments in low-risk, investment-grade debt instruments. As of December 31, 2023, we had cash, cash equivalents, and marketable debt securies totaling $777.1 million, which included bank deposits, money market funds, U.S. government treasury and agency securies, and investment-grade corporate bond securies which are subject to default, changes in credit rang, and changes in market value. The securies in our investment porolio are classiﬁed as available for sale and are subject to interest rate risk and will decrease in value if market interest rates increase. A hypothecal 100 basis point change in interest rates during any of the periods presented would not have had a material impact on the fair market value of our cash equivalents and marketable debt securies as of December 31, 2023. To date, we have not experienced a loss of principal on any of our investments and as of December 31, 2023, we did not record any allowance for credit loss from our investments. Foreign Currency Risk We face foreign exchange risk as a result of entering into transacons denominated in currencies other than U.S. dollars. Due to the uncertain ming of expected payments in foreign currencies, we do not ulize any forward exchange contracts. All foreign transacons sele on the applicable spot exchange basis at the me such payments are made. Volale market condions arising from the macroeconomic environment (including ﬁnancial condions aﬀecng the banking system and ﬁnancial instuons), inﬂaon, or global polical instability may result in signiﬁcant changes in exchange rates, and in parcular a weakening of foreign currencies relave to the U.S. dollar may negavely aﬀect our revenue and operang income as expressed in U.S. dollars. An adverse movement in foreign exchange rates could have a material eﬀect on payments made to foreign suppliers and payments related to license agreements. For the year ended December 31, 2023, a majority of our revenue, expenses, and capital expenditures were denominated in U.S. dollars. A hypothecal 10% change in foreign exchange rates during any of the periods presented would not have had a material impact on our Consolidated Financial Statements. 79 Item 8. Financial Statements and Supplementary Data Our ﬁnancial statements are annexed to this Annual Report beginning on page F-1 and are incorporated by reference into this Item 8. Item 9. Changes in and Disagreements with Accountants on Accounng and Financial Disclosure None. Item 9A. Controls and Procedures Evaluaon of Disclosure Controls and Procedures Management carried out an evaluaon, under the supervision and with the parcipaon of our Principal Execuve Oﬃcer and our Principal Financial Oﬃcer, of the eﬀecveness of our “disclosure controls and procedures” as of the end of the period covered by this Annual Report, pursuant to Rules 13a- 15(e) and 15d-15(e) under the Securies Exchange Act of 1934, or the Exchange Act. In connecon with that evaluaon, our Principal Execuve Oﬃcer and our Principal Financial Oﬃcer concluded that our disclosure controls and procedures were eﬀecve and designed to provide reasonable assurance that the informaon required to be disclosed is recorded, processed, summarized, and reported within the me periods speciﬁed in the SEC rules and forms as of December 31, 2023. For the purpose of this review, disclosure controls and procedures means controls and procedures designed to ensure that informaon required to be disclosed by us in the reports that we ﬁle or submit is recorded, processed, summarized and reported within the me periods speciﬁed in the SEC’s rules and forms. These disclosure controls and procedures include, without limitaon, controls and procedures designed to ensure that informaon required to be disclosed by us in the reports that we ﬁle or submit is accumulated and communicated to management, including our Principal Execuve Oﬃcer and our Principal Financial Oﬃcer, as appropriate to allow mely decisions regarding required disclosure. In designing and evaluang the disclosure controls and procedures, our management recognizes that any controls and procedures, no maer how well designed and operated, can provide only reasonable assurance of achieving the desired control objecves, and our management necessarily applies its judgment in evaluang the cost-beneﬁt relaonship of possible controls and procedures. Management’s Annual Report on Internal Control Over Financial Reporng Management is responsible for establishing and maintaining adequate internal control over ﬁnancial reporng as deﬁned in Rules 13a-15(f) and 15d- 15(f) of the Exchange Act. Our management used the Commiee of Sponsoring Organizaons of the Treadway Commission Internal Control - Integrated Framework issued by the Commiee of Sponsoring Organizaons of the Treadway Commission (2013 framework), or the COSO framework, to evaluate the eﬀecveness of internal control over ﬁnancial reporng. Management believes that the COSO framework is a suitable framework for its evaluaon of ﬁnancial reporng because it is free from bias, permits reasonably consistent qualitave and quantave measurements of our internal control over ﬁnancial reporng, is suﬃciently complete so that those relevant factors that would alter a conclusion about the eﬀecveness of our internal control over ﬁnancial reporng are not omied and is relevant to an evaluaon of internal control over ﬁnancial reporng. Management has assessed the eﬀecveness of our internal control over ﬁnancial reporng as of December 31, 2023, and has concluded that as of such date, our internal control over ﬁnancial reporng was eﬀecve. Our independent registered public accounng ﬁrm, Ernst & Young LLP, has audited the ﬁnancial statements included in this Annual Report and has issued a report on the eﬀecveness of our internal control over ﬁnancial reporng. The report of Ernst & Young LLP is included below. Changes in Internal Control over Financial Reporng There have been no changes in our internal control over ﬁnancial reporng (as deﬁned in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) during our fourth quarter ended December 31, 2023, that have materially aﬀected, or are reasonably likely to materially aﬀect our internal control over ﬁnancial reporng. To the Stockholders and the Board of Directors of Ultragenyx Pharmaceucal Inc. Report of Independent Registered Public Accounng Firm Opinion on Internal Control Over Financial Reporng We have audited Ultragenyx Pharmaceucal Inc.’s internal control over ﬁnancial reporng as of December 31, 2023, based on criteria established in Internal Control—Integrated Framework issued by the Commiee of Sponsoring Organizaons of the 80 Treadway Commission (2013 framework) (the COSO criteria). In our opinion, Ultragenyx Pharmaceucal Inc. (the Company) maintained, in all material respects, eﬀecve internal control over ﬁnancial reporng as of December 31, 2023, based on the COSO criteria. We also have audited, in accordance with the standards of the Public Company Accounng Oversight Board (United States) (PCAOB), the consolidated balance sheets of the Company as of December 31, 2023 and 2022, the related consolidated statements of operaons, comprehensive loss, stockholders’ equity and cash ﬂows for each of the three years in the period ended December 31, 2023, and the related notes and our report dated February 21, 2024 expressed an unqualiﬁed opinion thereon. Basis for Opinion The Company’s management is responsible for maintaining eﬀecve internal control over ﬁnancial reporng and for its assessment of the eﬀecveness of internal control over ﬁnancial reporng included in the accompanying Management’s Annual Report on Internal Control Over Financial Reporng. Our responsibility is to express an opinion on the Company’s internal control over ﬁnancial reporng based on our audit. We are a public accounng ﬁrm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securies laws and the applicable rules and regulaons of the Securies and Exchange Commission and the PCAOB. We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether eﬀecve internal control over ﬁnancial reporng was maintained in all material respects. Our audit included obtaining an understanding of internal control over ﬁnancial reporng, assessing the risk that a material weakness exists, tesng and evaluang the design and operang eﬀecveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our opinion. Deﬁnion and Limitaons of Internal Control Over Financial Reporng A company’s internal control over ﬁnancial reporng is a process designed to provide reasonable assurance regarding the reliability of ﬁnancial reporng and the preparaon of ﬁnancial statements for external purposes in accordance with generally accepted accounng principles. A company’s internal control over ﬁnancial reporng includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reﬂect the transacons and disposions of the assets of the company; (2) provide reasonable assurance that transacons are recorded as necessary to permit preparaon of ﬁnancial statements in accordance with generally accepted accounng principles, and that receipts and expenditures of the company are being made only in accordance with authorizaons of management and directors of the company; and (3) provide reasonable assurance regarding prevenon or mely detecon of unauthorized acquision, use, or disposion of the company’s assets that could have a material eﬀect on the ﬁnancial statements. Because of its inherent limitaons, internal control over ﬁnancial reporng may not prevent or detect misstatements. Also, projecons of any evaluaon of eﬀecveness to future periods are subject to the risk that controls may become inadequate because of changes in condions, or that the degree of compliance with the policies or procedures may deteriorate. /s/ Ernst & Young LLP San Mateo, California February 21, 2024 Item 9B. Other Informaon On November 10, 2023, Corsee Sanders, Ph.D., a member of the Company’s Board of Directors, adopted a trading arrangement intended to sasfy the aﬃrmave defense of Rule 10b5-1(c), to sell up to 2,322 shares of the Company’s common stock through July 12, 2024, subject to certain condions. On December 7, 2023, Mahew Fust, a member of the Company’s Board of Directors, adopted a trading arrangement intended to sasfy the aﬃrmave defense of Rule 10b5-1(c), to sell up to 12,195 shares of the Company’s common stock through December 6, 2024, subject to certain condions. Item 9C. Disclosure Regarding Foreign Jurisdicons that Prevent Inspecons Not applicable. 81 Item 10. Directors, Execuve Oﬃcers and Corporate Governance PART III Except as set forth below, the informaon required by this Item is incorporated herein by reference to informaon in the proxy statement for our 2024 Annual Meeng of Stockholders, which we will ﬁle with the SEC within 120 days of the end of the ﬁscal year to which this Annual Report relates, or the “2024 Proxy Statement”, including under the headings “Nominees and Incumbent Directors,” “Execuve Oﬃcers,” ““Board of Directors and Commiees,” and, as applicable, “Delinquent Secon 16(a) Beneﬁcial Ownership Reports.” We have adopted a code of ethics that applies to all of our directors, oﬃcers and employees, including our principal execuve, principal ﬁnancial and principal accounng oﬃcers, or persons performing similar funcons, or Code of Ethics. Our Code of Ethics is posted on our website located at hps://ir.ultragenyx.com/ under “Corporate Governance”. We intend to disclose future amendments to certain provisions of the Code of Ethics, and waivers of the Code of Ethics granted to execuve oﬃcers and directors, on the website within four business days following the date of the amendment or waiver. Item 11. Execuve Compensaon The informaon required by this Item is incorporated herein by reference to informaon in the 2024 Proxy Statement, including under the headings “Execuve Compensaon,” “Director Compensaon,” and “Board of Directors and Commiees.” Item 12. Security Ownership of Certain Beneﬁcial Owners and Management and Related Stockholder Maers The informaon required by this Item is incorporated herein by reference to informaon in the 2024 Proxy Statement, including under the headings “Security Ownership of Certain Beneﬁcial Owners and Management” and “Equity Compensaon Plan Informaon.” Item 13. Certain Relaonships and Related Transacons, and Director Independence The informaon required by this Item is incorporated herein by reference to informaon in the 2024 Proxy Statement, including under the headings “Certain Relaonships and Related-Person Transacons,” “Corporate Governance,” and “Board of Directors and Commiees.” Item 14. Principal Accountant Fees and Services The informaon required by this Item is incorporated herein by reference to informaon in the 2024 Proxy Statement, including under the heading “Proposal No. 3—Raﬁcaon of the Selecon of Independent Registered Public Accounng Firm.” 82 Item 15. Exhibits and Financial Statement Schedules (a) The following documents are ﬁled as part of this Annual Report. (1) Consolidated Financial Statements PART IV Consolidated Financial Statements—See Index to Consolidated Financial Statements at page F-1 of this Annual Report. (2) Consolidated Financial Statement Schedules Consolidated Financial Statement schedules have been omied in this Annual Report because they are not applicable, not required under the instrucons, or the informaon requested is set forth in the Consolidated Financial Statements or related notes thereto. (b) Exhibits Exhibit Descripon Form Date Number Incorporated by Reference Filed Herewith Amended and Restated Cerﬁcate of Incorporaon Second Amended and Restated Bylaws Form of Common Stock Cerﬁcate Form of Indenture Form of Pre-Funded Warrant Descripon of Common Stock Collaboraon and License Agreement, eﬀecve as of August 29, 2013, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 1 to Collaboraon and License Agreement, eﬀecve as of August 24, 2015, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 2 to Collaboraon and License Agreement, eﬀecve as of November 28, 2016, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 3 to Collaboraon and License Agreement, eﬀecve September 29, 2017, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 4 to Collaboraon and License Agreement, eﬀecve as of January 29, 2018, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 5 to Collaboraon and License Agreement, eﬀecve as of April 30, 2018, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. Amendment No. 6 to Collaboraon and License Agreement, eﬀecve as of February 1, 2019, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. 83 8-K 8-K S-1 2/5/2014 12/21/2023 11/8/2013 S-3 ASR 2/12/2021 8-K 10-K 10/23/2023 2/14/2020 S-1/A 12/23/2013 10-Q 11/10/2015 10-K 2/21/2018 10-K 2/21/2018 10-K 2/21/2018 10-Q 8/3/2018 10-Q 5/7/2019 3.1 3.1 4.2 4.2 4.1 4.3 10.1 10.2 10.3 10.4 10.5 10.1 10.2 Exhibit Number 3.1 3.2 4.1 4.2 4.3 4.4 10.1* 10.2 10.3 10.4* 10.5* 10.6* 10.7* 10.8* Amendment No. 7 to Collaboraon and License Agreement, eﬀecve as of December 5, 2018, between Ultragenyx Pharmaceucal Inc. and Kyowa Hakko Kirin Co., Ltd. 10-Q 5/7/2019 10.9* Amendment No. 8 to Collaboraon and License Agreement, eﬀecve 10-Q 8/2/2019 10.3 10.1 as of July 4, 2019, between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. (formerly, Kyowa Hakko Kirin Co., Ltd.) 10.10* Amendment No. 9 to Collaboraon and License Agreement, eﬀecve December 23, 2019, between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. 10-K 2/14/2020 10.10 10.11* Amendment No. 10 to Collaboraon and License Agreement, 10-Q 5/7/2020 10.2 eﬀecve as of April 1, 2020, between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. 10.12* Amendment No. 11 to Collaboraon and License Agreement, 10-K 2/16/2022 10.13 eﬀecve as of December 17, 2021 between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. 10.13* Amendment No. 12 to Collaboraon and License Agreement, 10-Q 11/3/2022 eﬀecve as of September 29, 2022, between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. 10.14* Amendment No. 13 to Collaboraon and License Agreement, 10-Q 8/3/2023 eﬀecve as of May 16, 2023, between Ultragenyx Pharmaceucal Inc. and Kyowa Kirin Co., Ltd. 10.15* Unit Purchase Agreement, dated as of July 15, 2022, by and among Ultragenyx Pharmaceucal Inc., GeneTx Biotherapeucs LLC, the Unitholders and Deborah A. Guagliardo 10-Q 7/29/2022 10.1 10.1 10.2 10.16* Commercial Supply and Services Agreement – Drug Substance, 10-K 2/21/2018 10.18 eﬀecve December 7, 2017, between Ultragenyx Europe GmbH and Rentschler Biopharma SE 10.17* Commercial Master Service Agreement – Drug Product, eﬀecve 10-K 2/17/2023 10.25 February 22, 2021, between Ultragenyx Pharmaceucal Inc. and BSP Pharmaceucals S.p.A 10.18* Commercial Supply Agreement, dated June 19, 2023, between Ultragenyx Pharmaceucal Inc. and IOI Oleo GmbH 10.19* Royalty Purchase Agreement, dated as of December 17, 2019, between Ultragenyx Pharmaceucal Inc. and RPI Finance Trust 10-K 2/14/2020 10.20* Royalty Purchase Agreement, dated as of July 14, 2022, by and 10-Q 7/29/2022 among Rare Delaware Inc., Ultragenyx Pharmaceucal Inc. and OCM LS23 Holdings LP 10.21# 2014 Incenve Plan (as amended) 10-K 2/17/2017 10.22# Form of Incenve Stock Opon Agreement (2014 Plan) S-1/A 1/17/2014 10.23# Form of Non Statutory Stock Opon Agreement (Employees) (2014 S-1/A 1/17/2014 Plan) 10.24# Form of Restricted Stock Unit Agreement (Employees) (2014 Plan) 84 10-Q 5/10/2016 10.25 10.1 10.20 10.14 10.15 10.1 X 10.25# Form of Non-Statutory Stock Opon Agreement (Annual Grant for 10-Q 8/3/2021 Directors) (2014 Plan) 10.26# Form of Restricted Stock Unit Agreement (Annual Grant for 10-Q 8/3/2021 Directors) (2014 Plan) 10.27# Form of Non-Statutory Stock Opon Agreement (Grant for New 10-Q 8/3/2021 Directors) (2014 Plan) 10.28# Form of Restricted Stock Unit Agreement (Grant for New 10-Q 8/3/2021 Directors) (2014 Plan) 10.29# 2023 Incenve Plan S-8 6/8/2023 10.30# Form of Incenve Stock Opon Agreement (2023 Plan) 10.31# Form of Non Statutory Stock Opon Agreement (Employees)(2023 Plan) 10.32# 10.33# 10.34# 10.35# 10.36# 10.37# 10.38# Form of Restricted Stock Unit Agreement (Employees)(2023 Plan) Form of Non-Statutory Stock Opon Agreement (Annual Grant for Directors) (2023 Plan) Form of Restricted Stock Unit Agreement (Annual Grant for Directors) (2023 Plan) Form of Non-Statutory Stock Opon Agreement (Grant for New Directors)(2023 Plan) Form of Restricted Stock Unit Agreement (Grant for New Directors) (2023 Plan) Form of Performance Stock Unit Agreement (2022) Form of Performance Stock Unit Agreement (2023) 10.39# Amended and Restated 2014 Employee Stock Purchase Plan 10.40# Corporate Bonus Plan 10.41# Employment Inducement Plan 10.42# First Amendment to Employment Inducement Plan 10.43# Form of Non Statutory Stock Opon Agreement (Inducement Plan) 10.44# Form of Non Statutory Stock Opon Agreement (Inducement Plan) (ex-US) 10.45# Form of Restricted Stock Unit Agreement (Inducement Plan) 10.46# Form of Restricted Stock Unit Agreement (Inducement Plan)(ex-US) 10.47# Ultragenyx Pharmaceucal Inc. Deferred Compensaon Plan 10.48# Amendment No. 1 to the Ultragenyx Pharmaceucal Inc. Deferred Compensaon Plan 10-Q 10-Q S-8 5/6/2022 5/4/2023 6/8/2023 S-1/A 1/17/2014 10-K S-8 10-K 10-K 10-K 10-K 10-Q 10-Q 2/12/2021 6/8/2023 2/12/2021 2/12/2021 2/12/2021 2/12/2021 8/3/2021 11/3/2021 10.49# Execuve Employment Agreement, dated as of June 15, 2011, S-1 11/8/2013 between Ultragenyx Pharmaceucal Inc. and Emil D. Kakkis, M.D., Ph.D. X X X X X X X 10.2 10.3 10.4 10.5 4.4 10.1 10.1 4.5 10.27 10.43 4.7 10.44 10.45 10.46 10.47 10.1 10.1 10.18 10.50# Amendment No. 1 to Execuve Employment Agreement, dated 10-Q 8/11/2014 10.2 August 8, 2014, between Ultragenyx Pharmaceucal Inc. and Emil D. Kakkis, M.D., Ph.D. 85 10.51# Amendment No. 2, dated September 13, 2022, to Execuve 10-Q 11/3/2022 10.2 Employment Agreement between Ultragenyx Pharmaceucal Inc. and Emil D. Kakkis, M.D., Ph.D. 10.52# Oﬀer Leer, dated as of October 31, 2011, between Ultragenyx S-1 11/8/2013 10.19 Pharmaceucal Inc. and Thomas Kassberg 10.53# 10.54# Amendment No. 1 to Oﬀer Leer, dated as of August 8, 2014, between Ultragenyx Pharmaceucal Inc. and Thomas Kassberg Amendment No. 2, dated September 13, 2022, to Oﬀer Leer between Ultragenyx Pharmaceucal Inc. and Thomas Kassberg 10-Q 8/11/2014 10-Q 11/3/2022 10.55# Oﬀer Leer, dated as of April 26, 2016, between Ultragenyx 10-Q 8/9/2016 Pharmaceucal Inc. and Karah Parschauer 10.56# Amendment, dated September 13, 2022, to Oﬀer Leer between 10-Q 11/3/2022 Ultragenyx Pharmaceucal Inc. and Karah Parschauer 10.57# Oﬀer Leer, dated as of February 20, 2015, between Ultragenyx 10-K 2/17/2017 Pharmaceucal Inc. and Dennis Huang 10.58# Amendment, dated September 13, 2022, to Oﬀer Leer between 10-Q 11/3/2022 Ultragenyx Pharmaceucal Inc. and Dennis Huang 10.59# Oﬀer Leer, dated as of June 11, 2015, between Ultragenyx 10-K 2/17/2017 Pharmaceucal Inc. and John R. Pinion II 10.60# Amendment, dated September 13, 2022, to Oﬀer Leer between 10-Q 11/3/2022 Ultragenyx Pharmaceucal Inc. and John R. Pinion II 10.61# Amended and Restated Oﬀer Leer, dated March 31, 2023, between 10-Q 5/4/2023 Ultragenyx Pharmaceucal Inc. and Eric Crombez, M.D. 10.62# Oﬀer Leer, dated June 2, 2023, between Ultragenyx Pharmaceucal 8-K 7/12/2023 Inc. and Howard Horn 10.63# Amendment, dated September 6, 2023, to the Oﬀer Leer between 8-K 9/8/2023 Ultragenyx Pharmaceucal Inc. and Howard Horn 10.64# Oﬀer Leer, dated May 16, 2017, between Ultragenyx 10-Q 8/2/2019 Pharmaceucal Inc. and Erik Harris 10.65# Addendum #1, dated August 8, 2017, to Oﬀer Leer dated May 16, 10-Q 8/2/2019 2017 between Ultragenyx Pharmaceucal Inc. and Erik Harris 10.66# Addendum #2, dated June 19, 2019, to Oﬀer Leer dated May 16, 10-Q 8/2/2019 2017 between Ultragenyx Pharmaceucal Inc. and Erik Harris 10.67# Amendment No. 3, dated September 13, 2022, to Oﬀer Leer 10-Q 11/3/2022 between Ultragenyx Pharmaceucal Inc. and Erik Harris 10.68# Form of Indemniﬁcaon Agreement 10.69 Standard Lease, dated as of July 5, 2011, between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10-K S-1 3/24/2014 11/8/2013 86 10.3 10.5 10.3 10.6 10.36 10.7 10.37 10.9 10.2 10.1 10.1 10.4 10.5 10.6 10.8 10.23 10.22 10.70 Addendum One to Standard Lease, dated as of July 5, 2011, between 10-K 2/26/2016 Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10.71 Addendum Two to Standard Lease, dated as of March 7, 2012, 10-K 2/26/2016 between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10.72 Addendum #3 to Standard Lease, eﬀecve as of February 12, 2014, between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10.73 Addendum #4 to Standard Lease, eﬀecve as of March 9, 2015, between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 8-K 8-K 2/25/2014 3/13/2015 10.34 10.35 10.1 10.1 10.74 Addendum #5 to Standard Lease, eﬀecve as of April 7, 2015, 10-K 2/26/2016 10.38 between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10.75 Addendum #6 to Standard Lease, eﬀecve as of April 29, 2019, 10-Q 8/2/2019 10.3 between Ultragenyx Pharmaceucal Inc. and Condio Enterprises, Inc. 10.76 Lease Agreement, dated as of December 8, 2015, between Marina 10-K 2/26/2016 Boulevard Property, LLC and Ultragenyx Pharmaceucal Inc. 10.77 Lease Agreement, dated November 2, 2015, between Dimension 10-K 2/21/2018 Therapeucs, Inc. and ARE-MA Region No. 20, LLC, and Consent to Assignment to Ultragenyx Pharmaceucal Inc. 10.78 First Amendment to Lease Agreement, dated March 20, 2018, 10-Q 5/8/2018 between Ultragenyx Pharmaceucal Inc. and ARE-MA Region No. 20, LLC 10.79 Second Amendment to Lease Agreement, dated July 1, 2018, 10-Q 8/3/2018 between Ultragenyx Pharmaceucal Inc. and ARE-MA Region No. 20, LLC 10.80 Third Amendment to the Lease Agreement, dated July 29, 2019, 10-Q 7/30/2020 between Ultragenyx Pharmaceucal Inc. and ARE-MA Region No., LLC. 10.81 Amended and Restated Fourth Amendment, dated August 4, 2020, 10-Q 10/27/2020 to the Lease Agreement between Ultragenyx Pharmaceucal Inc. and ARE-MA Region No., LLC. 10.82 Lease Agreement, dated December 15, 2019, between Ultragenyx 10-K 2/12/2021 Pharmaceucal Inc. and ARE-San Francisco No. 17, LLC. 10.83 First Amendment, dated September 20, 2020, to the Lease 10-K 2/12/2021 Agreement between Ultragenyx Pharmaceucal Inc. and ARE-San Francisco No. 17, LLC. 10.43 10.66 10.6 10.3 10.2 10.5 10.81 10.82 10.84 Second Amendment, dated October 21, 2020, to the Lease 10-K 2/12/2021 10.83 Agreement between Ultragenyx Pharmaceucal Inc. and ARE-San Francisco No. 17, LLC. 10.85 Third Amendment, dated July 27, 2022, to the Lease Agreement 10-K 2/16/2023 10.92 between Ultragenyx Pharmaceucal Inc. and ARE-San Francisco No. 17, LLC 87 10.86 Oﬃce Lease, dated April 19, 2019, between Ultragenyx Pharmaceucal Inc. and Woburn MCB II, LLC 10.87 Commercial Lease, dated July 2, 2018, between Ultragenyx Pharmaceucal Inc. and 32 Leveroni LLC 10-K 10-K 2/14/2020 2/14/2020 10.88 Lease, dated August 18, 2022, between Ultragenyx Pharmaceucal 10-K 2/17/2023 10.70 10.71 10.95 21.1 23.1 24.1 31.1 Inc. and Brickboom I QOZB L.P. Subsidiaries of Ultragenyx Pharmaceucal Inc. Consent of Independent Registered Public Accounng Firm Power of Aorney (included on the signature page of this report) Cerﬁcaon of Principal Execuve Oﬃcer of Ultragenyx Pharmaceucal Inc., as required by Rule 13a-14(a) or Rule 15d-14(a) of the Exchange Act as adopted pursuant to Secon 302 of the Sarbanes-Oxley Act of 2002 31.2 Cerﬁcaon of Principal Financial Oﬃcer of Ultragenyx Pharmaceucal Inc., as required by Rule 13a-14(a) or Rule 15d-14(a) of the Exchange Act as adopted pursuant to Secon 302 of the Sarbanes-Oxley Act of 2002 32.1§ Cerﬁcaon by the Principal Execuve Oﬃcer and Principal Financial Oﬃcer, as required by Rule 13a-14(b) or Rule 15d-14(b) and Secon 1350 of Chapter 36 of Title 18 of the United States Code (18 U.S.C. §1350) 97.1 Ultragenyx Pharmaceucal Inc. Clawback Policy 101.INS XBRL Instance Document, formaed in Inline XBRL 101.SCH Inline XBRL Taxonomy Extension Schema Document 104 The cover page from this Annual Report on Form 10-K, formaed in Inline XBRL and contained in Exhibit 101 X X X X X X X X X * Certain idenﬁed informaon has been omied by means of marking such informaon with asterisks in reliance on Item 601(b)(10)(iv) of Regulaon S-K because it is both (i) not material and (ii) the type that the registrant treats as private or conﬁdenal. # Indicates management contract or compensatory plan. § The cerﬁcaon aached as Exhibit 32.1 that accompanies this Annual Report is not deemed ﬁled with the SEC and is not to be incorporated by reference into any ﬁling of Ultragenyx Pharmaceucal Inc. under the Securies Act or the Exchange Act, whether made before or aer the date of this Annual Report, irrespecve of any general incorporaon language contained in such ﬁling. Item 16. Form 10-K Summary None. 88 Pursuant to the requirements of Secon 13 or 15(d) of the Securies Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized. SIGNATURES ULTRAGENYX PHARMACEUTICAL I. By: /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D. President and Chief Execuve Oﬃcer (Principal Execuve Oﬃcer) Date: February 21, 2024 POWER OF ATTORNEY KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below constutes and appoints Emil D. Kakkis, M.D., Ph.D. and Howard Horn, and each of them, as his or her true and lawful aorneys-in-fact and agents, with full power of substuon for him or her, and in his or her name in any and all capacies, to sign any and all amendments to this Annual Report, and to ﬁle the same, with exhibits thereto and other documents in connecon therewith, with the Securies and Exchange Commission, granng unto said aorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done therewith, as fully to all intents and purposes as he or she might or could do in person, hereby rafying and conﬁrming all that said aorneys-in-fact and agents, and any of them, his or her substute or substutes, may lawfully do or cause to be done by virtue hereof. Pursuant to the requirements of the Securies Exchange Act of 1934, this report has been signed below by the following persons on behalf of the registrant and in the capacies and on the dates indicated. Signature /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D. /s/ Howard Horn Howard Horn /s/ Theodore A. Huizenga Theodore A. Huizenga /s/ Daniel G. Welch Daniel G. Welch /s/ Deborah Dunsire Deborah Dunsire, M.D. /s/ Mahew K. Fust Mahew K. Fust /s/ Michael Narachi Michael Narachi /s/ Amrit Ray Amrit Ray, M.D. /s/ Corsee D. Sanders Corsee D. Sanders, Ph.D. /s/ Shehnaaz Suliman Shehnaaz Suliman, M.D. Title President and Chief Execuve Oﬃcer and Director (Principal Execuve Oﬃcer) Execuve Vice President, Chief Financial Oﬃcer, Corporate Strategy (Principal Financial Oﬃcer) Senior Vice President and Chief Accounng Oﬃcer (Principal Accounng Oﬃcer) Chairman of the Board Director Director Director Director Director Director 89 Date February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 February 21, 2024 Ultragenyx Pharmaceucal Inc. INDEX TO FINANCIAL STATEMENTS Report of Independent Registered Public Accounng Firm (PCAOB ID: 42) Consolidated Financial Statements: Consolidated Balance Sheets Consolidated Statements of Operaons Consolidated Statements of Comprehensive Loss Consolidated Statements of Stockholders’ Equity Consolidated Statements of Cash Flows Notes to Consolidated Financial Statements F-1 Page F-2 F-4 F-5 F-5 F-6 F-7 F-9 Report of Independent Registered Public Accounng Firm To the Stockholders and the Board of Directors of Ultragenyx Pharmaceucal Inc. Opinion on the Financial Statements We have audited the accompanying consolidated balance sheets of Ultragenyx Pharmaceucal Inc. (the Company) as of December 31, 2023 and 2022, the related consolidated statements of operaons, comprehensive loss, stockholders' equity and cash ﬂows for each of the three years in the period ended December 31, 2023, and the related notes (collecvely referred to as the “consolidated ﬁnancial statements”). In our opinion, the consolidated ﬁnancial statements present fairly, in all material respects, the ﬁnancial posion of the Company at December 31, 2023 and 2022, and the results of its operaons and its cash ﬂows for each of the three years in the period ended December 31, 2023, in conformity with U.S. generally accepted accounng principles. We also have audited, in accordance with the standards of the Public Company Accounng Oversight Board (United States) (PCAOB), the Company's internal control over ﬁnancial reporng as of December 31, 2023, based on criteria established in Internal Control—Integrated Framework issued by the Commiee of Sponsoring Organizaons of the Treadway Commission (2013 framework), and our report dated February 21, 2024 expressed an unqualiﬁed opinion thereon. Basis for Opinion These ﬁnancial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company’s ﬁnancial statements based on our audits. We are a public accounng ﬁrm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securies laws and the applicable rules and regulaons of the Securies and Exchange Commission and the PCAOB. We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the ﬁnancial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the ﬁnancial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the ﬁnancial statements. Our audits also included evaluang the accounng principles used and signiﬁcant esmates made by management, as well as evaluang the overall presentaon of the ﬁnancial statements. We believe that our audits provide a reasonable basis for our opinion. Crical Audit Maer The crical audit maer communicated below is a maer arising from the current period audit of the ﬁnancial statements that was communicated or required to be communicated to the audit commiee and that: (1) relates to accounts or disclosures that are material to the ﬁnancial statements and (2) involved our especially challenging, subjecve or complex judgments. The communicaon of the crical audit maer does not alter in any way our opinion on the consolidated ﬁnancial statements, taken as a whole, and we are not, by communicang the crical audit maer below, providing a separate opinion on the crical audit maer or on the accounts or disclosures to which it relates. Descripon of the Maer Liabilies for sales of future royales As discussed in Note 10, the Company has entered into two royalty purchase agreements, under which the Company sold its rights to receive royalty payments arising from the net sales of Crysvita in the European and North American markets in exchange for $320 million and $500 million, respecvely. The proceeds from each transacon were recorded as liabilies that are being amorzed using the eﬀecve interest method over the esmated lives of the respecve arrangements. In order to determine the amorzaon of the liabilies, the Company is required to esmate the total amount of future royalty payments to be paid to the respecve counterparty, subject to the capped amount, over the life of the arrangement. The Company esmates an imputed interest on the unamorzed poron of the liability and records non-cash interest expense relang to the transacon. Auding the Company’s liabilies related to the sale of future royales was complex due to the subjecve judgments required to forecast the expected royalty payments subject to each agreement. Speciﬁcally, the forecasted revenues of Crysvita involve signiﬁcant esmaon uncertainty given the limited historical Crysvita sales data. F-2 How We Addressed the Maer in Our Audit We obtained an understanding, evaluated the design and tested the operang eﬀecveness of controls over the Company’s process of accounng for the liabilies related to the sale of future royales, including controls over the Company’s esmates of projected sales of Crysvita in the European and North American markets. To test management’s esmates of the future royales and the imputed eﬀecve interest rates, we performed audit procedures that included, among others, evaluang the reasonableness of management’s assumpons related to the treatable paent populaons, esmated pricing and reimbursement, and the rate of adopon. We compared the signiﬁcant assumpons with historical trends of actual sales, analyst expectaons and performed sensivity analyses of esmated future royales to evaluate the changes in the future royales on the implied eﬀecve interest rates. /s/ Ernst & Young LLP We have served as the Company’s auditor since 2012. San Mateo, California February 21, 2024 F-3 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED BALANCE SHEETS (In thousands, except share and per share amounts) ASSETS December 31, 2023 2022 Current assets: Cash and cash equivalents Marketable debt securies Accounts receivable, net Inventory Other assets Total current assets Property, plant, and equipment, net Marketable debt securies Intangible assets, net Goodwill Other assets Total assets Current liabilies: Accounts payable Accrued liabilies Contract liabilies Lease liabilies Liabilies for sales of future royales Total current liabilies Lease liabilies Deferred tax liabilies Liabilies for sales of future royales Other liabilies Total liabilies Commitments and conngencies (Notes 9 and 15) Stockholders’ equity: LIABILITIES AND STOCKHOLDERS' EQUITY Preferred stock, par value of $0.001 per share—25,000,000 shares authorized; nil outstanding in 2023 and in 2022 Common stock, par value of $0.001 per share—250,000,000 shares authorized; outstanding—82,315,590 in 2023 and 70,197,297 in 2022 Treasury stock, at cost, 9,559 in 2023 and nil in 2022 Deferred compensaon obligaon Addional paid-in capital Accumulated other comprehensive income (loss) Accumulated deﬁcit Total stockholders’ equity Total liabilies and stockholders’ equity See accompanying notes. F-4 $ $ $ $ 213,584 $ 363,625 73,390 33,969 47,616 732,184 290,566 199,901 166,271 44,406 57,685 1,491,013 $ 42,114 $ 196,486 — 12,595 29,242 280,437 30,574 30,058 862,325 12,205 1,215,599 132,944 614,818 40,445 26,766 68,926 883,899 259,726 148,970 160,105 44,406 48,338 1,545,444 43,274 204,678 1,479 11,779 — 261,210 19,814 31,667 875,439 4,820 1,192,950 — — 82 (432 ) 432 3,662,346 647 (3,387,661 ) 275,414 1,491,013 $ 70 — — 3,140,019 (6,573 ) (2,781,022 ) 352,494 1,545,444 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except share and per share amounts) Revenues: Product sales Royalty revenue Collaboraon and license Total revenues Operang expenses: Cost of sales Research and development Selling, general and administrave Total operang expenses Loss from operaons Interest income Change in fair value of equity investments Non-cash interest expense on liabilies for sales of future royales Other expense Loss before income taxes Beneﬁt from (provision for) income taxes Net loss Net loss per share, basic and diluted Year Ended December 31, 2022 2023 2021 $ 180,413 $ 182,652 71,184 434,249 118,927 $ 21,692 222,710 363,329 45,209 648,449 309,799 1,003,457 (569,208 ) 26,688 397 (66,004 ) (337 ) (608,464 ) 1,825 (606,639 ) $ (8.25 ) $ 28,320 705,789 278,139 1,012,248 (648,919 ) 11,074 (19,299 ) (43,015 ) (1,566 ) (701,725 ) (5,696 ) (707,421 ) $ (10.12 ) $ $ $ 77,017 17,951 256,438 351,406 16,008 497,153 219,982 733,143 (381,737 ) 1,928 (42,063 ) (29,422 ) (1,687 ) (452,981 ) (1,044 ) (454,025 ) (6.70 ) Shares used in compung net loss per share, basic and diluted 73,543,862 69,914,225 67,795,540 See accompanying notes. ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS (In thousands) 2023 Net loss Other comprehensive income (loss): Foreign currency translaon adjustments Unrealized gain (loss) on available-for-sale securies Other comprehensive income (loss): Total comprehensive loss $ $ See accompanying notes. F-5 Year Ended December 31, 2022 (707,421 ) $ (606,639 ) $ 239 6,981 7,220 (599,419 ) $ (724 ) (4,445 ) (5,169 ) (712,590 ) $ 2021 (454,025 ) (550 ) (1,543 ) (2,093 ) (456,118 ) ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF STOCKHOLDERS’ EQUITY (In thousands, except share amounts) Common Stock Addional Paid-In Shares Amount Capital Accumulated Other Comprehens ive Income (Loss) Accumulate d Deﬁcit Balance as of December 31, 2020 66,818,520 $ 67 $ 2,773,195 $ 689 $ (1,619,576 ) $ Deferred Compensa on Total Stockholders ' Treasury Stock Obligaon — $ — Equity $ 1,154,375 Issuance of common stock in connecon with at-the-market oﬀering, net of issuance costs Stock-based compensaon Issuance of common stock under equity plan awards, net of tax Other comprehensive loss Net loss Balance as of December 31, 2021 Stock-based compensaon Issuance of common stock under equity plan awards, net of tax Other comprehensive loss Net loss Balance as of December 31, 2022 Issuance of common stock and pre-funded warrants in connecon with underwrien public oﬀering, net of issuance costs Issuance of common stock in connecon with at-the-market oﬀering, net of issuance costs Stock-based compensaon Issuance of common stock under equity plan awards, net of tax Deferred compensaon Other comprehensive income Net loss 1,050,372 — 1,476,106 — — 69,344,998 — $ 852,299 — — 1 — 1 — — 69 — 1 — — 78,942 105,260 40,100 — — $ 2,997,497 131,710 10,812 — — — — — (2,093 ) — — — — — (454,025 ) $ (1,404 ) $ (2,073,601 ) $ — — (5,169 ) — — — — (707,421 ) — — — — — — — — — — $ — — — — — — — — — — $ 78,943 105,260 40,101 (2,093 ) (454,025 ) 922,561 131,710 10,813 (5,169 ) (707,421 ) 70,197,297 $ 70 $ 3,140,019 $ (6,573 ) $ (2,781,022 ) $ — $ — $ 352,494 9,833,334 10 326,446 1,175,584 — 1,109,375 — — — 1 — 1 — — — 53,298 134,169 8,414 — — — — — — — — 7,220 — — — — — — — (606,639 ) — — — — (432 ) — — (432 ) $ — 326,456 — — — 432 — — 432 $ 53,299 134,169 8,415 — 7,220 (606,639 ) 275,414 Balance as of December 31, 2023 82,315,590 $ 82 $ 3,662,346 $ 647 $ (3,387,661 ) $ See accompanying notes. F-6 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF CASH FLOWS (In thousands) Operang acvies: Net loss Adjustments to reconcile net loss to net cash used in operang acvies: Stock-based compensaon Acquired in-process research and development Amorzaon of premium (discount) on marketable debt securies, net Depreciaon and amorzaon Change in fair value of equity investments Non-cash collaboraon royalty revenue Non-cash interest expense on liabilies for sales of future royales Other Changes in operang assets and liabilies: Accounts receivable Inventory Other assets Accounts payable, accrued, and other liabilies Contract liabilies, net Deferred tax liabilies Net cash used in operang acvies Invesng acvies: Purchase of property, plant, and equipment Acquision, net of cash acquired Purchase of marketable debt securies Proceeds from sale of marketable debt securies Proceeds from sale of equity investments Proceeds from maturies of marketable debt securies Payment for intangible asset Other Net cash provided by (used in) invesng acvies Financing acvies: Proceeds from the sale of future royales, net Proceeds from the issuance of common stock and pre-funded warrants in connecon with underwrien public oﬀerings, net of issuance costs Proceeds from the issuance of common stock in connecon with at-the-market oﬀering, net of issuances costs Proceeds from the issuance of common stock from exercise of warrants and equity plan awards, net Other Net cash provided by ﬁnancing acvies Eﬀect of exchange rate changes on cash Net increase (decrease) in cash, cash equivalents, and restricted cash Cash, cash equivalents, and restricted cash at beginning of year Cash, cash equivalents, and restricted cash at end of year $ F-7 Year Ended December 31, 2022 2023 2021 $ (606,639 ) $ (707,421 ) $ (454,025 ) 135,227 — (12,842 ) 26,006 (397 ) (69,364 ) 66,004 2,300 (22,778 ) (6,930 ) 15,325 2,380 (1,479 ) (1,619 ) (474,806 ) (44,267 ) — (526,382 ) 50,672 — 695,525 (2,500 ) (5,048 ) 168,000 130,377 75,033 2,699 18,220 19,299 (21,692 ) 43,015 (230 ) (12,068 ) (9,701 ) 3,798 87,442 (7,597 ) (1,639 ) (380,465 ) (116,123 ) (75,025 ) (614,735 ) 84,275 10,094 450,706 (30,000 ) (844 ) (291,652 ) — 490,950 326,456 53,299 8,415 (28 ) 388,142 462 81,798 137,601 219,399 $ — — 10,813 (555 ) 501,208 (1,075 ) (171,984 ) 309,585 137,601 $ 104,952 — 6,606 13,239 42,063 (17,951 ) 29,422 235 (5,432 ) (3,117 ) (29,508 ) 32,313 (57,492 ) — (338,695 ) (73,093 ) — (1,012,187 ) 92,896 79,843 718,111 — (942 ) (195,372 ) — — 78,943 40,101 (492 ) 118,552 (1,194 ) (416,709 ) 726,294 309,585 See accompanying notes. ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF CASH FLOWS (In thousands) Supplemental disclosures of non-cash invesng and ﬁnancing informaon: Acquired lease liabilies arising from obtaining right-of-use assets and property, plant, and equipment Costs of property, plant and equipment included in accounts payable, accrued, and other liabilies $ Non-cash interest expense on liabilies for sales of future royales capitalized during the year into ending property, plant and equipment $ $ See accompanying notes. F-8 Year Ended December 31, 2022 2023 2021 22,162 $ 1,577 $ 1,168 $ 17,963 $ 3,142 18,993 9,431 $ 11,380 $ 4,650 1. Organization and Basis of Presentaon Ultragenyx Pharmaceucal Inc., or the Company, is a biopharmaceucal company incorporated in Delaware. ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements The Company is focused on the idenﬁcaon, acquision, development, and commercializaon of novel products for the treatment of serious rare and ultrarare genec diseases. The Company operates as one reportable segment and has four commercially approved products. Crysvita® (burosumab) is approved in the United States, or U.S., the European Union, or EU, and certain other regions for the treatment of X-linked hypophosphatemia, or XLH, in adult and pediatric paents one year of age and older. Crysvita is also approved in the U.S. and certain other regions for the treatment of ﬁbroblast growth factor 23, or FGF23-related hypophosphatemia in tumor-induced osteomalacia, or TIO, associated with phosphaturic mesenchymal tumors that cannot be curavely resected or localized in adults and pediatric paents 2 years of age and older. Mepsevii® (vestronidase alfa) is approved in the U.S., the EU and certain other regions, as the ﬁrst medicine for the treatment of children and adults with mucopolysaccharidosis VII, or MPS VII, also known as Sly syndrome. Dojolvi® (triheptanoin) is approved in the U.S. and certain other regions for the treatment of pediatric and adult paents severely aﬀected by long- chain fay acid oxidaon disorders, or LC-FAOD. Evkeeza® (evinacumab) is approved in the U.S. and the European Economic Area, or EEA, for the treatment of homozygous familial hypercholesterolemia, or HoFH. The Company has exclusive rights to commercialize Evkeeza® (evinacumab) outside of the U.S. In addion to the approved products, the Company has the following ongoing clinical development programs: • • • • • • UX111 (formerly ABO-102) is an AAV9 gene therapy product candidate for the treatment of paents with Sanﬁlippo syndrome type A, or MPS IIIA, a rare lysosomal storage disease; DTX401 is an adeno-associated virus 8, or AAV8, gene therapy product candidate for the treatment of paents with glycogen storage disease type Ia, or GSDIa; DTX301 is an AAV8 gene therapy product candidate in development for the treatment of paents with ornithine transcarbamylase, or OTC deﬁciency, the most common urea cycle disorder; UX143 (setrusumab), which is subject to the Company’s collaboraon agreement with Mereo BioPharma 3, or Mereo, is a fully human monoclonal anbody that inhibits sclerosn, a protein that acts on a key bone-signaling pathway and inhibits the acvity of bone-forming cells for the treatment of paents with osteogenesis imperfect, or OI; GTX-102 is an ansense oligonucleode, or ASO for the treatment of Angelman syndrome, a debilitang and rare neurogenec disorder caused by loss-of-funcon of the maternally inherited allele of the UBE3A gene.; and UX701 is an adeno-associated virus 9, or AAV9, gene therapy designed to deliver stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion to improve copper distribuon and excreon from the body and reverse pathological ﬁndings of Wilson liver disease; The Company has sustained operang losses and expects such annual losses to connue over the next several years. The Company’s ulmate success depends on the outcome of its research and development and commercializaon acvies. Through December 31, 2023, the Company has relied primarily on its sale of equity securies, its revenues from commercial products, its sale of future royales, and strategic collaboraon arrangements to ﬁnance its operaons. The Company may need to raise addional capital to fully implement its business plans through the issuance of equity, borrowings, or strategic alliances with partner companies. However, if such ﬁnancing is not available at adequate levels, the Company would need to reevaluate its operang plans. 2. Summary of Signiﬁcant Accounng Policies Basis of Consolidaon The Consolidated Financial Statements include the accounts of Ultragenyx Pharmaceucal Inc. and its wholly owned subsidiaries. All intercompany balances and transacons have been eliminated. ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Use of Esmates The accompanying Consolidated Financial Statements have been prepared in accordance with U.S. generally accepted accounng principles, or GAAP. The preparaon of the Consolidated Financial Statements in conformity with GAAP requires management to make esmates and assumpons that aﬀect the reported amounts of assets and liabilies, disclosure of conngent liabilies and the reported amounts of expenses in the Consolidated Financial Statements and the accompanying notes. On an ongoing basis, management evaluates its esmates, including those related to clinical trial accruals, fair value of assets and liabilies, income taxes, stock-based compensaon, revenue recognion, and the liabilies for sales of future royales. Management bases its esmates on historical experience and on various other market-speciﬁc and relevant assumpons that management believes to be reasonable under the circumstances. Actual results could diﬀer from those esmates. Cash, Cash Equivalents, and Restricted Cash The Company considers all highly liquid investments with original maturies of three months or less from the date of purchase to be cash equivalents. Cash equivalents consist primarily of amounts invested in money market accounts. Restricted cash primarily consists of money market accounts used as collateral for the Company’s obligaons under its facility leases and the gene therapy building construcon project. The following table provides a reconciliaon of cash, cash equivalents, and restricted cash reported within the Consolidated Balance Sheets that sum to the total of the same such amounts shown in the Consolidated Statements of Cash Flows (in thousands): December 31, Cash and cash equivalents $ Restricted cash included in other current assets Restricted cash included in other non-current assets Total cash, cash equivalents, and restricted cash shown in the statements of cash ﬂows 2021 2022 2023 213,584 $ 132,944 $ 307,584 — 2,001 2,008 3,807 862 3,795 $ 219,399 $ 137,601 $ 309,585 Marketable Debt Securies All marketable debt securies have been classiﬁed as “available-for-sale” and are carried at esmated fair value as determined based upon quoted market prices or pricing models for similar securies. Management determines the appropriate classiﬁcaon of its investments at the me of purchase and reevaluates such designaon as of each balance sheet date. Investments with a maturity of one year or less from the balance sheet date are reported as current marketable debt securies and investments with a maturity of greater than one year from the balance sheet date are reported as non-current marketable debt securies. Unrealized gains and losses are excluded from earnings and are reported as a component of comprehensive loss. Realized gains and losses and declines in fair value judged to be other than temporary, if any, on available-for-sale securies are included in other income (expense). The cost of securies sold is based on the speciﬁc-idenﬁcaon method. Interest on investments is included in interest income. Equity Investments The Company records investments in equity securies, other than equity method investments, at fair market value, if the fair value is readily determinable. Equity securies with no readily determinable fair values are recorded using the measurement alternave of cost adjusted for observable price changes in orderly transacons for idencal or similar investments of the same issuer less impairment, if any. Investments in equity securies are recorded in Equity investments on the Company's Consolidated Balance Sheets. Unrealized gains and losses are reported in Change in fair value of equity investments on the Company’s Consolidated Statements of Operaons. The Company regularly reviews its non-marketable equity securies for indicators of impairment. F-10 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Concentraon of Credit Risk, Credit Losses, and Other Risks and Uncertaines Financial instruments that potenally subject the Company to a concentraon of credit risk consist of cash, cash equivalents, and investments. The Company’s cash, cash equivalents, and investments are held by ﬁnancial instuons that management believes are of high credit quality. The Company’s investment policy limits investments to ﬁxed income securies denominated and payable in U.S. dollars such as U.S. government obligaons, money market instruments and funds, corporate bonds, commercial paper, and asset-backed securies and places restricons on maturies and concentraons by type and issuer. Such deposits may, at mes, exceed federally insured limits. The Company has not experienced any losses on its deposits of cash and cash equivalents and its accounts are monitored by management to migate risk. The Company is exposed to credit risk in the event of default by the ﬁnancial instuons holding its cash and cash equivalents, corporate issuers, and other ﬁnancial instruments, to the extent recorded in the Consolidated Balance Sheets. The Company is exposed to credit losses primarily through receivables from customers and collaborators and through its available-for-sale debt securies. For trade receivables and other instruments, the Company uses a forward-looking expected loss model that generally results in the earlier recognion of allowances for losses. For available-for-sale debt securies with unrealized losses, the losses are recognized as allowances rather than as reducons in the amorzed cost of the securies. The Company’s expected loss allowance methodology for the receivables is developed using historical collecon experience, current and future economic market condions, a review of the current aging status and ﬁnancial condion of the enes. Speciﬁc allowance amounts are established to record the appropriate allowance for customers that have a higher probability of default. Balances are wrien oﬀ when determined to be uncollecble. The Company’s expected loss allowance methodology for the debt securies is developed by reviewing the extent of the unrealized loss, the size, term, geographical locaon, and industry of the issuer, the issuers’ credit rangs and any changes in those rangs, as well as reviewing current and future economic market condions and the issuers’ current status and ﬁnancial condion. There was no allowance for losses on available-for-sale debt securies which were aributable to credit risk for the years ended December 31, 2023 and 2022. The Company is dependent on third-party manufacturers to supply products for research and development acvies in its programs. In parcular, the Company relies and expects to connue to rely on a small number of manufacturers to supply it with its requirements for the acve pharmaceucal ingredients and formulated drugs related to these programs. These programs could be adversely aﬀected by a signiﬁcant interrupon in the supply of acve pharmaceucal ingredients and formulated drugs. Inventory The Company values inventory at the lower of cost and net realizable value and determines the cost of inventory using the average-cost method. The Company expenses costs associated with the manufacture of product candidates prior to regulatory approval. Inventories consist of currently approved products. The Company periodically reviews its inventories for excess amounts or obsolescence and writes down obsolete or otherwise unmarketable inventory to its esmated net realizable value. Management determines excess inventory based on expected future demand. Esmates related to future demand are sensive to signiﬁcant inputs and assumpons such as acceptance by paents and physicians and the availability of formulary coverage and adequate reimbursement from private third-party payers for the product. Property, Plant, and Equipment Property, plant, and equipment are stated at cost, less accumulated depreciaon and amorzaon. Depreciaon and amorzaon is computed using the straight-line method over the esmated useful lives of the respecve assets. Depreciaon and amorzaon begins when the asset is placed in service. Interest costs incurred during the construcon of major capital projects are capitalized unl the underlying asset is ready to be placed in service. Maintenance and repairs are charged to operaons as incurred. Upon sale or rerement of assets, the cost and related accumulated depreciaon or amorzaon are removed from the balance sheet and the resulng gain or loss, if any, is reﬂected in operaons. See “Note 4. Balance Sheet Components” for further disclosure on the useful lives of property, plant, and equipment. Intangible Assets Finite-lived intangibles consist of contractual payments made for certain milestones achieved with collaboraon partners. The contractual payments are recorded as intangible assets and are amorzed over their esmated useful lives. The Company reviews its deﬁnite-lived intangible assets when events or circumstances may indicate that the carrying value of these assets is not recoverable and exceeds their fair value. The Company measures fair value based on the esmated future undiscounted cash ﬂows associated with these assets in addion to other assumpons and projecons that the Company deems to be reasonable and supportable. F-11 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Indeﬁnite-lived intangibles consist of acquired in-process research and development, or IPR&D. IPR&D assets represent capitalized incomplete research projects that the Company acquired through business combinaons. Such assets are inially measured at their acquision date fair values and are tested for impairment annually and whenever events or changes in circumstances indicate that the carrying amount may not be recoverable. When development of the project is complete, which generally occurs when regulatory approval to market a product is obtained, the associated assets will be deemed ﬁnite-lived and will be amorzed over a period that best reﬂects the economic beneﬁts provided by these assets. If it is determined that an intangible asset becomes impaired, the carrying value is wrien down to its fair value with the related impairment charge recognized in Consolidated Statements of Operaons in the period in which the impairment occurs. The Company has not recorded any impairments of intangible assets to date. Goodwill Goodwill represents the excess of purchase price over fair value of net assets acquired in a business combinaon and is not amorzed. Goodwill is subject to impairment tesng at least annually during the fourth quarter or when a triggering event occurs that could indicate a potenal impairment. If it is determined that the goodwill becomes impaired, the carrying value is wrien down to its fair value with the related impairment charge recognized in Consolidated Statements of Operaons in the period in which the impairment occurs. The Company has not recorded any impairments of goodwill. Impairment of Long-Lived Assets The Company evaluates its long-lived assets, including property and equipment, for impairment whenever events or changes in circumstances indicate that the carrying value of these assets may not be recoverable. Recoverability of these assets is measured by comparison of the carrying amount of each asset to the future undiscounted cash ﬂows expected to result from the use of the asset and its eventual disposion. If the asset is considered to be impaired, the amount of any impairment is measured as the diﬀerence between the carrying value and the fair value of the impaired asset. The Company has not recorded material impairment of any long-lived assets. Accruals of Research and Development Costs The Company records accruals for esmated costs of research, preclinical and clinical studies and manufacturing development. These costs are a signiﬁcant component of the Company’s research and development expenses. A substanal poron of the Company’s ongoing research and development acvies are conducted by third-party service providers, including contract research organizaons. The Company accrues the costs incurred under its agreements with these third pares based on actual work completed in accordance with agreements established with these third pares. The Company determines the actual costs through obtaining informaon from external service providers as to the progress or stage of compleon of the services and the agreed-upon fee to be paid for such services. Revenue Recognion Product Sales The Company sells its approved products through a limited number of distributors. Under ASC 606, revenue from product sales is recognized at the point in me when control is transferred to these distributors. The Company also recognizes revenue from sales of certain products on a “named paent” basis, which are allowed in certain countries prior to the commercial approval of the product. Prior to recognizing revenue, the Company makes esmates of the transacon price, including any variable consideraon that is subject to a constraint. Amounts of variable consideraon are included in the transacon price to the extent that it is probable that a signiﬁcant reversal in the amount of cumulave revenue recognized will not occur and when the uncertainty associated with the variable consideraon is subsequently resolved. Product sales are recorded net of esmated government-mandated rebates and chargebacks, esmated product returns, and other deducons. Provisions for returns and other adjustments are provided for in the period the related revenue is recorded, as esmated by management. These reserves are based on esmates of the amounts earned or to be claimed on the related sales and are reviewed periodically and adjusted as necessary. The Company’s esmates of government mandated rebates, chargebacks, esmated product returns, and other deducons depends on the idenﬁcaon of key customer contract terms and condions, as well as esmates of sales volumes to diﬀerent classes of payors. If actual results vary, the Company may need to adjust these esmates, which could have a material eﬀect on earnings in the period of the adjustment. F-12 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Collaboraon, License, and Royalty Revenue The Company has certain license and collaboraon agreements that are within the scope of Accounng Standards Codiﬁcaon, or ASC, 808, Collaborave Agreements, which provides guidance on the presentaon and disclosure of collaborave arrangements. Generally, the classiﬁcaon of the transacons under the collaborave arrangements is determined based on the nature of contractual terms of the arrangement, along with the nature of the operaons of the parcipants. The Company records its share of collaboraon revenue, net of transfer pricing related to net sales in the period in which such sales occur, if the Company is considered as an agent in the arrangement. The Company is considered an agent when the collaboraon partner controls the product before transfer to the customers and has the ability to direct the use of and obtain substanally all of the remaining beneﬁts from the product. Funding received related to research and development services and commercializaon costs is generally classiﬁed as a reducon of research and development expenses and selling, general and administrave expenses, respecvely, in the Consolidated Statements of Operaons, because the provision of such services for collaborave partners are not considered to be part of the Company’s ongoing major or central operaons. The Company ulizes certain informaon from its collaboraon partners to record collaboraon revenue, including revenue from the sale of the product, associated reserves on revenue, and costs incurred for development and sales acvies. For the periods covered in the ﬁnancial statements presented, there have been no material changes to prior period esmates of revenues and expenses. The Company also records royalty revenues under certain of the Company’s license or collaboraon agreements in exchange for license of intellectual property. The Company sold the right to receive certain royalty payments from net sales of Crysvita in certain territories to RPI Finance Trust, or RPI, an aﬃliate of Royalty Pharma, and to OCM LS23 Holdings LP, an investment vehicle for Ontario Municipal Employees Rerement System, or OMERS, as further described in “Note 10. Liabilies for Sales of Future Royales.” The Company records the royalty revenue from the net sales of Crysvita in the applicable territories on a prospecve basis as non-cash royalty revenue in the Consolidated Statements of Operaons over the term of the applicable arrangement. The terms of the Company’s collaboraon and license agreements may contain mulple performance obligaons, which may include licenses and research and development acvies. The Company evaluates these agreements under ASC 606, Revenue from Contracts with Customers, or ASC 606, to determine the disnct performance obligaons. The Company analogizes to ASC 606 for the accounng for disnct performance obligaons for which there is a customer relaonship. Prior to recognizing revenue, the Company makes esmates of the transacon price, including variable consideraon that is subject to a constraint. Amounts of variable consideraon are included in the transacon price to the extent that it is probable that a signiﬁcant reversal in the amount of cumulave revenue recognized will not occur and when the uncertainty associated with the variable consideraon is subsequently resolved. Total consideraon may include nonrefundable upfront license fees, payments for research and development acvies, reimbursement of certain third-party costs, payments based upon the achievement of speciﬁed milestones, and royalty payments based on product sales derived from the collaboraon. If there are mulple disnct performance obligaons, the Company allocates the transacon price to each disnct performance obligaon based on its relave standalone selling price. The standalone selling price is generally determined based on the prices charged to customers or using expected cost-plus margin. The Company esmates the eﬀorts needed to complete the performance obligaons and recognizes revenue by measuring the progress towards complete sasfacon of the performance obligaons using input measures. Deferred Compensaon Plan The Company maintains a nonqualiﬁed deferred compensaon plan whereby certain employees and members of the board of directors are able to defer certain equity awards and other compensaon. Amounts deferred are invested into shares of the Company's common stock, mutual funds, and other investment opons. The plan complies with the provisions of Secon 409A of the Internal Revenue Code. All of the various mutual funds held in the plan are classiﬁed as trading securies and recorded at fair value in other non-current assets in the Consolidated Balance Sheets with changes in fair value recognized as earnings in the period they occur. The short-term poron of the corresponding liability for the plan is included in accrued expenses. The long-term poron of the liability is included in other non-current liabilies in the Consolidated Balance Sheets. Certain equity awards deferred under the plan are required to be seled through the issuance of Company stock. These awards are recorded as treasury stock and deferred compensaon obligaon within stockholders’ equity. Leases Lease agreements are evaluated to determine whether an arrangement is or contains a lease in accordance with ASC 842, Leases. The Company determines if an arrangement includes a lease at incepon. Right-of-use lease assets and lease liabilies are F-13 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) recognized based on the present value of the future minimum lease payments over the lease term at the commencement date. The right-of-use lease asset includes any lease payments made and excludes lease incenves. Incremental borrowing rate is used in determining the present value of future payments. The Company applies a porolio approach to the property leases to apply an incremental borrowing rate to leases with similar lease terms. The lease terms may include opons to extend or terminate the lease. The Company recognizes the opons to extend the lease as part of the right-of-use lease assets and lease liabilies only if it is reasonably certain that the opon would be exercised. Lease expense for minimum lease payments is recognized on a straight-line basis over the non-cancelable lease term. The Company has elected to not separate lease and non-lease components. See “Note 9. Leases” for further disclosure. Comprehensive Loss Comprehensive loss is the change in stockholders’ equity from transacons and other events and circumstances other than those resulng from investments by stockholders and distribuons to stockholders. The Company’s other comprehensive loss is comprised of unrealized gains and losses on investments in available-for-sale securies and foreign currency translaon adjustments. Research and Development Research and development costs are expensed as incurred and consist of salaries and beneﬁts, stock-based compensaon expense, lab supplies and facility costs, as well as fees paid to other nonemployees and enes that conduct certain research and development acvies on the Company’s behalf. Amounts incurred in connecon with license agreements are also included in research and development expense. Nonrefundable advance payments for goods or services to be received in the future for use in research and development acvies are deferred. The deferred amounts are expensed as the related goods are delivered or the services are performed. Stock-Based Compensaon Stock-based awards issued to employees, including stock opons, performance stock opons, or PSOs, restricted stock units, or RSUs, and performance stock units, or PSUs are recorded at fair value as of the grant date and recognized as expense on a straight-line basis over the employee’s requisite service period (generally the vesng period). PSOs and PSUs vest only if certain speciﬁed criteria are achieved and the employees’ connued service requirements are met; therefore, the expense recognion occurs when the likelihood of the PSOs and PSUs being earned is deemed probable. Stock compensaon expense on awards expected to vest is recognized net of esmated forfeitures. Income Taxes The Company uses the liability method of accounng for income taxes. Under this method, deferred tax assets and liabilies are determined based on the diﬀerences between the ﬁnancial reporng and the tax bases of assets and liabilies and are measured using the enacted tax rates and laws that will be in eﬀect when the diﬀerences are expected to reverse. The Company must then assess the likelihood that the resulng deferred tax assets will be realized. A valuaon allowance is provided when it is more likely than not that some poron or all of a deferred tax asset will not be realized. Due to the Company’s lack of earnings history, the net deferred tax assets have been fully oﬀset by a valuaon allowance. In conjuncon with the acquision of Dimension Therapeucs, Inc., or Dimension, a deferred tax liability was recorded reﬂecng the tax impact of the diﬀerence between the book basis and tax basis of acquired IPR&D. Such deferred income tax liability is not used to oﬀset deferred tax assets when analyzing the Company’s valuaon allowance as the acquired IPR&D is considered to have an indeﬁnite life unl the Company completes or abandons development of the acquired IPR&D. The Company recognizes beneﬁts of uncertain tax posions if it is more likely than not that such posions will be sustained upon examinaon based solely on their technical merits, as the largest amount of beneﬁt that is more likely than not to be realized upon the ulmate selement. The Company’s policy is to recognize interest and penales related to the underpayment of income taxes as a component of income tax expense or beneﬁt. To date, there have been no interest or penales charged in relaon to the unrecognized tax beneﬁts. F-14 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Foreign Currency Assets and liabilies of non-U.S. subsidiaries that operate in a local currency environment, where the local currency is the funconal currency, are translated to U.S. dollars at exchange rates in eﬀect at the balance sheet date, with the resulng translaon adjustments directly recorded to a separate component of accumulated other comprehensive loss. Income and expense accounts are translated at average exchange rates for the period. Transacons which are not in the funconal currency of the enty are remeasured into the funconal currency and gains or losses resulng from the remeasurement recorded in other income (expense). Net Loss per Share Basic net loss per share is calculated by dividing the net loss by the weighted-average number of shares of common stock outstanding during the period, without consideraon for common stock equivalents. Shares of common stock into which pre-funded warrants may be exercised are considered outstanding for the purposes of compung basic net loss per share because the shares may be issued for lile or no consideraon, are fully vested and are exercisable aer the original issuance date. Diluted net loss per share is the same as basic net loss per share, since the eﬀects of potenally diluve securies are andiluve. In periods when we have incurred a net loss, opons and warrants to purchase common stock are considered common stock equivalents, but have been excluded from the calculaon of diluted net loss per share, as their eﬀect is andiluve. 3. Fair Value Measurements Financial assets and liabilies are recorded at fair value. The carrying amount of certain ﬁnancial instruments, including cash and cash equivalents, accounts receivable, accounts payable and accrued liabilies approximate fair value due to their relavely short maturies. Assets and liabilies recorded at fair value on a recurring basis in the balance sheets are categorized based upon the level of judgment associated with the inputs used to measure their fair values. Fair value is deﬁned as the exchange price that would be received for an asset or an exit price that would be paid to transfer a liability in the principal or most advantageous market for the asset or liability in an orderly transacon between market parcipants on the measurement date. The authoritave guidance on fair value measurements establishes a three-er fair value hierarchy for disclosure of fair value measurements as follows: Level 1—Inputs are unadjusted, quoted prices in acve markets for idencal assets or liabilies at the measurement date; Level 2—Inputs are observable, unadjusted quoted prices in acve markets for similar assets or liabilies, unadjusted quoted prices for idencal or similar assets or liabilies in markets that are not acve, or other inputs that are observable or can be corroborated by observable market data for substanally the full term of the related assets or liabilies; and Level 3—Unobservable inputs that are signiﬁcant to the measurement of the fair value of the assets or liabilies that are supported by lile or no market data. The Company’s ﬁnancial instruments consist of Level 1, Level 2, and Level 3 assets. Where quoted prices are available in an acve market, securies are classiﬁed as Level 1. Money market funds and U.S. Government treasury bills are classiﬁed as Level 1. Level 2 assets consist primarily of corporate bonds, asset backed securies, commercial paper, U.S. Government Treasury and agency securies, and debt securies in government-sponsored enes based upon quoted market prices for similar movements in acve markets, quoted prices for idencal or similar instruments in markets that are not acve and model-based valuaon techniques for which all signiﬁcant inputs are observable in the market or can be corroborated by observable market data for substanally the full term of the assets. Where applicable these models project future cash ﬂows and discount the future amounts to a present value using market-based observable inputs obtained from various third-party data providers, including but not limited to, benchmark yields, interest rate curves, reported trades, broker/dealer quotes and reference data. The Company determines the fair value of its equity investments in Solid Biosciences, Inc., or Solid, by using the quoted market prices, which are Level 1 fair value measurements. F-15 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The following tables set forth the fair value of the Company’s ﬁnancial assets remeasured on a recurring basis based on the three-er fair value hierarchy (in thousands): Financial Assets: Money market funds Cerﬁcates of deposit and me deposits Corporate bonds Commercial paper Asset-backed securies U.S. Government Treasury and agency securies Investment in Solid common stock Deferred compensaon assets Total ﬁnancial assets Financial Liabilies: Deferred compensaon liabilies Financial Assets: Money market funds Cerﬁcates of deposit and me deposits Corporate bonds Commercial paper Asset-backed securies U.S. Government Treasury and agency securies Debt securies in government-sponsored enes Investment in Solid common stock Deferred compensaon assets Total ﬁnancial assets Financial Liabilies: Deferred compensaon liabilies Level 1 Level 2 Level 3 Total December 31, 2023 162,289 — — — — 57,437 3,204 — 222,930 $ $ — 17,986 215,166 20,620 2,712 259,605 — 10,220 526,309 $ $ — — — — — — — — — $ $ 162,289 17,986 215,166 20,620 2,712 317,042 3,204 10,220 749,239 — $ 10,365 $ — $ 10,365 Level 1 Level 2 Level 3 Total December 31, 2022 102,847 — — — — 27,645 — 2,807 — 133,299 $ $ — 25,972 427,598 135,393 11,980 129,345 15,855 — 4,575 750,718 $ $ — — — — — — — — — — $ $ 102,847 25,972 427,598 135,393 11,980 156,990 15,855 2,807 4,575 884,017 — $ 4,657 $ — $ 4,657 $ $ $ $ $ $ Deferred compensaon assets are recorded at fair value in other non-current assets in the Consolidated Balance Sheets. There have been no signiﬁcant gains or losses on deferred compensaon assets for the periods presented. Deferred compensaon liabilies consist of short-term liabilies of $0.2 million and nil as of December 31, 2023 and 2022, respecvely, included in accrued liabilies on the Consolidated Balance Sheets, and long-term liabilies of $10.1 million and $4.7 million as of December 31, 2023 and 2022, respecvely, included in other non-current liabilies on the Consolidated Balance Sheets. F-16 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 4. Balance Sheet Components Cash Equivalents and Marketable Debt Securies The fair values of cash equivalents and marketable debt securies classiﬁed as available-for-sale securies consisted of the following (in thousands): December 31, 2023 Gross Unrealized Amorzed Cost Gains Losses Esmated Fair Value Money market funds Cerﬁcates of deposit and me deposits Corporate bonds Commercial paper Asset-backed securies U.S. Government Treasury and agency securies Total $ $ 162,289 17,986 214,792 20,620 2,715 316,160 734,562 Money market funds Cerﬁcates of deposit and me deposits Corporate bonds Commercial paper Asset-backed securies U.S. Government Treasury and agency securies Debt securies in government-sponsored enes Total Amorzed Cost $ 102,847 25,972 432,211 135,393 12,002 157,933 16,005 882,363 $ $ $ $ $ — — 711 — — 982 1,693 $ $ — — (337 ) — (3 ) (100 ) (440 ) December 31, 2022 Gross Unrealized Gains Losses — — 87 — — 320 — 407 $ $ — — (4,700 ) — (22 ) (1,263 ) (150 ) (6,135 ) $ $ $ $ 162,289 17,986 215,166 20,620 2,712 317,042 735,815 Esmated Fair Value 102,847 25,972 427,598 135,393 11,980 156,990 15,855 876,635 At December 31, 2023, the remaining contractual maturies of available-for-sale securies were less than three years. There have been no signiﬁcant realized gains or losses on available-for-sale securies for the periods presented. Inventory Inventory consists of the following (in thousands): Work-in-process Finished goods Total inventory December 31, 2023 2022 $ $ 18,859 $ 15,110 33,969 $ 17,486 9,280 26,766 F-17 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Property, Plant, and Equipment, net Property, plant, and equipment, net consists of the following (in thousands): Building Leasehold improvements Research and development equipment Furniture and oﬃce equipment Computer equipment and soware Manufacturing equipment Land Construcon-in-progress Other Property, plant, and equipment, gross Less: accumulated depreciaon Property, plant, and equipment, net Useful life (years) $ 20-30 Shorter of lease term or esmated useful life 5 5 3-5 5-15 Not applicable Not applicable Varies by asset $ December 31, 2023 181,356 $ 2022 2,798 58,683 56,347 6,419 16,196 37,297 16,619 867 183 373,967 (83,401 ) 290,566 $ 43,941 50,291 5,540 13,876 570 16,619 189,448 24 323,107 (63,381 ) 259,726 Depreciaon expense for the years ended December 31, 2023, 2022, and 2021 was $22.2 million, $15.0 million and $12.9 million, respecvely. Amorzaon of leasehold improvements and soware is included in depreciaon expense. Construcon in progress reﬂects amounts incurred for construcon or improvements of property or costs for equipment that has not been placed in service. The construcon-in-progress balance as of December 31, 2022 is primarily the construcon costs for the gene therapy manufacturing facility in Bedford, Massachuses. Accrued Liabilies Accrued liabilies consists of the following (in thousands): Research, clinical study, and manufacturing expenses Payroll and related expenses Other Total accrued liabilies December 31, 2023 2022 $ $ 65,326 $ 82,936 48,224 196,486 $ 73,558 78,938 52,182 204,678 5. Intangible Assets, net Indeﬁnite-lived Intangibles The Company has IPR&D assets of $129.0 million as of December 31, 2023 and 2022. IPR&D assets represent the fair value of acquired programs to develop an AAV gene therapy for OTC deﬁciency and to develop an AAV gene therapy for glycogen storage disease type Ia. The fair value of IPR&D assets acquired was determined based on the discounted present value of each research project’s projected cash ﬂows using an income approach, including the applicaon of probability factors related to the likelihood of success of the program reaching ﬁnal development and commercializaon. Addionally, the projecons consider the relevant market sizes and growth factors, esmated future cash ﬂows from product sales resulng from completed products and in- process projects and ming and costs to complete the in-process projects. The rates ulized to discount the net cash ﬂows to their present value are commensurate with the stage of development of the projects and uncertaines in the economic esmates used in the projecons. IPR&D assets are considered to be indeﬁnite-life unl the compleon or abandonment of the associated research and development eﬀorts. Finite-lived Intangibles F-18 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Subsequent to the FDA approval of Dojolvi for the treatment of LC-FAOD in 2020, the Company recorded $4.8 million for the aainment of various development and commercial milestones as ﬁnite-lived intangible assets which are amorzed over a weighted-average useful life of 5.7 years. In January 2022, the Company announced a collaboraon with Regeneron to commercialize Evkeeza for HoFH outside of the U.S. Upon closing of the transacon in January 2022, the Company paid Regeneron a $30.0 million upfront payment. During the year ended December 31, 2023, a $10.0 million regulatory milestone was achieved. As both the upfront payment and the regulatory milestone are related to the Company’s use of intellectual property for Evkeeza for HoFH, these amounts were recorded as intangible assets, which are amorzed over a weighted-average useful life of ten years. The Company's intangible assets were as follows: Indeﬁnite-lived intangibles Finite-lived intangibles Total intangible assets Indeﬁnite-lived intangibles Finite-lived intangibles Total intangible assets Gross Carrying Amount $ $ 129,000 44,775 173,775 Gross Carrying Amount $ $ 129,000 34,775 163,775 December 31, 2023 Weighted- Average Life (Years) Accumulated Amorzaon Net Carrying Amount — $ 9.6 — $ — $ (7,504 ) (7,504 ) $ 129,000 37,271 166,271 December 31, 2022 Weighted- Average Life (Years) Accumulated Amorzaon Net Carrying Amount — $ 9.9 — $ — $ (3,670 ) (3,670 ) $ 129,000 31,105 160,105 The Company recorded costs of sales of $3.8 million, $3.2 million and $0.3 million for the years ended December 31, 2023, 2022, and 2021, respecvely, related to the amorzaon of the intangible assets. The expected amorzaon of the intangible assets, as of December 31, 2023, for each of the next ﬁve years and thereaer is as follows: 2024 2025 2026 2027 2028 Thereaer Total $ $ 4,903 4,903 4,903 4,462 4,022 14,078 37,271 F-19 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 6. Revenue The following table disaggregates total revenues from external customers by product sales, royalty revenue, and collaboraon and license revenue (in thousands): Product sales: Crysvita Mepsevii Dojolvi Evkeeza Total product sales Crysvita royalty revenue Collaboraon and license revenue: Crysvita collaboraon revenue in Proﬁt-Share Territory Crysvita royalty revenue in European Territory Daiichi Sankyo Total collaboraon and license revenue Total revenues Year Ended December 31, 2022 2023 2021 $ $ 75,697 30,441 70,633 3,642 180,413 182,652 69,705 — 1,479 71,184 434,249 $ $ 42,678 20,637 55,612 — 118,927 21,692 215,024 — 7,686 222,710 363,329 $ $ 21,422 16,035 39,560 — 77,017 17,951 171,198 244 84,996 256,438 351,406 The following table disaggregates total revenues based on geographic locaon (in thousands): North America Lan America Europe Japan Total revenues Year Ended December 31, 2022 2023 2021 $ $ 307,149 77,342 47,534 2,224 434,249 $ $ 281,088 44,711 36,369 1,161 363,329 $ $ 301,110 23,636 26,660 — 351,406 The following table presents the acvity and ending balances for sales-related accruals and allowances (in thousands): Year Ended December 31, 2022 2023 2021 Balance of product sales reserve at beginning of year Provisions Payments Adjustments Balance of product sales reserve at end of year $ $ 11,487 18,761 (12,746 ) (473 ) 17,029 $ $ $ 7,181 13,525 (9,613 ) 394 11,487 $ 3,913 9,586 (6,120 ) (198 ) 7,181 The following table presents changes in the contract liabilies for the years ended December 31, 2023 and 2022 (in thousands): Balance of contract liabilies at beginning of period Addions Deducons Balance of contract liabilies at end of period, net F-20 Year Ended December 31, 2022 2023 $ $ 1,479 — (1,479 ) — $ $ 9,076 89 (7,686 ) 1,479 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) See Note 8 for addional details on contract liabilies acvies. The Company’s largest accounts receivable balance was from a collaboraon partner and was 53% and 68% of the total accounts receivable balance as of December 31, 2023 and 2022, respecvely. 7. GeneTx Acquision In August 2019, the Company entered into a Program Agreement and a Unitholder Opon Agreement with GeneTx Biotherapeucs LLC, or GeneTx, to collaborate on the development of GeneTx’s GTX-102, an ASO for the treatment of Angelman syndrome. In July 2022, pursuant to the terms of the Unitholder Opon Agreement, as amended, the Company exercised the opon to acquire GeneTx and entered into a Unit Purchase Agreement, or the Purchase Agreement, pursuant to which the Company purchased all the outstanding units of GeneTx. In accordance with the terms of the Purchase Agreement, the Company paid the opon exercise price of $75.0 million and an addional $15.6 million to acquire the outstanding cash of GeneTx, and adjustments for working capital and transacon expenses of $0.6 million, for a total purchase consideraon of $91.2 million. The Company may be required to make payments of up to $190.0 million upon the achievement of certain milestones, including up to $30.0 million in milestone payments upon achievement of the earlier of iniaon of a Phase 3 clinical study or product approvals in Canada and the U.K., up to $85.0 million in addional regulatory approval milestones for the achievement of U.S. and EU product approvals, and up to $75.0 million in commercial milestone payments based on annual worldwide net product sales. The Company will also pay ered mid- to high single-digit percentage royales based on licensed product annual net sales. If the Company receives and resells an FDA priority review voucher, or PRV, in connecon with a new drug applicaon approval, GeneTx is entled to receive a poron of proceeds from the sale or a cash payment from the Company if the Company choses to retain the PRV. As part of the Company's acquision of GeneTx, the Company assumed a License Agreement with Texas A&M University, or TAMU. Under this agreement, TAMU is eligible to receive from the Company up to $23.5 million upon the achievement of various future milestones, a nominal annual license fee that may increase up to a maximum of $2.0 million, as well as royales in the mid-single-digits of net sales. The transacon was accounted as an asset acquision, as substanally all of the fair value of the gross assets acquired was concentrated in a single idenﬁable in-process research and development intangible asset. Prior to the achievement of certain development and regulatory milestones, the acquired in-process research and development intangible asset has not yet reached technological feasibility and has no alternave future use. Accordingly, the Company recorded the acquision price of $75.0 million, net of cash and working capital acquired, as in-process research and development expense during the year ended December 31, 2022. 8. License and Research Agreements Kyowa Kirin Co., Ltd. In August 2013, the Company entered into a collaboraon and license agreement with Kyowa Kirin Co., Ltd., or KKC. Under the terms of this collaboraon and license agreement, as amended, the Company and KKC collaborate on the development and commercializaon of Crysvita in the ﬁeld of orphan diseases in the U.S. and Canada, or the Proﬁt-Share Territory, and in the European Union, United Kingdom, and Switzerland, or the European Territory, and the Company has the right to develop and commercialize such products in the ﬁeld of orphan diseases in Mexico and Central and South America, or Lan America. Development Acvies In the ﬁeld of orphan diseases, except for ongoing studies being conducted by KKC, the Company was the lead party for development acvies in the Proﬁt-Share Territory and in the European Territory unl the applicable transion date. The Company shared the costs for development acvies in the Proﬁt- Share Territory and the European Territory conducted pursuant to the development plan before the applicable transion date equally with KKC. In April 2023, which was the transion date for the Proﬁt-Share Territory, KKC became the lead party and became responsible for the costs of the subsequent development acvies. However, the Company will connue to equally share in the costs of the studies with KKC that commenced prior to the applicable transion date. The collaboraon and license agreements are within the scope of ASC 808, which provides guidance on the presentaon and disclosure of collaborave arrangements. Collaboraon and Royalty Revenue for Sales in the Proﬁt-Share Territory The Company and KKC shared commercial responsibilies and proﬁts in the Proﬁt-Share Territory unl April 2023. Under the collaboraon agreement, KKC manufactured and supplied Crysvita for commercial use in the Proﬁt-Share Territory and charged the Company a transfer price of 30% of net sales in 2023, and 35% prior to December 31, 2022. The remaining proﬁt or loss aer supply F-21 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) costs from commercializing products in the Proﬁt-Share Territory was shared between the Company and KKC on a 50/50 basis unl April 2023. In April 2023, commercializaon responsibilies for Crysvita in the Proﬁt-Share Territory transioned to KKC. Thereaer, the Company is entled to receive a ered double- digit revenue share from the mid-20% range up to a maximum rate of 30%. In 2022, the Company entered into an amendment to the collaboraon agreement which granted the Company the right to connue to support KKC in commercial ﬁeld acvies in the U.S. through April 2024, subject to the limitaons and condions set forth in the amendment. The pares subsequently mutually agreed to extend the Company's right to connue to support KKC in commercial ﬁeld acvies in the U.S. through December 31, 2024, and as a result, the Company will connue to support commercial ﬁeld eﬀorts in the U.S. through a cost share arrangement through December 2024. Aer December 31, 2024, the Company’s rights to promote Crysvita in the U.S. will be limited to medical genecists and the Company will solely bear its expenses for the promoon of Crysvita in the Proﬁt-Share Territory. As KKC was the principal in the sale transacon with the customer during the proﬁt-share period, the Company recognized a pro-rata share of collaboraon revenue, net of transfer pricing, in the period the sale occurs. The Company concluded that its poron of KKC’s sales in the Proﬁt-Share Territory prior to April 2023 was analogous to a royalty and therefore recorded its share as collaboraon revenue, similar to a royalty. Starng in April 2023, the Company began to record the royalty revenue as the underlying sales occur. In July 2022, the Company sold to OMERS its right to receive 30% of the future royalty payments due to the Company based on net sales of Crysvita in the U.S. and Canada, subject to a cap, beginning in April 2023, as further described in Note 10. The Company records this revenue as royalty revenue. Product Sales Revenue for Other Territories The Company is responsible for commercializing Crysvita in Lan America and Turkey. The Company is considered the principal in these territories as the Company controls the product before it is transferred to the customer. Accordingly, the Company records revenue on a gross basis for the sale of Crysvita once the product is delivered and the risk and tle of the product is transferred to the distributor. KKC has the opon to assume responsibility for commercializaon eﬀorts in Turkey from the Company, aer a certain minimum period. Under the collaboraon agreement, KKC manufactures and supplies Crysvita, which is purchased by the Company for sales in Lan American territories and charges the Company a transfer price of 30% of net sales. The transfer price on these sales was 35% prior to December 31, 2022. The Company also pays to KKC a low single-digit royalty on net sales in Lan America. Total Crysvita revenue was as follows (in thousands): Revenue in proﬁt-share territory: Collaboraon revenue Royalty revenue Non-cash royalty revenue Total revenue in Proﬁt-Share Territory Product sales Royalty revenue in European Territory Non-cash royalty revenue in European Territories Total Crysvita revenue Year Ended December 31, 2022 2023 2021 $ $ 69,705 113,288 48,581 231,574 75,697 — 20,783 328,054 $ $ 215,024 — — 215,024 42,678 — 21,692 279,394 $ $ 171,198 — — 171,198 21,422 244 17,951 210,815 Royalty Revenue for Sales in the European Territory KKC has the commercial responsibility for Crysvita in the European Territory. In December 2019, the Company sold its right to receive royalty payments based on sales in the European Territory to Royalty Pharma, eﬀecve January 1, 2020, as further described in Note 10. Prior to the Company’s sale of the royalty, the Company received a royalty of up to 10% on net sales in the European Territory, which was recognized as the underlying sales occur. Beginning in 2020, the Company records the royalty revenue as non-cash royalty revenues. The Company records this revenue as royalty revenue. F-22 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Collaboraon Cost Sharing and Payments Under the collaboraon agreement, KKC and the Company share certain development and commercializaon costs and as a result, the Company was reimbursed for these costs and operang expenses were reduced. Addionally, KKC is owed a transfer price fee and royales on certain revenues and the Company recorded amounts owed to KKC in cost of sales. These amounts were recognized in the Company’s Statements of Operaons in connecon with the collaboraon agreement with KKC as follows (in thousands): Research and development Selling, general and administrave Cost of sales Collaboraon Receivable and Payable Year Ended December 31, 2022 2023 2021 $ $ $ (6,510 ) (17,199 ) 18,476 $ $ $ (15,974 ) (37,217 ) 13,250 $ $ $ (21,657 ) (32,629 ) 6,701 The Company had accounts receivable from KKC in the amount of $39.2 million and $27.5 million from proﬁt-share revenue and royales and other receivables recorded in other current assets of $1.1 million and $6.4 million and accrued liabilies of $5.3 million and $3.1 million from commercial and development acvity reimbursements, as of December 31, 2023 and 2022, respecvely. Saint Louis University In November 2010, the Company entered into a license agreement with Saint Louis University, or SLU. Under the terms of this license agreement, SLU granted the Company an exclusive worldwide license to make, have made, use, import, oﬀer for sale, and sell therapeucs related to SLU’s beta-glucuronidase product for use in the treatment of human diseases. The Company made a milestone payment of $0.1 million upon approval of Mepsevii for treatment of MPS 7. The Company is required to pay to SLU a low single-digit royalty on net sales of the licensed products in any country or region, upon reaching a certain level of cumulave worldwide sales of the product. Baylor Research Instute In September 2012, the Company entered into a license agreement with Baylor Research Instute, or BRI. Under the terms of this license agreement, as amended, BRI exclusively licensed to the Company its territories for certain intellectual property related to Dojolvi (triheptanoin) for the treatment of LC- FAOD. For the years ended December 31, 2023 and 2022, the Company recorded nil and $2.5 million, respecvely, for the aainment of various development and commercial milestones as ﬁnite-lived intangible assets. The Company is obligated to make addional future payments of up to $7.5 million conngent upon aainment of various development and commercial milestones. Addionally, the Company is paying BRI a mid- single-digit royalty on net sales of the licensed product in the licensed territories. REGENXBIO, Inc. The Company has a license agreement with REGENXBIO, Inc., or REGENX, for an exclusive, sublicensable, worldwide commercial license under certain intellectual property for preclinical and clinical research and development, and commercializaon of drug therapies using REGENX's licensed patents for the treatment of hemophilia A, OTC deﬁciency, and GSD1a. The Company will pay an annual fee and certain milestone fees per disease indicaon, low to mid- single-digit royalty percentages on net sales of licensed products, and milestone and sublicense fees owed by REGENX to its licensors, conngent upon the aainment of certain development acvies as outlined in the agreement. The Company also has an opon and license agreement with REGENX under which the Company has an exclusive, sublicensable, worldwide license to make, have made, use, import, sell, and oﬀer for sale licensed products to treat Wilson disease and CDKL5 deﬁciency. For each disease indicaon, the Company is obligated to pay an annual maintenance fee of $0.1 million and up to $9.0 million upon achievement of various milestones, as well as mid- to high single-digit royales on net sales of licensed products and mid- single-digit to low double-digit percentage sublicenses fees, if any. In March 2020, the Company entered into a license agreement with REGENX, for an exclusive, sublicensable, worldwide license to REGENX’s NAV AAV8 and AAV9 vectors for the development and commercializaon of gene therapy treatments for a rare metabolic disorder. In return for these rights, the Company made an upfront payment of $7.0 million. The Company will pay certain F-23 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) annual fees of $0.1 million, milestone payments of up to $14.0 million, and royales on any net sales of products incorporang the licensed intellectual property that range from a high single-digit to low double-digit royalty. Bayer HealthCare LLC The Company previously had a collaboraon and license agreement with Bayer Healthcare LLC, or Bayer, to research, develop and commercialize AAV gene therapy products for the treatment of hemophilia A, or DTX 201. Under this agreement, Bayer had been granted an exclusive license to develop and commercialize one or more novel gene therapies for hemophilia A. In October 2022, the Collaboraon and License Agreement for DTX201 with Bayer was terminated and all licensed rights to DTX201 have reverted back to the Company. The Company also obtained rights to all necessary data and informaon to further develop DTX201 or another hemophilia A program through a royalty-free, worldwide, sublicensable, perpetual license. University of Pennsylvania The Company has a research, collaboraon, and license agreement with University of Pennsylvania School of Medicine, or Penn, which provides the terms for the Company and Penn to collaborate with respect to the pre-clinical development of gene therapy products for the treatment of certain indicaons. Under the agreement, Penn granted the Company an exclusive, worldwide license to certain patent rights arising out of the research program, subject to certain retained rights, and a non-exclusive, worldwide license to certain Penn intellectual property, in each case to research, develop, make, have made, use, sell, oﬀer for sale, commercialize and import licensed products in each indicaon for the term of the agreement. The Company will fund the cost of the research program in accordance with a mutually agreed-upon research budget and will be responsible for clinical development, manufacturing and commercializaon of each indicaon. The Company may be obligated to make milestone payments of up to $5.0 million for each indicaon, if certain development milestones are achieved over me. The Company is also obligated to make milestone payments of up to $25.0 million per approved product if certain commercial milestones are achieved, as well as low to mid- single-digit royales on net sales of each licensed product. Arcturus Therapeucs Holdings Inc. In October 2015, the Company entered into a Research Collaboraon and License Agreement with Arcturus Therapeucs Holdings Inc., or Arcturus, to collaborate on the research and development of therapies for select rare diseases. Arcturus was responsible for conducng certain research services, funded by the Company, and the Company was responsible for development and commercializaon costs. On a product-by-product basis, the Company is obligated to make development and regulatory milestone payments of up to $24.5 million, and commercial milestone payments of up to $45.0 million if certain milestones are achieved. For the year ended December 31, 2021, the Company achieved a $1.0 million development milestone, which was paid with a corresponding credit received from Arcturus for prior research and collaboraon acvies. The Company is also obligated to pay Arcturus royales on any net sales of products incorporang the licensed intellectual property that may range from a mid- single-digit to low double-digit percentage. There were no material expenses for this arrangement during the years ended December 31, 2023, 2022, and 2021. In June 2019, the Company entered into an Equity Purchase Agreement and an amendment to the Research Collaboraon and License Agreement, or License Agreement, to expand the ﬁeld of use and increase the number of disease targets to include mRNA, DNA and siRNA therapeucs for up to 12 rare diseases. Pursuant to the agreements, the Company paid $6.0 million in cash upfront to Arcturus and purchased 2,400,000 shares of Arcturus’ common stock at a stated value of $10.00 per share, resulng in a total of $30.0 million of consideraon paid at the close of the transacon. As a result, the Company received expanded license rights under the License Agreement, Arcturus common stock, and an opon to purchase an addional 600,000 shares of Arcturus’ common stock at $16.00 per share. In May 2020, the Company exercised its opon to purchase 600,000 shares of Arcturus common stock for a total purchase price of $9.6 million. The Company’s investment in Arcturus was accounted at fair value, as the fair value was readily determinable. During the year ended December 31, 2022, the Company sold 500,000 shares of Arcturus common stock, at a weighted-average price of $20.39 per share. As of December 31, 2022, the Company held no shares of Arcturus common stock. F-24 The changes in the fair value of the Company’s equity investment in Arcturus were as follows (in thousands): ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) December 31, 2021 Change in fair value Sale of shares December 31, 2022 Daiichi Sankyo $ $ Arcturus Common Stock 18,505 (8,411 ) (10,094 ) — In March 2020, the Company executed a License and Technology Access Agreement, or the License Agreement, with Daiichi Sankyo Co., Ltd., or Daiichi Sankyo. Pursuant to the License Agreement, the Company granted Daiichi Sankyo a non-exclusive license to intellectual property, including know-how and patent applicaons, with respect to its Pinnacle PCLTM producer cell line plaorm, or Pinnacle PCL Plaorm, and HEK293 transient transfecon manufacturing technology plaorms for AAV-based gene therapy products. Under the terms of the License Agreement, Daiichi Sankyo made an upfront payment of $125.0 million and an addional $25.0 million upon compleon of the technology transfer of the Pinnacle PCL Plaorm and HEK293 plaorm. Daiichi Sankyo reimbursed the Company for all costs associated with the transfer of the manufacturing technology. The Company also entered into a Stock Purchase Agreement, or SPA, with Daiichi Sankyo, pursuant to which Daiichi Sankyo purchased 1,243,913 shares of the Company’s common stock in exchange for $75.0 million in cash during the ﬁrst quarter of 2020. The fair market value of the common stock issued to Daiichi Sankyo was $55.3 million based on the stock price of $44.43 per share on the date of issuance, resulng in a $19.7 million premium on the SPA. In June 2020, the Company executed a subsequent license agreement, or the Sublicense Agreement, with Daiichi Sankyo for transfer of certain technology in consideraon for an upfront payment of $8.0 million and annual maintenance fees, milestone payments, and royales on any net sales of products incorporang the licensed intellectual property. The Company evaluated the License Agreement and the Sublicense Agreement under ASC 606 and determined that the performance obligaons under the agreements are (i) intellectual property with respect to its Pinnacle PCL Plaorm and HEK293 transient transfecon manufacturing technology plaorm together with the inial technical assistance and technology transfer services, and (ii) the transfer of any know-how and improvements aer the compleon of the inial technology transfer through the end of the three year technology transfer period. The Company allocated the total transacon price to the two performance obligaons on a relave stand-alone selling price basis. Revenue allocated to the intellectual property and the technology transfer services was recognized over an inial period which was completed during the ﬁrst quarter of 2022, measuring the progress toward complete sasfacon of the individual performance obligaon using an input measure. Revenue for know-how and improvements aer the compleon of technology transfer was recognized on a straight-line basis over the remaining technology transfer period, which ended in March 2023, as it was expected that Daiichi Sankyo would receive and consume the beneﬁts consistently throughout the period. The Company’s current obligaons under the License Agreement and the Sublicense Agreement were completed following the conclusion of the technology transfer period. Total revenue recognized under the arrangement through December 31, 2023 was $183.3 million. The Company recognized $1.5 million, $7.7 million, and $85.0 million for the years ended December 31, 2023, 2022, and 2021, respecvely, in revenue related to this arrangement. Accordingly, the Company recorded contract liabilies of nil and $1.5 million, net, for this arrangement as of December 31, 2023 and 2022, respecvely. Mereo In December 2020, the Company entered into a License and Collaboraon Agreement with Mereo to collaborate on the development of setrusumab. Under the terms of the agreement, the Company will lead future global development of setrusumab in both pediatric and adult paents with OI. The Company was granted an exclusive license to develop and commercialize setrusumab in the U.S., Turkey, and the rest of the world, excluding the European Economic Area, United Kingdom, and Switzerland, or the F-25 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Mereo Territory, where Mereo retains commercial rights. Each party will be responsible for post-markeng commitments and commercial supply in their respecve territories. Upon the closing of the transacon in January 2021, the Company made a payment of $50.0 million to Mereo and will be required to make payments of up to $254.0 million upon the achievement of certain clinical, regulatory, and commercial milestones. The Company will pay for all global development costs as well as ered double-digit percentage royales to Mereo on net sales in the U.S., Turkey, and the rest of the world (excluding the Mereo Territory), and Mereo will pay the Company a ﬁxed double-digit percentage royalty on net sales in the Mereo Territory. Although Mereo is a variable interest enty, the Company is not the primary beneﬁciary as it does not have the power to direct the acvies that would most signiﬁcantly impact the economic performance of Mereo. Prior to the achievement of certain development milestones, all consideraon paid to Mereo represents rights to potenal future beneﬁts associated with Mereo’s in-process research and development acvies, which have not reached technological feasibility and have no alternave future use. For the years ended December 31, 2023, 2022, and 2021, the Company recorded research and development expense of $9.0 million for the achievement of a clinical milestone, nil, and $50.0 million for the upfront payment, respecvely. Regeneron In January 2022, the Company announced a collaboraon with Regeneron Pharmaceucals, or Regeneron, to commercialize Evkeeza for HoFH outside of the U.S. Evkeeza is approved in the U.S., where it is marketed by Regeneron, and in the EU and U.K. as a ﬁrst-in-class therapy for use together with diet and other low-density lipoprotein-cholesterol-lowering therapies to treat adults and adolescents aged 12 years and older with HoFH. Pursuant to the terms of the agreement, the Company received the rights to develop, commercialize and distribute the product for HoFH in countries outside of the U.S. The Company is obligated to pay up to $63.0 million in future milestone payments, conngent upon the achievement of certain regulatory and sales milestones. The Company may share in certain costs for global trials led by Regeneron and also received the right to opt into other potenal indicaons. The collaboraon agreement is within the scope of ASC 808 which provides guidance on the presentaon and disclosure of collaborave arrangements. As the Company would be the principal in future sale transacons with the customer, the Company will recognize product sales and cost of sales in the period the related sales occur and the related revenue recognion criteria are met. Under the collaboraon agreement, Regeneron supplies the product and charges the Company a transfer price from the low 20% range up to 40% on net sales, which is recognized as cost of sales in the Company’s Statement of Operaons. The Company paid Regeneron a $30.0 million upfront payment upon the closing of the transacon in January 2022, and during the year ended December 31, 2023, a $10.0 million regulatory milestone was achieved. As these payments are for the Company’s use of intellectual property for Evkeeza for HoFH, they were recorded as intangible assets. See Note 5 for addional details. Under the collaboraon agreement, the Company reimbursed Regeneron for development costs of $7.6 million, $7.3 million, and nil for the years ended December 31, 2023, 2022, and 2021, respecvely, which were recorded as research and development expense on the Consolidated Statements of Operaons. The Company had collaboraon payables for this arrangement included in accrued liabilies on the Consolidated Balance Sheets of $10.6 million and $6.8 million as of December 31, 2023 and December 31, 2022, respecvely. Addionally, Regeneron is owed a transfer price fee and royales on certain revenues and the Company recorded amounts owed to Regeneron of $0.7 million in cost of sales on the Consolidated Statements of Operaons for the year ended December 31, 2023. Abeona In May 2022, the Company announced an exclusive License Agreement for the AAV gene therapy for UX111 with Abeona for the treatment of MPS IIIA. Under the terms of the agreement, the Company assumed responsibility for the UX111 program and in return, Abeona is eligible to receive ered royales of up to 10% on net sales and commercial milestone payments of up to $30.0 million following regulatory approval of the product. Addionally, the Company entered into an Assignment and Assumpon Agreement with Abeona to transfer and assign to the Company the exclusive license agreement between Naonwide Children’s Hospital, or NCH, and Abeona for certain rights related to UX111. Under this agreement, NCH is eligible to receive from the Company up to $1.0 million in development and regulatory milestones as well as royales in the low single-digits of net sales. F-26 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The Company is obligated to pay Abeona certain prior development costs and other transion costs related to UX111. Prior to product regulatory approval, all consideraon paid to Abeona represents rights to potenal future beneﬁts associated with Abeona’s in-process research and development acvies, which have not reached technological feasibility and have no alternave future use. Accordingly, the value of the acquired intellectual property rights and clinical inventory as well as prior development costs and transion costs of $3.1 million, were recorded as research and development expense for the year ended December 31, 2022. The Company did not incur any other material costs related to this agreement in the years presented. Solid Biosciences, Inc. In October 2020, the Company entered into a strategic Collaboraon and License Agreement with Solid Biosciences Inc., or Solid, and received an exclusive license for any pharmaceucal product that expresses Solid’s proprietary microdystrophin construct from AAV8 and variants thereof in clade E for use in the treatment of Duchenne muscular dystrophy and other diseases resulng from lack of funconal dystrophin, including Becker muscular dystrophy. The Company is collaborang to develop products that combine Solid’s diﬀerenated microdystrophin construct, the Company’s Pinnacle PCL Plaorm, and the Company’s AAV8 variants. Solid is providing development support and was granted an exclusive opon to co-invest in products the Company develops for proﬁt-share parcipaon in certain territories. On a product-by-product basis, the Company is obligated to make development milestone payments of up to $25.0 million, regulatory milestone payments of up to $65.0 million, and commercial milestone payments of up to $165.0 million, if such milestones are achieved, as well as royales on any net sales of products incorporang the licensed intellectual property that range from a low to mid-double-digit percentage. The royalty rate changes to mid- to high double-digit percentage if Solid decides to co-invest in the product. The Company also entered into a Stock Purchase Agreement and the Investor Agreement with Solid, pursuant to which, the Company purchased 7,825,797 shares of Solid’s common stock for an aggregate purchase price of $40.0 million. In October 2022, Solid announced a 1 for 15 reverse stock split. Aer the split, the Company held 521,719 shares of Solid's common stock. The Company’s investment in Solid is being accounted at fair value, as the fair value is readily determinable. The Company recorded the common stock investment at $26.8 million on the transacon date, which was based on the quoted market price on the closing date. Although Solid is a variable interest enty, the Company is not the primary beneﬁciary as it does not have the power to direct the acvies that would most signiﬁcantly impact the economic performance of Solid. Prior to the achievement of certain development milestones, all consideraon paid to Solid represents rights to potenal future beneﬁts associated with Solid’s in-process research and development acvies, which have not reached technological feasibility and have no alternave future use. Accordingly, the remaining $13.2 million of the total $40.0 million paid as consideraon was aributed to the license rights obtained and was recorded as in-process research and development expense during the year ended December 31, 2020. The changes in the fair value of the Company’s investment in Solid’s common stock were as follows (in thousands): December 31, 2021 Change in fair value December 31, 2022 Change in fair value December 31, 2023 Solid Common Stock 13,695 (10,888 ) 2,807 397 3,204 $ $ 9. Leases The Company leases oﬃce space and research, tesng and manufacturing laboratory space in various facilies in Novato and Brisbane, California, in Somerville, and Woburn, Massachuses, and in certain foreign countries, under operang agreements expiring at various dates through 2029. Certain lease agreements include opons for the Company to extend the lease for mulple renewal periods and provide for annual minimum increases in rent, usually based on a consumer price index or annual minimum increases. None of these oponal periods have been considered in the determinaon of the right-of-use lease asset or the lease liability for the leases as the Company did not consider it reasonably certain that it would exercise any such opons. The Company recognizes lease expense on a straight-line basis over the non-cancelable term of its operang leases. The variable lease expense primarily consists of common area maintenance and other operang costs. F-27 The components of lease expense were as follows (in thousands): ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Operang lease expense Variable lease expense Financing: Amorzaon Interest expense Total Year Ended December 31, 2022 2021 2023 12,883 $ 5,272 11,775 $ 4,785 203 — 18,358 $ 343 37 16,940 $ 11,209 4,142 310 58 15,719 $ $ Cash paid for amounts included in the measurement of operang lease liabilies for the years ended December 31, 2023, 2022, and 2021 was $13.4 million, $13.1 million, and $11.8 million, respecvely, and was included in net cash used in operang acvies in the Consolidated Statements of Cash Flows. Right-of-use lease assets were $23.9 million and $26.0 million as of December 31, 2023 and 2022, respecvely, and were included in other non-current assets on the Consolidated Balance Sheets. The following table summarizes maturies of lease liabilies and the reconciliaon of lease liabilies as of December 31, 2023: Year Ending December 31, 2024 2025 2026 2027 2028 Thereaer Total future lease payments Less: Amount represenng interest Present value of future lease payments Less: Lease liabilies, current Lease liabilies, non-current Operang 16,234 11,932 8,430 5,867 5,887 6,009 54,359 (11,190 ) 43,169 (12,595 ) 30,574 $ $ Lease liabilies are based on the net present value of the remaining lease payments over the remaining lease term. For the years ended December 31, 2023 and 2022, the weighted-average remaining operang lease terms were 4.5 years and 3.0 years, the weighted-average remaining ﬁnancing lease terms were nil and 2.8 years, the weighted-average discount rates used to determine the lease liability for operang leases were 9.6% and 6.7%, and the weighted- average discount rates used to determine the lease liability for ﬁnance leases were nil and 5.1% respecvely. 10. Liabilies for Sales of Future Royales In December 2019, the Company entered into a Royalty Purchase Agreement with RPI. Pursuant to the agreement, RPI paid $320.0 million to the Company in consideraon for the right to receive royalty payments eﬀecve January 1, 2020, arising from the net sales of Crysvita in the EU, the U.K., and Switzerland under the terms of the Company’s Collaboraon and License Agreement with KKC dated August 29, 2013, as amended, or the KKC Collaboraon Agreement. The agreement with RPI will automacally terminate, and the payment of royales to RPI will cease, in the event aggregate royalty payments received by RPI are equal to or greater than $608.0 million prior to December 31, 2030, or in the event aggregate royalty payments received by RPI are less than $608.0 million prior to December 31, 2030, or when aggregate royalty payments received by RPI are equal to $800.0 million. In July 2022, the Company entered into a Royalty Purchase Agreement with OMERS. Pursuant to the agreement, OMERS paid $500.0 million to the Company in consideraon for the right to receive 30% of the future royalty payments due to the Company from KKC based on net sales of Crysvita in the U.S. and Canada under the terms of the KKC Collaboraon Agreement. The calculaon of royalty payments to OMERS is based on net sales of Crysvita beginning in April 2023 and will expire upon the earlier of the date on which aggregate payments received by OMERS equals $725.0 million or the date the ﬁnal royalty payment is made to the Company under the KKC Collaboraon Agreement. Proceeds from these transacons were recorded as liabilies for sales of future royales on the Consolidated Balance Sheets. Upon incepon of the respecve arrangements, the Company recorded $320.0 million and $500.0 million, net of transacon costs of $5.8 million and $9.1 million for RPI and OMERS, respecvely, using the eﬀecve interest method over the esmated life of the applicable arrangement. In order to determine the amorzaon of the liabilies, the Company is required to esmate the total F-28 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) amount of future royalty payments to be received by the Company and paid to RPI and OMERS, subject to the capped amount, over the life of the arrangements. The excess of future esmated royalty payments (subject to the capped amount) to RPI and OMERS, over the $314.2 million and $491.0 million, respecvely, of net proceeds, is recorded as non-cash interest expense over the life of the arrangements. Consequently, the Company esmates an imputed interest on the unamorzed poron of the liabilies and records interest expense relang to the transacons. The Company records the royalty revenue arising from the net sales of Crysvita in the applicable territories as royalty revenue in the Consolidated Statements of Operaons over the term of the arrangements. Royales earned under the RPI and OMERS arrangements from incepon to December 31, 2023 have been $73.4 million and $48.6 million, respecvely. The Company periodically assesses the expected royalty payments using a combinaon of historical results, internal projecons and forecasts from external sources. To the extent such payments are greater or less than the Company’s inial esmates or the ming of such payments is materially diﬀerent than its original esmates, the Company will prospecvely adjust the amorzaon of the liabilies and the eﬀecve interest rate. The Company’s eﬀecve annual interest rates were 6.2% and 7.8%, for RPI and OMERS, respecvely, as of December 31, 2023. There are a number of factors that could materially aﬀect the amount and ming of royalty payments from KKC in the applicable territories, most of which are not within the Company’s control. Such factors include, but are not limited to, the success of KKC’s sales and promoon of Crysvita, changing standards of care, macroeconomic and inﬂaonary pressures, the introducon of compeng products, pricing for reimbursement in various territories, manufacturing or other delays, intellectual property maers, adverse events that result in governmental health authority imposed restricons on the use of Crysvita, signiﬁcant changes in foreign exchange rates as the royalty payments are made in U.S. dollars, or USD, while signiﬁcant porons of the underlying sales of Crysvita are made in currencies other than USD, and other events or circumstances that could result in reduced royalty payments from sales of Crysvita, all of which would result in a reducon of royalty revenue and the non-cash interest expense over the life of the arrangement. Conversely, if sales of Crysvita in the relevant territories are more than expected, the royalty revenue and the non-cash interest expense recorded by the Company would be greater over the term of the arrangements. The following table shows the acvity within the liability account (in thousands): December 31, 2021 Net proceeds from sale of future royales Royalty revenue Non-cash interest expense December 31, 2022 Royalty revenue Non-cash interest expense December 31, 2023 11. Equity At-the-Market Oﬀerings Liabilies for Sales of Future Royales OMERS RPI Total 351,786 $ — (21,692 ) 35,095 365,189 (20,783 ) 32,235 376,641 $ — $ 490,950 — 19,300 510,250 (38,524 ) 43,200 514,926 $ 351,786 490,950 (21,692 ) 54,395 875,439 (59,307 ) 75,435 891,567 $ $ In May 2021, the Company entered into an Open Market Sale Agreement with Jeﬀeries LLC, or Jeﬀeries, pursuant to which the Company may oﬀer and sell shares of the Company’s common stock having an aggregate oﬀering proceeds up to $350.0 million, from me to me, in at-the-market, or ATM, oﬀerings through Jeﬀeries. During the year ended December 31, 2023, there were 1,175,584 shares sold under the ATM resulng in net proceeds of $53.3 million. There were no shares sold under the ATM for year ended December 31, 2022. As of December 31, 2023, the Company has sold a total of 2,225,956 shares under the ATM, resulng in net proceeds of $132.2 million. Underwrien Public Oﬀering In October 2023, the Company completed an underwrien public oﬀering in which 9,833,334 shares of common stock were sold, including the exercise in full by the underwriters of their opon to purchase an addional 1,500,000 shares, at a public oﬀering price of $30.00 per share. In connecon with the oﬀering, the Company sold to certain investors pre-funded warrants, in lieu of common stock, to purchase 1,666,722 shares of common stock at a purchase price of $29.999 per pre-funded warrant, which equals the public oﬀering price per share of common stock less the $0.001 exercise price per share of each pre-funded warrant. The total F-29 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) proceeds that the Company received from the oﬀering were $326.5 million, net of underwring discounts and commissions. As of December 31, 2023, none of the pre-funded warrants had been exercised. The pre-funded warrants were classiﬁed as a component of permanent equity in the Company's Consolidated Balance Sheets as they are freestanding ﬁnancial instruments that are immediately exercisable, do not embody an obligaon for the Company to repurchase its own shares and permit the holders to receive a ﬁxed number of shares of common stock upon exercise. All of the shares underlying the pre-funded warrants have been included in the weighted- average number of shares of common stock used to calculate net loss per share, basic and diluted, aributable to common stockholders because the shares may be issued for lile or no consideraon, are fully vested, and are exercisable aer the original issuance date of the pre-funded warrants. 12. Stock-Based Awards Equity Plan Awards In 2014, the Company adopted the 2014 Incenve Plan, or the 2014 Plan, for the granng of stock-based awards to employees, directors, and consultants under terms and provisions established by the board of directors. The 2014 Plan had 2,250,000 shares of common stock available for future issuance at the me of its incepon. The 2014 Plan provided for automac annual increases in shares available for grant, beginning on January 1, 2015 through June 7, 2023. In June 2023, the Company adopted the 2023 Incenve Plan which had 4,500,000 shares of common stock available for future issuance at the me of its incepon, plus the number of shares subject to the 2014 Plan cancelled aer June 7, 2023. No further shares were granted under the 2014 Plan aer June 7, 2023.In February 2021, the Company adopted the Employment Inducement Plan, or the Inducement Plan, which was subsequently amended in June 2023 to provide for a maximum of 850,000 shares available for grant under the plan. In 2014, the Company adopted the 2014 Incenve Plan, or the 2014 Plan, for the granng of stock-based awards to employees, directors, and consultants under terms and provisions established by the board of directors. Under the terms of the 2023 Plan and Inducement Plan, awards may be granted at an exercise price not less than fair market value. The exercise price of an opon may not be less than the fair market value. The term of an award granted under the 2023 Plan and Inducement Plan may not exceed ten years. Typically, the vesng schedule for opon grants to the employees provides that ¼ of the grant vests upon the ﬁrst anniversary of the date of grant, with the remainder of the shares vesng monthly thereaer at a rate of 1/48 of the total shares subject to the opon. Typically, the vesng schedule for RSU grants provides that ¼ of the grant vests upon the annual anniversary of the date of grant over the period of four years. As of December 31, 2023, an aggregate of 19,610,125 shares of common stock have been authorized for issuance under the 2014 Plan, the 2023 Plan, and the Inducement Plan. Stock Opon Acvity The following table summarizes acvity under the Company’s stock opon plans and related informaon: Outstanding — December 31, 2022 Opons granted Opons exercised Opons cancelled Outstanding — December 31, 2023 Vested and exercisable — December 31, 2023 Vested and expected to vest — December 31, 2023 Opons Outstanding Number of Opons Weighted- Average Exercise Price Weighted- Average Remaining Contractual Term (Years) 7,773,367 $ 2,123,256 (209,793 ) (899,118 ) 8,787,712 5,415,110 8,461,973 72.56 45.05 13.07 71.56 67.43 73.28 67.96 6.60 6.39 4.96 6.29 Aggregate Intrinsic Value (In thousands) 8,476 $ 7,558 1,214 6,794 The aggregate intrinsic values of opons outstanding, vested and exercisable, and vested and expected to vest were calculated as the diﬀerence between the exercise price of the opons and the fair value of the Company’s common stock. The total intrinsic value of opons exercised during the years ended December 31, 2023, 2022, and 2021 was $4.9 million, $2.6 million, and $38.8 million, respecvely. Cash received from the exercise of opons was $2.7 million, $6.2 million, and $36.6 million for the years ended December 31, 2023, 2022, and 2021, respecvely. F-30 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The weighted-average esmated fair value of stock opons granted was $25.53, $34.77, and $70.84 per share of the Company’s common stock during the years ended December 31, 2023, 2022, and 2021, respecvely. The total esmated grant date fair value of opons vested during the years ended December 31, 2023, 2022, and 2021 was $59.7 million, $58.7 million, and $48.1 million, respecvely. Performance Stock Opons The following table summarizes acvity under the Company’s Performance Stock Opon, or PSO, plans and related informaon: PSOs Outstanding Outstanding — December 31, 2022 PSOs cancelled Outstanding — December 31, 2023 Vested and exercisable — December 31, 2023 Vested and expected to vest — December 31, 2023 Number of Opons 1,624,599 $ (243,601 ) 1,380,998 117,865 983,173 Weighted- Average Exercise Price 67.37 67.37 67.37 67.37 67.37 Weighted- Average Remaining Contractual Term (Years) Aggregate Intrinsic Value — 4.14 $ 3.15 3.09 3.14 — — — During the year ended December 31, 2022, PSOs were granted to certain nonexecuve employees. PSOs are subject to vest only if speciﬁed operaonal milestones are achieved and the employees’ connued service with the Company. The Company uses the Black-Scholes method to calculate the fair value at the grant date and is recognizing stock-based compensaon expense for the PSOs that are expected to vest. Stock-based compensaon for PSOs is recognized over the service period, beginning in the period the Company determines it is probable that a milestone will be achieved. Forfeitures of PSOs are recognized as they occur. The Company reassesses the probability of the performance condion at each reporng period and adjusts the compensaon cost based on the probability assessment. As of December 31, 2023, certain operaonal milestones were deemed probable of achievement. The aggregate intrinsic values of PSOs outstanding, vested and exercisable, and vested and expected to vest were calculated as the diﬀerence between the exercise price of the PSOs and the fair value of the Company’s common stock. The total esmated grant date fair value of PSOs vested during the year ended December 31, 2023, was $3.4 million. No PSOs were granted or were exercised during the year ended December 31, 2023. The weighted-average esmated fair value of PSOs granted was $28.76 during the year ended December 31, 2022. Restricted Stock Units The following table summarizes acvity under the Company’s Restricted Stock Units, or RSU, plans and related informaon: Unvested — December 31, 2022 RSUs granted RSUs vested RSUs cancelled Unvested — December 31, 2023 RSUs Outstanding Number of Shares 2,129,153 $ 2,447,170 (738,130 ) (394,081 ) 3,444,112 Weighted- Average Grant Date Fair Value 75.11 44.52 73.99 61.22 55.21 The fair value of the RSUs is determined on the grant date based on the fair value of the Company’s common stock. The fair value of the RSUs is recognized as expense ratably over the vesng period of one to four years. The total grant date fair value of the RSUs vested during the years ended December 31, 2023, 2022, and 2021 was $54.6 million, $47.1 million, and $35.5 million, respecvely. The aggregate intrinsic value of the shares of the RSUs vested during the years ended December 31, 2023, 2022, and 2021 was $33.0 million, $37.8 million, and $69.9 million, respecvely. F-31 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Performance Stock Units The following table summarizes acvity under the Company’s Performance Stock Units, or PSUs and related informaon: Unvested — December 31, 2022 PSUs granted PSUs vested PSUs cancelled Unvested — December 31, 2023 PSUs Outstanding Number of Shares 209,230 $ 362,470 (27,581 ) (38,013 ) 506,106 Weighted- Average Grant Date Fair Value 98.09 50.29 141.86 106.80 60.82 The fair value of the PSUs is determined on the grant date based on the fair value of the Company’s common stock, except for certain PSUs with a market vesng condion, for which fair value is esmated using a Monte Carlo simulaon model. PSUs are subject to vest only if certain speciﬁed criteria are achieved and the employees’ connued service with the Company. For certain PSUs, the number of PSUs that may vest are also subject to the achievement of certain speciﬁed criteria, including both performance condions and market condions. As of December 31, 2023, certain speciﬁed criteria were deemed probable of achievement or already achieved. Stock-based compensaon for PSUs is recognized over the service period beginning in the period the Company determines it is probable that the performance criteria will be achieved. The total grant date fair value of the PSUs vested during the years ended December 31, 2023, 2022, and 2021 was $3.9 million, $1.6 million, and $9.2 million, respecvely, with an aggregate intrinsic value of the shares of $1.3 million, $2.0 million and $18.9 million, respecvely. Employee Stock Purchase Plan In January 2014, the Company adopted the 2014 Employee Stock Purchase Plan, or ESPP, which was amended and restated in June 2023. Under the ESPP, eligible employees may purchase common stock at 85% of the lesser of the fair market value of common stock on the oﬀering date or the purchase date with a six-month look-back feature. ESPP purchases are seled with common stock from the ESPP’s previously authorized and available pool of shares. During the year ended December 31, 2023, the Company issued 195,462 shares of common stock under the ESPP. As of December 31, 2023, an aggregate of 6,609,795 shares of common stock have been authorized for future issuance on the ESPP. Stock-Based Compensaon Expense Total stock-based compensaon recognized was as follows (in thousands): Cost of sales Research and development Selling, general and administrave Total stock-based compensaon expense Year Ended December 31, 2022 2023 2021 $ $ 1,166 $ 74,531 59,516 135,213 $ 902 $ 74,464 55,002 130,368 $ 871 59,097 45,011 104,979 Stock-based compensaon of $1.9 million, $2.2 million, and $1.7 million was capitalized into inventory for the years ended December 31, 2023, 2022, and 2021, respecvely. Capitalized stock-based compensaon is recognized as cost of sales when the related product is sold. As of December 31, 2023, the total unrecognized compensaon expense related to unvested equity awards, net of esmated forfeitures, was $219.8 million, which the Company expects to recognize over an esmated weighted-average period of 2.2 years. In determining the esmated fair value of the stock opons, PSOs and ESPP, the Company uses the Black-Scholes opon-pricing model and assumpons discussed below. Each of these inputs is subjecve and generally requires signiﬁcant judgment to determine. Expected Term—The Company’s expected term represents the period that the Company’s stock-based awards are expected to be outstanding and is determined using the simpliﬁed method (based on the mid-point between the vesng date and the end of the contractual term). Expected Volality—The Company’s expected volality is based on historical volality over the look-back period corresponding to the expected term. F-32 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Risk-Free Interest Rate—The risk-free interest rate is based on the U.S. Treasury zero coupon issues in eﬀect at the me of grant for periods corresponding with the expected term of opon. Expected Dividend—The Company has never paid dividends on its common stock and has no plans to pay dividends on its common stock. Therefore, the Company used an expected dividend yield of zero. Strike price for opons awards and PSOs is equal to the closing market value of our common stock on the date of grant. The fair value of stock opon awards granted was esmated at the date of grant using a Black-Scholes opon-pricing model with the following weighted-average assumpons: Expected term (years) Expected volality Risk-free interest rate Expected dividend rate Year Ended December 31, 2023 6.07 55% 4.2% 0.0% 2022 6.07 56% 2.0% 0.0% 2021 6.06 60% 1.0% 0.0% The fair value of PSOs granted was esmated at the date of grant using a Black-Scholes opon-pricing model with the following weighted-average assumpons: Expected term in years Expected volality Risk-free interest rate Expected dividend rate 13. Deﬁned Contribuon Plan Year Ended December 31, 2022 3.60 57% 1.5% 0.0% The Company sponsors a rerement plan in which substanally all of its full-me employees in the U.S. and certain other foreign countries are eligible to parcipate. Eligible parcipants may contribute a percentage of their annual compensaon to this plan, subject to statutory limitaons. The Company recorded $9.7 million, $9.0 million, and $5.5 million as expense related to the plan for the years ended December 31, 2023, 2022, and 2021, respecvely. 14. Income Taxes The components of the Company’s loss before income taxes were as follows (in thousands): Domesc Foreign Total loss before income taxes Year Ended December 31, 2022 2023 2021 $ $ 608,166 $ 298 608,464 $ 703,411 $ (1,686 ) 701,725 $ 455,314 (2,333 ) 452,981 F-33 The components of the Company’s income tax provision were as follows (in thousands): ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Year Ended December 31, 2022 2023 2021 Current provision for income taxes: Federal State Internaonal Total current tax provision Deferred tax provision: Federal State Internaonal $ — $ — $ (3,187 ) 3,127 (60 ) — (1,608 ) (157 ) (1,765 ) (1,825 ) $ 6,062 1,274 7,336 — (1,640 ) — (1,640 ) 5,696 $ — (14 ) 1,058 1,044 — — — — 1,044 Total deferred tax provision Total (beneﬁt from) provision for income taxes $ The Company has incurred net operang losses since incepon. The Company has not reﬂected any beneﬁt of such net operang loss carryforwards in the accompanying ﬁnancial statements. The Company has established a full valuaon allowance against its deferred tax assets due to the uncertainty surrounding the realizaon of such assets. Beginning in 2022, the Tax Cuts and Jobs Act of 2017 eliminated the right to deduct research and development expenditures for tax purposes in the period the expenses were incurred and instead requires all U.S. and foreign research and development expenditures to be amorzed over ﬁve and ﬁeen tax years, respecvely. Due to this required capitalizaon of research and development expenditures and the signiﬁcant taxable income generated as a result of our sale of royales in July 2022, the Company has recorded current state income tax expense of $6.1 million for the year ended December 31, 2022. For the year ended December 31, 2023, the Company recognized an income tax beneﬁt of $4.8 million aributable to modiﬁcaons in its state apporonment methodology. The Company realized no beneﬁt for current year losses due to a full valuaon allowance against the U.S. net deferred tax assets. The beneﬁt was oﬀset by an income tax expense of $3.0 million from foreign jurisdicons. The eﬀecve tax rate of our provision for income taxes diﬀers from the federal statutory rate as follows: Federal statutory income tax rate State income taxes, net of federal beneﬁt Federal tax credits Other Nondeducble permanent items Stock-based compensaon Uncertain tax posions Change in valuaon allowance Foreign rate diﬀerenal Provision for income taxes Year Ended December 31, 2022 2023 2021 21.0 % 0.8 7.3 (0.7 ) (0.3 ) (1.8 ) (1.4 ) (24.1 ) (0.5 ) 0.3 % 21.0 % (0.4 ) 5.9 (0.1 ) (0.6 ) (1.2 ) (1.2 ) (24.0 ) (0.2 ) (0.8 ) % 21.0 % — 7.2 0.5 (0.8 ) 1.3 (1.4 ) (27.9 ) (0.1 ) (0.2 ) % F-34 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The tax eﬀect of temporary diﬀerences that give rise to signiﬁcant porons of the deferred tax assets is presented below (in thousands): Deferred tax assets: Loss carryforwards Tax credits Stock opons Accruals and reserves Fixed assets and intangibles Liabilies for sales of future royales Basis diﬀerence in equity investments Capitalized research and development costs Other Gross deferred tax assets Valuaon allowance Total deferred tax assets Deferred tax liabilies: In-process research and development Right-of-use lease assets Gross deferred tax liabilies Net deferred tax liabilies $ Year Ended December 31, 2022 2023 266,253 $ 305,198 44,795 27,694 33,853 205,400 8,423 149,898 281 1,041,795 (1,035,836 ) 5,959 231,835 260,546 39,784 27,029 39,233 214,900 8,971 75,335 3,028 900,661 (894,518 ) 6,143 (30,688 ) (5,329 ) (36,017 ) (30,058 ) $ (31,667 ) (6,143 ) (37,810 ) (31,667 ) $ As of December 31, 2023 and 2022, the Company had approximately $1,004.8 million and $756.6 million, respecvely, of federal net operang loss carryforwards available to reduce future taxable income that will begin to expire in 2031. As of December 31, 2023 and 2022, the Company had approximately $659.9 million and $710.0 million, respecvely, of state net operang loss carryforwards available to reduce future taxable income that will begin to expire in 2031. As of December 31, 2023 and 2022, the Company had federal research tax credit carryforwards of approximately $46.9 million and $32.6 million, respecvely, available to reduce future tax liabilies that will begin to expire in 2030. As of December 31, 2023 and 2022, the Company had state research credit carryforwards of $74.4 million and $59.9 million, respecvely, available to reduce future tax liabilies that will be carried forward indeﬁnitely. As of December 31, 2023 and 2022, the Company had federal Orphan Drug Credits of $269.6 million and $239.3 million, respecvely, available to reduce future tax liabilies that will begin to expire in 2031. The Company’s ability to use net operang loss and tax credit carryforwards to reduce future taxable income and liabilies may be subject to annual limitaons pursuant to Internal Revenue Code Secons 382 and 383 as a result of ownership changes in the past and future. As a result of ownership changes in 2012 and 2011, $3.6 million of federal net operang loss carryforwards, $3.6 million of state net operang loss carryforwards, and $0.2 million of federal tax credits are permanently limited. Deferred tax assets for net operang losses and tax credits have been reduced and a corresponding adjustment to the valuaon allowance has been recorded. The valuaon allowance increased by $141.3 million and $193.8 million during the years ended December 31, 2023 and 2022, respecvely. Due to a change in the state tax rates, the Company recorded a net decrease to the deferred tax liability of $1.6 million with a corresponding deferred income tax beneﬁt of $1.6 million for the year ended December 31, 2023. F-35 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The Company recorded unrecognized tax beneﬁts for uncertaines in income taxes. A reconciliaon of the Company’s unrecognized tax beneﬁts follows (in thousands): 2023 December 31, 2022 2021 Balance at beginning of year $ 66,794 $ 55,360 $ 46,662 Addions based on tax posions related to current year Addions for tax posions of prior years Reducons for tax posions of prior years Balance at end of year 12,562 642 — 79,998 $ 11,316 377 (259 ) 66,794 $ 8,542 356 (200 ) 55,360 $ Approximately $1.3 million in unrecognized tax beneﬁts would impact the Company’s eﬀecve tax rate if recognized. The Company has elected to include interest and penales as a component of tax expense. For the year ended December 31, 2023, the Company recognized accrued interest and penales of $0.2 million as a component of income tax expense. No accrued interest and penales were recognized as a component of income tax expense during the years ended December 31, 2022 and 2021. The Company does not ancipate that the amount of exisng unrecognized tax beneﬁts will signiﬁcantly increase or decrease during the next year. It is the Company’s intenon to reinvest the earnings of its non-U.S. subsidiaries in their operaons. As of December 31, 2023, the Company had not made a provision for any incremental foreign withholding taxes on approximately $10.8 million of the excess of the amount of net income for ﬁnancial reporng over the tax basis of investments in foreign subsidiaries that are essenally permanent in duraon. If these earnings were repatriated to the U.S., the deferred tax liability associated with these temporary diﬀerences would result in a nominal amount of withholding taxes. The Company ﬁles income tax returns in the U.S. federal, 40 state tax jurisdicons, and ten foreign countries. The federal and state income tax returns from incepon to December 31, 2023 remain subject to examinaon. 15. Commitments and Conngencies The Company has various manufacturing, construcon, clinical, research, and other contracts with vendors in the conduct of the normal course of its business. Other than as noted below, contracts are terminable, with varying provisions regarding terminaon. If a contract with a speciﬁc vendor were to be terminated, the Company would only be obligated for the products or services that the Company had received at the me the terminaon became eﬀecve. Manufacturing and service contract obligaons primarily relate to the manufacture of inventory for our approved products, the majority of which are due in the next 12 months. As of December 31, 2023, the aggregate payments under contractually-binding manufacturing and service agreements are as follows (in thousands): Manufacturing and Services $ 27,899 $ 5,718 $ 33,617 The terms of certain of the Company’s licenses, royales, development and collaboraon agreements, as well as other research and development acvies, require the Company to pay potenal future milestone payments based on product development success. The amount and ming of such obligaons are unknown or uncertain. These potenal obligaons are further described in “Note 8. License and Research Agreements.” 2024 Year Ended December 31, 2025 Total See “Note 9. Leases” for lease commitments. Conngencies While there are no material legal proceedings the Company is aware of, the Company may become party to various claims and complaints arising in the ordinary course of business. Management does not believe that any ulmate liability resulng from any of these potenal claims will have a material adverse eﬀect on its results of operaons, ﬁnancial posion, or liquidity. However, management cannot give any assurance regarding the ulmate outcome of these claims, and their resoluon could be material to operang results for any parcular period, depending upon the level of income for the period. F-36 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Guarantees and Indemniﬁcaons The Company indemniﬁes each of its directors and oﬃcers for certain events or occurrences, subject to certain limits, while the director or oﬃcer is or was serving at the Company’s request in such capacity, as permied under Delaware law and in accordance with its cerﬁcate of incorporaon and bylaws. The term of the indemniﬁcaon period lasts as long as a director or oﬃcer may be subject to any proceeding arising out of acts or omissions of such director and oﬃcer in such capacity. The maximum amount of potenal future indemniﬁcaon is unlimited; however, the Company currently holds director liability insurance. This insurance allows the transfer of risk associated with the Company’s exposure and may enable it to recover a poron of any future amounts paid. The Company believes that the fair value of these indemniﬁcaon obligaons is minimal. Accordingly, it has not recognized any liabilies relang to these obligaons for any period presented. 16. Related Party Transacon In July 2022, the Company entered into an agreement with a non-proﬁt foundaon in which two members of the Company’s board of directors, including the Company’s Chief Execuve Oﬃcer, also serve as board members of the foundaon, whereby an aggregate $1.0 million contribuon is being paid to the foundaon over a four-year period, beginning in the third quarter of 2022, to support rare disease educaon and awareness. As a result, the Company recorded $0.3 million and $0.3 million as research and development expense for this agreement for the years ended December 31, 2023 and 2022, respecvely. 17. Net Loss per Share The following table sets forth the computaon of the basic and diluted net loss per share during the years ended December 31, 2023, 2022, and 2021 (in thousands, except share and per share data): Numerator: Net loss Denominator: Year Ended December 31, 2022 2023 2021 $ (606,639 ) $ (707,421 ) $ (454,025 ) Weighted-average shares used to compute net loss per share, basic and diluted Net loss per share, basic and diluted 73,543,862 69,914,225 67,795,540 $ (8.25 ) $ (10.12 ) $ (6.70 ) The following weighted-average outstanding common stock equivalents were excluded from the computaon of diluted net loss per share for the periods presented because including them would have been andiluve: Opons to purchase common stock, restricted stock units, and performance stock units Employee stock purchase plan Year Ended December 31, 2022 2023 2021 14,152,286 11,290,935 8,214,063 8,450 14,160,736 7,581 11,298,516 3,511 8,217,574 18. Accumulated Other Comprehensive Income (Loss) Total accumulated other comprehensive income (loss) consisted of the following (in thousands): Cumulave foreign currency translaon adjustment Unrealized gain (loss) on securies available-for-sale Total accumulated other comprehensive income (loss) F-37 Year Ended December 31, 2023 2022 $ $ (606 ) $ 1,253 647 $ (845 ) (5,728 ) (6,573 ) [***] = CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY BRACKETS, HAS BEEN OMITTED BECAUSE THE INFORMATION (I) IS NOT MATERIAL AND (II) THE TYPE THAT THE REGISTRANT TREATS A PRIVATE OR CONFIDENTIAL. Exhibit 10.18 Commercial Supply Agreement Triheptanoin Ultrapure Between Ultragenyx Pharmaceucal Inc. 60 Leveroni Court Novato, CA 94949 USA (Herein known as UGX) And IOI Oleo GmbH Herrengraben 31 20459 Hamburg, Germany (Herein known as IOI) Hereinaer referred to individually as a “Party” and together as the “Pares” 1 Preamble Whereas, UGX is a company engaged in the pharmaceucal ﬁeld focusing on development of rare disease therapies and has obtained regulatory approval to market certain medicinal products based on acve pharmaceucal ingredients; Whereas, IOI is a supplier of oleochemical speciales for a large number of pharmaceucal and industrial applicaons, including the development and manufacturing of drug substance. Whereas, given IOI’s know-how, experse, capability, experience and infrastructure, Ultragenyx entrusted IOI with, and IOI accepted, the manufacturing, packing, releasing of Ultragenyx’s Triheptanoin Ultrapure Drug Substance (the PRODUCT) in accordance with the terms and condions of the Supply Agreement between CREMER OLEO GmbH & Co KG as legal predecessor of IOI and Ultragenyx Pharmaceucal Inc. of November 19th 2012 (“INITIAL AGREEMENT”); Whereas, as the PARTIES have determined the INITIAL AGREEMENT to be terminated and replaced with a modiﬁed agreement to beer regulate their collaboraon in parcular, but not limited to, the evolving regulatory status of PRODUCT across the world, both PARTIES have expressed their intenon to beer regulate respecve dues and obligaons in relaon to the manufacturing of Ultragenyx’s Triheptanoin Ultrapure Drug Substance; Whereas, each Party herewith expresses once again its commitment to (i) work in a partnership model, (ii) always apply the appropriate level of trust and transparency, (iii) respect a duty of good faith and fair dealing in connecon with its performance under this AGREEMENT, (iv) perform its obligaons under this AGREEMENT in a diligent, legal, ethical and professional manner so as to advance the purposes and intent of this AGREEMENT. Now, Therefore, in consideraon of the mutual agreements and covenants contained herein, and for other good and valuable consideraon, the receipt and suﬃciency of which are hereby acknowledged, the Pares, intending to be legally bound, hereby agree as follows: 2 Contents 1. DEFINITION 2. SCOPE OF THE AGREEMENT 3. IOI`S RESPONSIBILITIES 4. UGX RESPONSIBILITIES 5. GOVERNANCE MODEL 6. RECORDS, AUDITS AND INSPECTIONS 7. INTELLECTUAL PROPERTY 8. DEFECTIVE PRODUCT 9. INDEMNIFICATION FOR THIRD-PARTY CLAIMS 10. LIMITATION OF LIABILITIES 11. INSURANCE 12. FORCE MAJEURE 13. TERM AND TERMINATION 14. MISCELLANEOUS APPENDIX I (COMMERCIAL TERMS) APPENDIX II (COMPLIANCE) APPENDIX III (PRICES AND FEES) APPENDIX IV (QUALITY AND TECHNICAL AGREEMENT) 3 5 7 8 9 9 11 10 12 13 14 15 15 15 15 20 23 25 19 APPENDIX V (PRODUCT SPECIFICATION) APPENDIX VI (RAW MATERIAL SPECIFICATIONS) APPENDIX VII (CDA) APPENDIX VIII (THIRD PARTY LABORATORIES) 4 22 24 29 30 1. Deﬁnions AGREEMENT means this Commercial Supply AGREEMENT. ADDITIONAL SERVICE means any service provided by IOI and agreed by both PARTIES, except all acvies involved in MANUFACTURE and TECHNICAL RELEASES of PRODUCT. Addional services are subject to individual OFFERS. They are deﬁned in Appendix I. AFFILIATE shall mean with respect to a Party, any person, corporaon, company, partnership or other enty that controls, is controlled by, or is under common control with that Party. For the purpose of this deﬁnion, “control” shall mean direct ownership of ﬁy percent (50%) or more of the shares of stock entled to vote for the elecon of directors, in the case of a corporaon, or ﬁy percent (50%) or more of the equity interest in the case of any other type of legal enty, status as a general partner in any partnership, or any other arrangement whereby the enty or person controls or has the right to control the board of directors or equivalent governing body of a corporaon or other enty, or the ability to cause the direcon of the management or policies of a corporaon or other enty. BUSINESS DAY shall mean each day of the week on which a Party`s oﬃces are open for business (usually any day except Saturday, Sunday and legal holidays). CALENDAR QUARTER shall mean the respecve periods of 3 (three) consecuve CALENDAR MONTHs ending March 31st, June 30th, September 30th and December 31st. CALENDAR MONTH shall mean any of the 12 (twelve) CALENDAR MONTHs of a CALENDAR YEAR. CALENDAR YEAR shall mean a period of 12 (twelve) consecuve months corresponding to a calendar year commencing on the ﬁrst days of January. CONFIDENTIAL INFORMATION shall have the meaning as provided in Appendix 7. DELIVERY DATE means the point in me set out in the conﬁrmed FORECAST at which PRODUCT is delivered to UGX under the applicable Incoterm®. EQUIPMENT means any equipment system to support the manufacturing and/or packaging of UGX`s PRODUCT. EXECUTIVE LEADERSHIP shall mean for the purpose of this AGREEMENT the [***] of UGX and the [***] of IOI respecvely (or whoever is on these roles ad interim). FACILITY shall mean the IOI manufacturing site located in [***] adequate to MANUFACTURE the PRODUCT by means of validated processing equipment and manufacturing processes for the PRODUCT, trained and competent personnel with relevant knowledge and experience. FINAL RELEASE shall mean PRODUCT quality release by UGX or UGX`s delegate as per QTA. 5 FORCE MAJEURE shall have the meaning as provided in Secon 12. FORECAST shall have the meaning as provided in Appendix I. cGMP means those pracces related to the manufacture of medicinal products for human use laid down in internaonal guidelines and regulaons such as the GMP rules of the World Health Organizaon, the United States Code of Federal Regulaons (Title 21, Parts 210), and the European Union Guide to Good Manufacturing Pracce (Eudralex Volume 4). Current Good Manufacturing Pracce (cGMP) is the applicable term in the United States. For the purpose of this AGREEMENT, the terms GMP and cGMP are equivalent. HIDDEN DEFECT means a defect of PRODUCT already present at the me of delivery but not detectable at the me of the inspecon. IMPROVEMENT means technical and business process opmizaon that is beneﬁcial for the manufacturing process, product quality, ﬁnancial aspect or supply of PRODUCT. INTELLECTUAL PROPERTY RIGHTS or IP RIGHTS means rights in or arising from patents, patent applicaons (including all ulity and design patents and patent applicaons), invenons, trademarks, service marks, trade names, internet domain names, rights in designs, rights in get-up and trade dress, goodwill and the right to sue for passing oﬀ or unfair compeon, copyrights, (including all computer applicaons, programs and other soware, including without limitaon operang soware, network soware, ﬁrmware, middleware, and design soware rights in computer soware and databases), database rights, industrial property rights, moral rights of authors, rights to use and protect the conﬁdenality of, conﬁdenal informaon (including know-how and trade secrets), ulity models, any common law rights arising from use of the foregoing, all rights of use, renewal, connuaons, divisions, extensions and the like relang to the foregoing, and other intellectual property rights, in each case whether registered or unregistered and including any applicaons and rights to apply for the grant of any such rights and all rights and forms of protecon having an equivalent or similar eﬀect anywhere in the world. JOINT WORKING TEAM shall mean the team selected by the STEERING COMMITTEE in accordance with the criteria set out under Secon 5 of this AGREEMENT. MANUFACTURE or MANUFACTURING means compounding, ﬁlling and processing, producon, tesng and packaging of material by IOI to obtain PRODUCT in accordance with the SPECIFICATION under cGMP condions. MATERIAL CHANGE IN CONTROL or BUSINESS MODEL shall mean any of the following: (i) the sale or disposion of all or substanally all of the assets of a Party to a THIRD-PARTY, (ii) the acquision by a THIRD-PARTY, of more than 50% of a Party’s outstanding shares of vong capital stock (e.g. capital stock entled to vote generally for the elecon of directors), or (iii) the merger or consolidaon of a Party with or into another corporaon. References in this deﬁnion to a THIRD- PARTY shall exclude AFFILIATES. OFFER shall mean IOI`s quotaon containing the details of the proposed ADDITIONAL SERVICES subject to UGX`s binding order. 6 ON-TIME DELIVERY shall mean PRODUCT released by both Pares and ready to be picked up under the applicable INCOTERM® in accordance with the applicable FORECAST. PRODUCT shall mean Triheptanoin Ultrapure, a Drug Substance as speciﬁed in Appendix 5 to this agreement and solely used in pharmaceucal applicaons. PURCHASE ORDER shall mean a ﬁrm order placed and issued by UGX with a corresponding PURCHASE ORDER number to IOI reﬂecng forecasted DELIVERY DATE within the binding forecast period. QUALITY AND TECHNICAL AGREEMENT (QTA) shall be draed substanally in the same form as Appendix IV. QUARANTINE SHIPMENT means a shipment of PRODUCT before the quality release by IOI in accordance with the QTA. SERVICES means all acvies related to MANUFACTURING of PRODUCT as described in this AGREEMENT and includes all acvies involved in MANUFACTURING of PRODUCT and according to the quality standards set forth in the QTA including costs of in-process control, quality assurance, Connuous Process Veriﬁcaon, Product Quality Review, quality control and release, storage of raw materials, sharing raw analycal/process data, providing relevant documentaon and THIRD-PARTY MATERIAL procured by IOI, disposal of waste. SPECIFICATION means the PRODUCT speciﬁcaon [***], as amended from me to me by mutual agreement between the Pares, and as deﬁned in IOI’s quality system aached as Appendix V to this AGREEMENT and THIRD PARTY MATERIAL speciﬁcaons for [***] as deﬁned in Appendix VI. STEERING COMMITTEE shall mean the commiee selected by the Pares in accordance with the criteria set out under Secon 5 of this AGREEMENT. TECHNICAL RELEASE shall mean the release of PRODUCT by IOI and UGX in accordance with the QTA. THIRD-PARTY means any person other than UGX, IOI and their respecve AFFILIATES. THIRD-PARTY MATERIAL means all material procured by IOI for the MANUFACTURING of the PRODUCT. 2. Scope of the AGREEMENT 2.1. UGX hereby retains IOI to MANUFACTURE and supply PRODUCT as well as perform SERVICES and ADDITIONAL SERVICES to and for the beneﬁt of UGX in accordance with the terms of this AGREEMENT and the applicable SPECIFICATIONS and applicable QTA. On the term set forth herein, UGX will purchase and pay PRODUCT from IOI and pay ADDITIONAL SERVICES fees as detailed under this AGREEMENT. 2.2. Quality control tesng and analysis of any batch of PRODUCT MANUFACTURED by IOI shall be conducted by IOI and / or THIRD-PARTY labs as spulated in Appendix VIII. Any diﬀerent seng regarding where to perform Quality Control tesng and analysis of any batch of PRODUCT MANUFACTURED by IOI, for example quality control tesng and analysis by a THIRD- PARTY independent laboratory engaged by UGX, 7 shall be discussed and agreed in good faith by the PARTIES. It is understood by the PARTIES that: (i) [***] shall be [***] by UGX to [***], provided IOI’s [***]are [***] to [***]; and (ii) in no event [***]. 2.3. IOI undertakes to refrain from performing any manufacturing services of the PRODUCT for any party other than Ultragenyx, [***]. UGX shall purchase the PRODUCT exclusively from IOI. 2.4. Aached to this AGREEMENT are the following Appendixes which form an integral part of this AGREEMENT: Appendix I Commercial Terms Appendix II Compliance Appendix III Prices and Fees Appendix IV QUALITY AND TECHNICAL AGREEMENT (QTA) Appendix V PRODUCT SPECIFICATION Appndix VI RAW MATERIAL SPECIFICATIONS Appendix VII Appendix VIII CDA THIRD-PARTY laboratories 2.5. 2.6. In case of any inconsistencies between this AGREEMENT, the Appendices and/or an OFFER referring to it, the Appendices and/or the OFFER shall prevail. However, if there is any contradicon or inconsitency between this AGREEMENT and the QTA, then this AGREEMENT will take precedence. This AGREEMENT, including all its Appendixes constutes the enre understanding between the Pares as of the EFFECTIVE DATE with respect to the subject maer hereof and supersedes all prior agreements (including the INITIAL AGREEMENT), negoaons, understandings, representaons, statements and wrings relang thereto. 2.7. Neither Party shall alter or adjust this AGREEMENT or any Appendixes to it without the prior wrien permission of the other Party. 3. IOI`s Responsibilies 3.1. IOI shall comply with this AGREEMENT, all its Appendixes (including but not limited to Appendix IV) and cGMP. 8 3.2. 3.3. 3.4. IOI shall render the SERVICES, the ADDITIONAL SERVICES and MANUFACTURE the PRODUCT in the FACILITY unless diﬀerently agreed to by the Pares in wring. All the responsibilies and obligaons listed under Secons 3.1 and 3.2. will be covered by IOI at their [***]. In case IOI incurs costs in connecon with the [***]. IOI will nofy UGX immediately but not later than within [***] BUSINESS DAYS aer becoming aware of any potenal failure to deliver the PRODUCT within the melines agreed in each applicable FORECAST. 3.5. IOI will provide UGX an inventory report upon request. 3.6. IOI will undertake [***] to implement and operate an eﬀecve system for protecng MANUFACTURE and supply of PRODUCT against risks related to cyber-crime incidents. 4. UGX Responsibilies 4.1 UGX shall purchase and pay the quanty of PRODUCT set out in the BINDING PERIOD of the FORECAST, as speciﬁed in Appendix I. 4.2 UGX shall be responsible to provide IOI with complete and accurate informaon to enable IOI to MANUFACTURE the PRODUCT. 4.3 UGX shall comply with Appendices I and II. 4.4 UGX shall provide reasonable assistance to IOI in dealing with regulatory changes related to the PRODUCT, SERVICES or ADDITIONAL SERVICES. 5. Governance Model 5.1. The partnership model includes a STEERING COMMITTEE and a JOINT WORKING TEAM focusing on operaonal execuon. The JOINT WORKING TEAM will be led by a project/relaonship manager of each Party (Joint Working Team Leads). 5.2. The Pares shall establish a STEERING COMMITTEE consisng of [***] individuals. Each Party will nominate [***] STEERING COMMITTEE members. 5.3. Either Party may replace its STEERING COMMITTEE members by wrien noce to the other Party. 5.4. The purpose of the STEERING COMMITTEE is to: a) establish and maintain an eﬀecve and eﬃcient collaboraon between the Pares: 9 b) c) a) b) c) d) conﬁrm the Joint Working Team Leads by each Party; oversee the JOINT WORKING TEAM`s performance in business review meengs; evaluate in good faith and rafy any technical, business process and/or quality improvements proposed by the JOINT WORKING TEAMS; act as escalaon body for issue resoluon; deﬁne the framework for connuous improvement, mutual long-term objecves and priories; any other topics assigned to it in compliance with this AGREEMENT or following the mutual decision of the Pares. 5.5. The Pares shall establish a JOINT WORKING TEAM, consisng of at least [***] of each Party in the [***] and [***] of each Party in [***]. Thus, the minimum size of the JOINT WORKING TEAM shall be [***] members. 5.6. Either Party may replace its JOINT WORKING TEAM leads and members by noce to the other Party. 5.7. The purpose of the JOINT WORKING TEAM is to: a) b) drive and improve performance of MANUFACTURE, SERVICES and ADDITIONAL SERVICES, if any, and the JOINT WORKING TEAM funconality; establish, manage and review rounely other relevant key performance MANUFACTURING, SERVICES and ADDITIONAL SERVICES; indicators applicable to c) manage MANUFACTURING, SERVICES and ADDITIONAL SERVICES risks, including lead mes and safety stock management of PURCHASED MATERIALS; d) overseeing and monitoring MANUFACTURING and manage any and all issues related to MANUFACTURING, e) SERVICES and ADDITIONAL SERVICES; facilitate expedious resoluon of any issues, also in accordance with the instrucons from the JOINT STEERING COMMITTEE, if received; f) maintain a collaborave and construcve relaonship at operaonal level; potenally propose any IMPROVEMENT to the STEERING COMMITTEE. g) 5.8. 5.9. The JOINT WORKING TEAM shall conduct its discussion in good faith with a view to operang to the mutual beneﬁt of the Pares. In addion to any other topics to be discussed in the agenda of the relevant meeng, the following maers shall be considered to be discussed during the JOINT WORKING TEAM meengs: team member updates; a) b) performance review (services, quality, relaonship, ﬁnancials); c) d) risk evaluaon and associated risk migaon projects; review the status of past meeng acon items. 6. Records, Audits and Inspecons 6.1 At [***], IOI will create and maintain accurate and relevant records related to MANUFACTURING, SERVICES and ADDITIONAL SERVICES, limited to [***] (collecvely, the “RECORDS”). The Pares will [***] of 10 the RECORDS, to the extent they are [***] and do not [***]. In such a circumstance, each Party will [***] on the RECORDS containing [***]. 6.2 All original RECORDS of the development and MANUFACTURE of PRODUCT hereunder will be retained and archived by IOI for a period set in accordance with cGMP, APPLICABLE LAW and the QTA (the “RETENTION PERIOD”). In case of conﬂict between the menoned sources, the QTA shall prevail. Following the RETENTION PERIOD, IOI will not destroy any UGX PROPRIETARY RECORDS or JOINTLY OWNED RECORDS without ﬁrst giving UGX wrien noce and the opportunity to return the UGX PROPRIETARY RECORDS or JOINTLY OWNED RECORDS [***]. 6.3 Upon request, IOI agrees to share with UGX [***], which ascertains the accuracy of IOI’s annual balance sheet, as well as the key ﬁnancial data supporng IOI’s independent auditor’s report, provided that UGX shall keep [***] strictly conﬁdenal with the prohibion of disclosure it to any third party without IOI’s prior wrien consent. 6.4 UGX has the right to audit and inspect the FACILITY, equipment, materials and RECORDS as required by cGMP guidelines, this AGREEMENT and the QTA. 6.5 Not more frequently than [***] per [***], upon [***] advance wrien noce and subject to compliance with all applicable conﬁdenality provisions herein, UGX may request to perform cGMP audits at the FACILITY and IOI shall permit for such audits as outlined in the QTA. UGX and its duly authorized representaves may have access together with a IOI employee to the FACILITY, during operaonal hours and during acve MANUFACTURING, to enter and inspect any premises and MANUFACTURING SERVICES and/or ADDITIONAL SERVICES to ascertain compliance by IOI with the terms of this AGREEMENT. IOI will cooperate with UGX to facilitate the evaluaon and inspecon, and provide reasonable assistance to UGX. UGX will reasonably cooperate with IOI to migate disrupon to IOI’s operaons. Scope and further details are set forth in the QTA aached to Appendix III of this AGREEMENT. It is understood by the Pares that upon prior wrien approval by IOI UGX may be accompanied by or delegate to THIRD PARTY’s representaves the performance of such cGMP audits; provided that such THIRD PARTY’s representaves shall (i) be bound by conﬁdenality obligaons toward IOI no less stringent than those idenﬁed in this AGREEMENT and (ii) ﬁnalize a three-way conﬁdenality AGREEMENT which shall be accepted by all contracng pares. 6.6 UGX and/or its designees may perform for-cause audits as outlined in the QTA. IOI shall make the FACILITY and the relevant personnel involved in the performance of MANUFACTURING, SERVICES and ADDITIONAL SERVICES under this AGREEMENT available, within reasonable business hours, and advanced wrien noce ([***]) for the purpose of any UGX audits. 6.7 IOI shall [***] inform UGX of any inspecons by competent regulatory authories at the FACILITY which aﬀects the MANUFACTURE of PRODUCT under this AGREEMENT, within the terms provided in the QTA. In the event that the inspecon reveals that IOI is not in compliance with the APPLICABLE LAWS and applicable regulatory regulaons, including cGMP, and receives wrien observaons (or any other wrien communicaon) by such REGULATORY AUTHORITY which involve the PRODUCT, IOI shall (i) use its best eﬀorts to cure such non-compliance within the ming required by the REGULATORY AUTHORITY, (ii) 11 inform UGX of any proposed wrien response by IOI to any such REGULATORY AUTHORITY as far as it relates to MANUFACTURE of PRODUCT and (iii) provide UGX with copies of all documentaon as far as it relates to MANUFACTURE of PRODUCT within the terms provided in the QTA. UGX will have the opportunity to review and provide input to the response to IOI as promptly as praccable and in accordance with the QTA. 6.8 IOI agrees that for a jusﬁed and documented reason, and only aer prior wrien approval from IOI , which should not be unreasonably denied by IOI up to [***] PERSONS of UGX may be present at the FACILITY during the MANUFACTURING for the purpose of [***]. Any PERSON IN PLANT who are present at the FACILITY, shall comply with IOI’s site regulaons, SOPs and rules. 7. Intellectual Property 7.1. Neither Party shall, as a result of this AGREEMENT, acquire any right, tle, or interest in any INTELLECTUAL PROPERTY RIGHTS that the other Party owns or controls as of the EFFECTIVE DATE of this AGREEMENT, or that the other Party obtains ownership or control of separately and apart from the MANUFACTURING or performance of the SERVICES under this AGREEMENT (“BACKGROUND INTELLECTUAL PROPERTY”). 7.2. UGX shall own exclusively all rights, tles, and interests in any and all invenons, discoveries and INTELLECTUAL PROPERTY RIGHTS that IOI may conceive, invent, reduce to pracce, develop or make, solely or jointly with UGX in the performance of the SERVICES and/or ADDITIONAL SERVICES directly related to the PRODUCT or UGX's BACKGROUND INTELLECTUAL PROPERTY (collecvely, “UGX INTELLECTUAL PROPERTY”). IOI hereby assigns, and commits to assign and have assigned, to UGX all UGX INTELLECTUAL PROPERTY. In turn and always subject to the conﬁdenality terms outlined in this Agreement, UGX commits to grant to IOI during the Term (as herein deﬁned) the exclusive, free-of- charge, worldwide right and licence to pracce, use, execute, reproduce, display, modify and exploit in any manner whatsoever such UGX INTELLECTUAL PROPERTY [***]. For clarity’s sake, it is understood by the Pares that IOI's rights under this Secon 7.2. shall not include the right to grant sub licences to any persons, for any territories and on any terms. 7.3. Notwithstanding the foregoing, IOI shall own all rights, tles and interests in any invenons, discoveries and INTELLECTUAL PROPERTY RIGHTS that IOI may develop, conceive, invent, reduce to pracce or make in the course of MANUFACTURING of PRODUCT or performance of the SERVICES and/or ADDITIONAL SERVICES that is an improvement of or modiﬁcaon to the MANUFACTURE OF PRODUCT or IOI’s BACKGROUND INTELLECTUAL PROPERTY (collecvely, “IOI INTELLECTUAL PROPERTY”). 7.4. IOI commits to promptly inform UGX according to Secon 14.3 of any violaon of UGX BACKGROUND INTELLECTUAL PROPERTY and/or UGX INTELLECTUAL PROPERTY and further agrees, [***], to (i) assist UGX or its designee(s) under APPLICABLE LAWS, in obtaining, maintaining, defending and enforcing patents and all other instruments in nature of patents with respect to any UGX BACKGROUND INTELLECTUAL PROPERTY and/or UGX INTELLECTUAL PROPERTY, (ii) provide such informaon and assistance and execute such document as UGX or its designee(s) may request from me to me, and (iii) conﬁrm the assignments hereunder. For clarity, IOI agrees that UGX or its designee(s) shall be the only Party responsible for ﬁling, prosecung and maintaining any patent applicaon covering UGX BACKGROUND INTELLECTUAL PROPERTY and/or UGX INTELLECTUAL PROPERTY. 7.5. If the MANUFACTURING of PRODUCT and/or performance of the SERVICES and/or ADDITIONAL 12 SERVICES requires the use of IOI BACKGROUND INTELLECTUAL PROPERTY, IOI hereby grants to UGX the necessary rights of using IOI BACKGROUND INTELLECTUAL PROPERTY rights solely for the markeng, distribuon and sale of PRODUCT. Such license is granted for PRODUCT manufactured during the term of this AGREEMENT on a worldwide basis, non- exclusively and royalty-free, unless expressly agreed otherwise. Such rights shall be sublicensable by UGX to its AFFILIATES, licensees, collaboraon partners or other pares who receive a license(s) or sublicense(s) to UGX BACKGROUND INTELLECTUAL PROPERTY or UGX INTELLECTUAL PROPERTY from UGX. 7.6. If the performance of this AGREEMENT requires the use of IP RIGHTS of UGX or of THIRD-PARTIES, UGX hereby grants to or procures for IOI the necessary rights of use to these IP RIGHTS solely for the MANUFACTURING of PRODUCT and/or the performance of SERVICES and/or performance of ADDITIONAL SERVICES, [***]. 8. Defecve Product 8.1. If and to the extent permied by law, PRODUCT is delivered to UGX according to the condions and SPECIFICATIONS outlined in this AGREEMENT subject to the checks by UGX under Secon 8.2 and the inspecon by IOI under Secon 8.3. IOI makes no warranes, representaons of guarantees nor any terms and/or condions of any kind whatsoever, either expressed or implied whether by statute, common law, custom, course of dealing or otherwise, including any expressed or implied warranes of merchantability, non-infringement, ﬁtness for a parcular purpose other than those indicated in this AGREEMENT. 8.2. UGX or its designee(s) shall examine PRODUCT MANUFACTURED and delivered by or on behalf of IOI for compliance with the SPECIFICATIONS, shortage or chemical identy without undue delay as well as in line with the TECHNICAL RELEASE. Should any of PRODUCT fail to meet the SPECIFICATIONS, shortage or chemical identy, UGX shall inform IOI in wring without undue delay, [***] aer idenﬁcaon of such defects. HIDDEN DEFECTS can be claimed in wring within [***] aer being detected by UGX within [***] aer the TECHNICAL RELEASE. If UGX fails to nofy the defect within such a period, UGX shall be deemed to have accepted the defect. 8.3. In the event UGX noﬁes IOI within the period and for the reasons menoned in Secon 8.2 , IOI shall conduct its own evaluaon within the me frame deﬁned in the QTA. Following such evaluaon and in case IOI conﬁrms the non- conformity IOI will then repeat the MANUFACTURING and related SERVICES [***] unl the defect is corrected. This is [***]. If the conformity is disputable, IOI and UGX jointly will engage a neutral third party expert to perform a neutral evaluaon. The outcome will be binding for both pares. 13 9. Indemniﬁcaon for Third-Party Claims 9.1. 9.2. 9.3. Except for a claim arising out of [***] or [***] under this AGREEMENT, in the event of legal proceedings being instuted against IOI by a third party arising out of UGX's development, processing and commercializaon of the Product, UGX shall indemnify and keep indemniﬁed IOI in full against all damages, losses, injuries, costs and expenses in connecon with such legal proceedings. IOI will inform UGX about any legal proceedings being instuted against IOI without delay. UGX shall control the respecve legal proceedings but shall not sele any claim that admits fault on behalf of IOI without IOI's consent (not be unreasonably withheld). In the event of legal proceedings being instuted against UGX by a third party arising out of [***] or [***] under this Agreement, IOI shall indemnify and keep indemniﬁed UGX in full against all damages, losses, injuries, costs and expenses in connecon with such legal proceedings. UGX will inform IOI about any legal proceedings being instuted against UGX without delay. IOI shall control the respecve legal proceedings but shall not sele any claim without UGX's consent (not be unreasonably withheld). If IOI’s cooperaon is required in administrave proceedings, especially in proceedings relang to admission, customs or importaon of PRODUCT, UGX indemniﬁes IOI for any liability which may arise out of this cooperaon, except to the extent [***]. That applies, in parcular, in cases, where [***]. The procedural requirements of Secons 9.1-9.2 shall apply to any indemniﬁcaon claims by IOI under this Secon 9.3. 10. Limitaon of Liabilies 10.1. Subject to UGX’s obligaon to pay under Secon 4, the Pares’ overall liability arising out of or in connecon with this AGREEMENT, whether in contract, tort, statutory or otherwise is [***] Euro per [***], or [***] in the event this AGREEMENT expires or is terminated for whatever reason before the end of a CALENDAR YEAR. The limitaon under this Secon 10.1 does not apply to each Party’s obligaon to indemnify the other under [***] or any other liability that cannot be restricted by law. 10.2. Except for the indemnity under Secon 9, each Party excludes any liability for [***] provided that such damages have not been [***]. 10.3. EACH PARTY EXCLUDES ANY LIABILITY FOR SPECIAL, INDIRECT, INCIDENTAL, CONSEQUENTIAL OR PUNITIVE AND EXEMPLARY DAMAGES, RECALL COSTS, LOSS OF PROFIT ARISING OUT OF OR RELATED TO THIS AGREEMENT OR THE EXERCISE OF ITS RIGHTS HEREUNDER, HOWEVER CAUSED, PROVIDED THAT SUCH DAMAGES HAVE NOT BEEN CAUSED BY [***]. 14 11. Insurance 11.1. Either Party shall, at its sole cost and expense, obtain and maintain in force for the term of the AGREEMENT adequate and suitable insurance in the minimum amounts set forth below with a reputable insurance company to cover its liability under this AGREEMENT. 11.2. UGX will maintain a comprehensive products liability insurance, with combined single limits of [***] USD for each claim with respect to personal injury and/or damage to property and [***] USD aggregate. 11.3. IOI will maintain a comprehensive product liability insurance, with combined single limits of [***] USD for each claim with respect to personal injury and/or damage to property and [***] USD aggregate. 11.4. Such insurance must remain in place for the enre duraon of this AGREEMENT and [***] aer terminaon triggered in compliance with Secon 13. For the avoidance of any doubt, each Party is allowed to change the insurer during the validity term of this Secon 11.4 provided that all the condions described in this Secon 11 are properly met. 11.5. IOI will provide insurance cerﬁcates upon request to UGX. IOI must promptly nofy UGX if any of such insurance is canceled, terminated or not renewed. 12. Force Majeure Neither Party is liable to the other Party for failure or delay in performing its obligaons to the extent and for so long as such failure or delay results from causes that were not reasonably foreseeable at the me of signing the AGREEMENT, are beyond the reasonable control of such Party, including but not limited to ﬁres, earthquakes, ﬂoods, embargoes, wars, acts of war (whether war is declared or not), terrorist acts, insurrecons, riots, civil commoon, strikes, lockouts or other labor disturbances, acts of God or other acts, omissions, pandemics or delays in acng by any administrave authority (each, a “Force Majeure”), and the eﬀects of which cannot be avoided or overcome by such Party. In the event of the occurrence of Force Majeure, the Party aﬀected must nofy the other Party promptly of the Force Majeure event and its ancipated duraon, and each Party will use its [***] to migate the adverse consequences. 13. Term and Terminaon 13.1. This AGREEMENT is eﬀecve as of the last date of signature (“Eﬀecve Date”) and will last for an indeﬁnite period (“Term”). Each Party may terminate this AGREEMENT at will (without cause) with a pre-noce of [***] at any me. 13.2. If a Party commits a material breach of a material obligaon of this AGREEMENT and does not cure such breach within [***] of receiving noce of such breach from the non-breaching Party, the non- breaching Party may terminate this AGREEMENT with immediate eﬀect upon wrien noce to the breaching Party. 15 13.3. Each Party shall also be entled to terminate this AGREEMENT with [***] in case of MATERIAL CHANGE in CONTROL or BUSINESS MODEL of the respecve other Party which aﬀects such Party`s ability to fulﬁll its contractual obligaons. 13.4. Either Party shall be entled to terminate this AGREEMENT with [***] if the other Party fails to maintain the necessary rights, permits and approvals to perform the contractual obligaons under this AGREEMENT. 13.5. Either Party may terminate in the event for FORCE MAJEURE lasng longer than [***]. 13.6. In any event of terminaon (including terminaon at will by IOI, but excluding terminaon at will by UGX as per Secon 13.1 and terminaon by IOI for UGX’s breach under Secon 13.2) of this AGREEMENT triggered by any of the Pares or resulng from [***], UGX may by wrien noce to IOI seek assistance from IOI with respect to [***] and agreed to by IOI and UGX. IOI agrees to [***], which [***], with the excepon of the [***]. Except as speciﬁcally set forth in this paragraph, IOI will not [***] and will not provide, disclose or teach or otherwise reveal IOI INTELLECTUAL PROPERTY or IOI BACKGROUND INTELLECTUAL PROPERTY, consistent with the principles set forth in Secon 7. 14. Miscellaneous 14.1. No change of this AGREEMENT is valid unless it is in wring and signed by the Pares. This applies also to the foregoing sentence. 14.2. In case one of the secons is invalid or unenforceable, the other secons remain unaﬀected by this. The Pares shall negoate in good faith if they wish to replace such invalid or unenforceable secon. 14.3. Any noce or request required or permied to be given under or in connecon with this AGREEMENT or the subject maer hereof shall be given by prepaid registered or cerﬁed ﬁrst-class airmail, recognized internaonal carrier, e-mail or telefax to the recipient at its address set forth on the ﬁrst page of this AGREEMENT or to such other address as may have therefore been furnished in wring by the recipient to the sending Party. Any such aforemenoned noce or request concerning this AGREEMENT shall be eﬀecve upon receipt by the Party to which it is addressed. 14.4. Neither Party may assign or transfer this AGREEMENT or any rights or obligaons hereunder, by operaon or law or otherwise, without the prior wrien consent of the other Party, except that a Party may make such an assignment or transfer, by operaon of law or otherwise, without the other Party’s consent to its insurers, its AFFILIATE(S) or to an enty that acquires all or substanally all the business 16 of such Party to which this AGREEMENT relates, whether in a merger, consolidaon, reorganizaon, acquision, sale or otherwise. Notwithstanding anything to the contrary contained herein, in the event of an assignment to an AFFILIATE pursuant to this Secon 14.4, the assigning Party consents, acknowledges, covenants and guarantees that it shall remain jointly and severally liable, along with the assignee, to the non-assigning Party for all the obligaons contained herein. This AGREEMENT shall be binding on the successors and permied assigns of the assigning Party, and the name of a Party appearing herein shall be deemed to include the name(s) of such Party’s successors and permied assigns to the extent necessary to carry out the intent of this AGREEMENT. Any assignment or aempted assignment by either Party in violaon of this Secon 14.4, shall be null and void and of no legal eﬀect. 14.5. This AGREEMENT and any potenal subsequent amendment to it, may be executed in 2 (two) or more counterparts, each of which shall be deemed an original and all of which shall constute together the same instrument. In the event that any signature is delivered by facsimile transmission, by e-signature or by e-mail delivery of a .pdf format data ﬁle, such signature shall create a valid and binding obligaon of the party execung (or on whose behalf such signature is executed) with the same force and eﬀect as if such facsimile, electronic signature or “.pdf” signature page were an original thereof. 14.6. Any controversy, claim or dispute arising out of or relang to this AGREEMENT, including any queson regarding its existence, validity, breach or terminaon (a “DISPUTE”), shall be resolved in accordance with the following provisions: a) Any DISPUTE shall be seled, if possible, through good-faith negoaon between the Pares at the Steering Commiee (as set out in Secon 5). Such good faith negoaons shall commence promptly upon a Party’s receipt of noce of any claim or dispute from the other Party and connue for a period of [***]. [***]. b) c) If the Pares do not reach an amicable selement of the DISPUTE, it shall be submied to mediaon in accordance with the Swiss Rules of Mediaon of the Swiss Arbitraon Centre in force on the date when the request for mediaon was submied in accordance with these Rules. The seat of the mediaon shall be Bern, in Switzerland, although the meengs may be held in Basel, Switzerland, or in Hamburg, Germany. The mediaon shall be conducted in English or in German. If the Pares do not reach a resoluon of the DISPUTE by mediaon within [***] from the date when the mediator(s) has (have) been conﬁrmed or appointed by the Swiss Arbitraon Centre, it shall be exclusively resolved by the courts of Bern, Switzerland. 14.7. This AGREEMENT shall be governed by and construed in accordance with the laws of Switzerland without reference to any rules of conﬂicts of law and excluding the United Naons Convenon on Contracts for the Internaonal Sale of Goods (“CISG”). 14.8. Each Party hereto has a duty of good faith and fair dealing in connecon with its performance under this AGREEMENT. Each Party shall perform its obligaons under this AGREEMENT in a diligent, legal, ethical and professional manner so as to advance the purposes and intent of this AGREEMENT. 17 IN WITNESS WHEREOF, this AGREEMENT is executed as of the AGREEMENT Eﬀecve Date on behalf of the pares by their duly authorized representaves. U P I. IOI Oleo GmbH By: /s/ Siegfried Hackl Siegfried Hackl Printed Name SVP Product Supply Title 31-Mai-2023 Date /s/ Rene Fresen Rene Fresen Printed Name Chief Markeng Oﬃcer Title 15-June-2023 Date U P I. IOI Oleo GmbH By: /s/ Dennis Huang Dennis Huang Printed Name Chief Technical Ops Oﬃcer Title 06-June-2023 Date 18 /s/ Mark Tuchen Mark Tuchen Printed Name Chief Financial Oﬃcer Title 19-June-2023 Date Appendix I Commercial Terms I. Forecast and Purchase Order (i) The Pares hereby establish a forecast procedure, comprising a binding rolling forecast period and a non-binding long-term range as follows. (ii) UGX will provide a good faith rolling forecast covering the [***] no later than the [***] of each [***], specifying the ordered quanty of PRODUCT, the number of batches and the expected DELIVERY DATE (“FORECAST”). IOI will have [***] aer receipt to reject the FORECAST submied by UGX and to provide an alternave producon schedule. (iii) The ﬁrst [***] of the conﬁrmed FORECAST shall be binding (“BINDING PERIOD”) to [***] to both Pares with respect to [***]. (iv) UGX will issue PURCHASE ORDERS upon conﬁrmaon of FORECAST reﬂecng the quanes of PRODUCT to be delivered during the BINDING PERIOD and their DELIVERY DATE. [***]. IOI can reject Purchase Order and DELIVERY DATE within [***] of receipt of such PURCHASE ORDER aer which the Purchase Order and DELIVERY DATE will become binding on IOI. [***]. (v) In case a PURCHASE ORDER is changed by UGX and needs to be rescheduled within BINDING PERIOD, both Pares agree [***]. II. Delivery (i) Any delivery of PRODUCT by IOI to UGX or to a THIRD-PARTY named by UGX shall be [***], unless otherwise agreed in wring by the Pares. IOI will package PRODUCT according to the requirement of UGX for transport in line with the QTA or mutually agreed on shipping procedures. (ii) The transfer of property/tle of PRODUCT will be upon payment by UGX of the respecve invoice for PRODUCT. (iii) In urgent cases, UGX may request in wring: a) a QUARANTINED SHIPMENT; 19 UGX assumes all risks, responsibilies and costs associated with a QUARANTINED SHIPMENT, unless the reason for the non-compliance of the PRODUCT is caused by IOI. III. Prices and Payment (i) Price for the MANUFACTURING of PRODUCT (“PRICE") is outlined in Appendix III for the [***] -“INITIAL TERM”). [***] is determined by the [***] within the [***]. (ii) If aer the INITIAL TERM it is determined that [***] had been applied, the [***] will be applied aer such determinaon. Any [***] diﬀerences therefore will either be a) [***] or b) [***]. (iii) The PRICE may be [***], eﬀecve on the [***] from IOI to UGX. Such [***] shall be based on [***] in [***]. Any [***] shall be based [***]. (iv) Payments shall be made by UGX in Euro and within [***] aer receipt of a proper invoice. (v) Invoices sent via email will be submied to invoicing@ultragenyx.com and the responsible Joint Working Team member of UGX. For sake of clarity, IOI shall invoice UGX any batches of PRODUCT upon [***]. (vi) [***] (“OFFER”) following speciﬁc requests by UGX and shall become applicable upon UGX’s acceptance of an OFFER. (vii) PRICE for PRODUCT and fee for ADDITIONAL SERVICES shall not contain [***] IV. Third-Party Material (i) All Services requiring materials that are purchased, procured, stored and tested by IOI shall be [***]. (ii) IOI will promptly inform UGX if it encounters [***], including [***] with respect to any [***]. In such an event, [***]. 20 V. Special Costs All costs concerning [***]. In such a case, [***] of receipt of invoice and documentaon of such amounts. As soon as possible, UGX will inform IOI about any administrave requirement applicable to IOI in force in any country where UGX is markeng commercial PRODUCT. VI. Addional Services Upon request by UGX, IOI will perform ADDITIONAL SERVICES, as long as [***]. If [***], the [***]. These addional services might be but are not limited to: (i) [***]; (ii) Any [***] either requested by UGX (e.g. [***]) or resulng from any [***] requested by UGX, including [***], (iii) [***] work (iv) [***]speciﬁc for the manufacturing of PRODUCT (v) Any [***] work (vi) [***]; (vii) [***]. For the avoidance of doubt, [***]. For any other circumstance JOINT WORKING TEAM will engage in good faith to conclude the applicable fees. (viii) [***]. IOI will [***] ADDITIONAL SERVICE to UGX by wrien OFFER referring to this AGREEMENT. Upon agreement between the Pares about such OFFER, IOI will provide the ADDITIONAL SERVICES as described in the respecve OFFER. 21 Appendix II Compliance I. Compliance Statement To the extent applicable, IOI shall inform itself of and comply with applicable an-corrupon legislaon, including legislaon enacted pursuant to the 1997 OECD Convenon on Combang Bribery of Foreign Public Oﬃcials in Internaonal Business Transacons (the “OECD Convenon”), and the Foreign Corrupt Pracces Act of 1977, as amended (15 U.S.C. §§78dd-1, et. seq.) (the “FCPA”). If applicable to the MANUFACTURE, SERVICES and ADDITIONAL SERVICES provided hereunder, IOI declares that it understands the provisions of the OECD Convenon and the FCPA and agrees not to breach any such legislaon or to cause UGX to breach any such legislaon. IOI further agrees that, if applicable, it will educate its personnel and contractors engaged in MANUFACTURE, providing SERVICES and ADDITIONAL SERVICES to UGX hereunder in relaon to such legislaon. IOI agrees it has not, and covenants that it will not, in connecon with the conduct of its business acvies, promise, authorize, rafy or oﬀer to make, or take any act in furtherance of any payment, contribuon, gi, reimbursement or other transfer of anything of value, or any solicitaon, directly or indirectly: (i) to any individual including government oﬃcials; or (ii) to an intermediary for payment to any individual including government oﬃcials; or (iii) to any polical party for the purpose or eﬀect of public or commercial bribery, acceptance of or acquiescence in extoron, kickbacks or other unlawful, illegal or improper means. IOI has not, nor to the knowledge of IOI, have any of the IOI’s directors, oﬃcers, agents, stockholders or employees acng on behalf of IOI made any false or arﬁcial entries on any of its books or records for any reason. IOI also represents, but only to the best of their knowledge, that, except as disclosed to UGX in wring, it will collaborate with UGX to the best of its ability to represent on a CALENDAR YEAR basis whether neither it nor any of its oﬃcers, directors, shareholders or beneﬁcial owners is (i) an oﬃcer or employee of a government or any department, agency or instrumentality thereof (including a government-owned or controlled commercial enterprise), (ii) an oﬃcer or employee of a public internaonal organizaon, (iii) a person who acts in any oﬃcial capacity for or on behalf of any government or department, agency, instrumentality or public internaonal organizaon, or (iv) a polical party oﬃcial or candidate for polical oﬃce (each, a “GOVERNMENT OFFICIAL”). IOI will immediately disclose to UGX any current or future aﬃliaon or associaon between itself and any GOVERNMENT OFFICIAL as long as it becomes aware of that. II. Data Privacy Each Party shall collect, use, retain and disclose any personal data provided or belonging to the other Party in a fair, transparent and secure way in accordance to any Applicable Law. Each Party shall (i) use the other Party personal data only under such Party’s instrucons in wring and not use it for any purpose other than the performance of this AGREEMENT; (ii) ensure that eﬀecve organisaonal and security measures (both technological and physical) are applied to all personal data of the other Party to ensure the privacy of aﬀected individuals; (iii) appoint a representave who is accountable for data privacy and security; (iv) ensure informaon is protected and kept secure at all mes from unauthorised use, damage, disclosure, diversion or removal, whether through accident, improper act or breach of trust; (v) ensure employees who will have access to the other Party’s personal data are appropriately trained in their responsibilies around processing and protecng the personal data. 22 III. Documentaon of Business Transacons The documentaon of any and all business transacons must be complete, transparent, and in compliance with the statutory provisions as well as with any provisions and processes. IV. Social Responsibility IOI respects the dignity of every human being and is commied to compliance with and the protecon of human rights. IOI does not tolerate any kind of child labor as well as any exploitaon of children and adolescents. The minimum age for admission to employment must not be under the age for the fulﬁllment of compulsory educaon and in no case under 15 (ﬁeen) years. IOI disapproves of any form of forced labor. V. No Discriminaon IOI creates a working atmosphere characterized by respecul cooperaon and to strictly oppose any kind of discriminaon on grounds of race or ethnic origin, gender, religion or philosophy of life, disability, age, or sexual identy. VI. EHS (Environment, Health and Safety) IOI undertakes to operate in a safe and responsible manner with respect to the environment and health of employees, customers and the communies where they operate. IOI will not compromise environmental, health or safety values for other interests; value human life above all else and manage risks accordingly. IOI pursues and connually improves an EHS system and processes to achieve an EHS incident-free environment. IOI agrees to always comply with applicable laws and set standards for suppliers. 23 Appendix III Prices and Fees [***] 24 Appendix IV QUALITY AND TECHNICAL AGREEMENT (QTA) The current version of the QTA executed separately by the Pares. 25 Appendix V PRODUCT SPECIFICATION The current version of [***] 26 Appendix VI RAW MATERIAL SPECIFICATIONS [***] 27 Appendix VII [***] 28 Appendix VIII THIRD PARTY laboratories THIRD-PARTY labs are, but are not limited to: [***] 29 Exhibit 10.30 Name: Number of Shares of Stock subject to Stock Opon: Price Per Share: Date of Grant: Vesng Start Date: U P I. 2023 I P S O A This agreement (this “Agreement”) evidences a stock opon granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Oponee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Stock Opon. The Company grants to the Oponee on the date set forth above (the “Date of Grant”) an opon (the “Stock Opon”) to purchase, on the terms provided herein and in the Plan, up to the number of shares of Stock set forth above (the “Shares”) with an exercise price per Share as set forth above, in each case subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. The following terms have the following meanings: (a) “Beneﬁciary” means, in the event of the Oponee’s death, the beneﬁciary named in the wrien designaon (in form acceptable to the Administrator) most recently ﬁled with the Administrator by the Oponee prior to the Oponee’s death and not subsequently revoked, or, if there is no such designated beneﬁciary, the executor or administrator of the Oponee’s estate. An eﬀecve beneﬁciary designaon will be treated as having been revoked only upon receipt by the Administrator, prior to the Oponee’s death, of an instrument of revocaon in form acceptable to the Administrator. (b) “Opon Holder” means the Oponee or, if as of the relevant me the Stock Opon has passed to a Beneﬁciary, the Beneﬁciary. 3. Vesng; Method of Exercise; Treatment of the Stock Opon Upon Cessaon of Employment. (a) Vesng. As used herein with respect to the Stock Opon or any poron thereof, the term “vest” means to become exercisable and the term “vested” as applied to any outstanding Stock Opon means that the Stock Opon is then exercisable, subject in each case to the terms of the Plan. Unless earlier terminated, forfeited, relinquished or expired, the Stock Opon will vest as to 1/4th of the Shares inially subject to the Stock Opon on the ﬁrst (1st) anniversary of the Date of Grant (the "Anniversary Date"); thereaer, 1/48th of the Shares inially subject to the Stock Opon shall vest on each month as measured by the Anniversary Date. Notwithstanding the foregoing, Shares subject to the Stock Opon shall not vest on any vesng date DOCPROPERTY DocXDocID DMS=InterwovenIManage Format=<>_<> PRESERVELOCATION \* MERGEFORMAT 39776746_3 (b) unless the Oponee has remained in connuous Employment from the Date of Grant through such vesng date. Exercise of the Stock Opon. No poron of the Stock Opon may be exercised unl such poron vests. Each elecon to exercise any vested poron of the Stock Opon will be subject to the terms and condions of the Plan and shall be in wring, signed by the Opon Holder (or in such other form as is acceptable to the Administrator). Each such wrien exercise elecon must be received by the Company at its principal oﬃce or by such other party as the Administrator may prescribe and be accompanied by payment in full as provided in the Plan. The exercise price may be paid (i) by cash or check acceptable to the Administrator, (ii) to the extent permied by the Administrator, through a broker-assisted cashless exercise program acceptable to the Administrator, (iii) by such other means, if any, as may be acceptable to the Administrator, or (iv) by any combinaon of the foregoing permissible forms of payment. In the event that the Stock Opon is exercised by a person other than the Oponee, the Company will be under no obligaon to deliver shares hereunder unless and unl it is sasﬁed as to the authority of the Opon Holder to exercise the Stock Opon and compliance with th applicable securies laws. The latest date on which the Stock Opon or any poron thereof may be exercised will be the 10 anniversary of the Date of Grant (the “Final Exercise Date”). If the Stock Opon is not exercised by the Final Exercise Date the Stock Opon or any remaining poron thereof will thereupon immediately terminate. (c) Treatment of the Stock Opon Upon Cessaon of Employment. If the Oponee’s Employment ceases, the Stock Opon, to the extent not already vested will be immediately forfeited, and any vested poron of the Stock Opon that is then outstanding will be treated as follows: (i) Subject to clauses (ii) and (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment, will remain exercisable unl the earlier of (A) the date that is three months following the date of such cessaon of Employment, or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(i) will thereupon immediately terminate. (ii) Subject to clauses (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment due to death, will remain exercisable unl the earlier of (A) the ﬁrst anniversary of the Oponee’s death or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(ii) will thereupon immediately terminate. (iii) If the Oponee’s Employment is terminated by the Company and its subsidiaries in connecon with an act or failure to act constung Cause (as the Administrator, in its sole discreon, may determine), or such terminaon occurs in circumstances that in the determinaon of the Administrator would have entled the Company and its subsidiaries to terminate the Oponee’s Employment for Cause, the Stock Opon (whether or not vested) will immediately terminate and be forfeited upon such terminaon. 4. Forfeiture; Recovery of Compensaon. (a) (b) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Stock Opon at any me if the Oponee is not in compliance with all applicable provisions of this Agreement and the Plan. By accepng the Stock Opon, the Oponee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Stock Opon, under the Stock Opon to any Stock acquired under the Stock Opon or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 8 of this Agreement. 5. Transfer of Stock Opon. The Stock Opon may not be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 6. Taxes. (a) (b) (c) (d) Withholding. If at the me this Stock Opon is exercised the Company determines that under applicable law and regulaons it could be liable for the withholding of any federal or state tax upon exercise or with respect to a disposion of any Stock acquired upon exercise of this Stock Opon, the Oponee expressly acknowledges and agrees that the Oponee’s rights hereunder, including the right to be issued shares upon exercise, are subject to the Oponee promptly paying to the Company in cash (or by such other means as may be acceptable to the Administrator in its discreon) all taxes required to be withheld. No shares will be transferred pursuant to the exercise of this Stock Opon unless and unl the person exercising this Stock Opon has remied to the Company an amount in cash suﬃcient to sasfy any federal, state, or local withholding tax requirements, or has made other arrangements sasfactory to the Company with respect to such taxes. The Oponee authorizes the Company and its subsidiaries to withhold such amount from any amounts otherwise owed to the Oponee, but nothing in this sentence shall be construed as relieving the Oponee of any liability for sasfying his or her obligaon under the preceding provisions of this Secon. Disqualifying Disposion. If the Oponee disposes of the Shares acquired upon exercise of this Stock Opon within two years from the Grant Date or one year aer such Shares were acquired pursuant to the exercise of this Stock Opon, within 15 days of such disposion, the Oponee shall nofy the Company in wring of such disposion. Annual Limit for Incenve Stock Opons. To the extent that the aggregate fair market value (determined at the me of grant) of the shares of Stock with respect to which this Stock Opon and all other incenve stock opons the Oponee holds are exercisable for the ﬁrst me during any calendar year (under all plans of the Company and its related corporaons) exceeds $100,000, the opons held by such Oponee or porons thereof that exceed such limit (according to the order in which they were granted in accordance with the regulaons under Secon 422 of the Code) shall be treated as a non-qualiﬁed stock opon. Limitaon on Liability. The Oponee acknowledges and agrees that the Company or the Administrator may take any acon permied under the Plan without regard to the eﬀect such acon may have on the status of this Stock Opon as an incenve stock opon under Secon 422 of the Code and that such acons may cause this Stock Opon to fail to be treated as an incenve stock opon under Secon 422 of the Code. The Oponee further acknowledges and agrees that neither the Company, nor any of its Aﬃliates, nor the Administrator, nor any person acng on behalf of the Company, any of its Aﬃliates, or the Administrator, will be liable to the Oponee or to the estate or beneﬁciary of the Oponee or to any other person by reason of the failure the Stock Opon to sasfy the requirements of Secon 422 of the Code. 7. Eﬀect on Employment. Neither the grant of the Stock Opon, nor the issuance of Shares upon exercise of the Stock Opon, will give the Oponee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Oponee at any me, or aﬀect any right of such Oponee to terminate his or her Employment at any me. 8. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Oponee. By exercising all or any part of the Stock Opon, the Oponee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. Acknowledgements. The Oponee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which 9. shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Oponee. The Stock Opon evidenced by this Agreement is intended to be an incenve stock opon under Secon 422 of the Code and is granted to the Oponee in connecon with the Oponee’s employment by or service to the Company and its qualifying subsidiaries. For purposes of the immediately preceding sentence, “qualifying subsidiary” means a subsidiary of the Company as to which the Company has a “controlling interest” as described in Treas. Regs. §1.409A-1(b)(5)(iii)(E)(1). [The remainder of this page is intenonally le blank] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized officer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Executive Officer Title: Dated: Acknowledged and Agreed: By_______________________ Exhibit 10.31 Name: Number of Shares of Stock subject to Stock Opon: Price Per Share: Date of Grant: Vesng Start Date: U P I. 2023 I P N- S O A (E) This agreement (this “Agreement”) evidences a stock opon granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Oponee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Stock Opon. The Company grants to the Oponee on the date set forth above (the “Date of Grant”) an opon (the “Stock Opon”) to purchase, on the terms provided herein and in the Plan, up to the number of shares of Stock set forth above (the “Shares”) with an exercise price per Share as set forth above, in each case subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. The following terms have the following meanings: (a) “Beneﬁciary” means, in the event of the Oponee’s death, the beneﬁciary named in the wrien designaon (in form acceptable to the Administrator) most recently ﬁled with the Administrator by the Oponee prior to the Oponee’s death and not subsequently revoked, or, if there is no such designated beneﬁciary, the executor or administrator of the Oponee’s estate. An eﬀecve beneﬁciary designaon will be treated as having been revoked only upon receipt by the Administrator, prior to the Oponee’s death, of an instrument of revocaon in form acceptable to the Administrator. (b) “Opon Holder” means the Oponee or, if as of the relevant me the Stock Opon has passed to a Beneﬁciary, the Beneﬁciary. 3. Vesng; Method of Exercise; Treatment of the Stock Opon Upon Cessaon of Employment. (a) Vesng. As used herein with respect to the Stock Opon or any poron thereof, the term “vest” means to become exercisable and the term “vested” as applied to any outstanding Stock Opon means that the Stock Opon is then exercisable, subject in each case to the terms of the Plan. Unless earlier terminated, forfeited, relinquished or expired, the Stock Opon will vest as to 1/4th of the Shares inially subject to the Stock Opon on the ﬁrst (1st) anniversary of the Date of Grant (the "Anniversary Date"); thereaer, 1/48th of the Shares inially subject to the Stock Opon shall vest on each month as measured by the Anniversary Date. Notwithstanding the foregoing, Shares subject to the Stock Opon shall not vest on any vesng date (b) unless the Oponee has remained in connuous Employment from the Date of Grant through such vesng date. Exercise of the Stock Opon. No poron of the Stock Opon may be exercised unl such poron vests. Each elecon to exercise any vested poron of the Stock Opon will be subject to the terms and condions of the Plan and shall be in wring, signed by the Opon Holder (or in such other form as is acceptable to the Administrator). Each such wrien exercise elecon must be received by the Company at its principal oﬃce or by such other party as the Administrator may prescribe and be accompanied by payment in full as provided in the Plan. The exercise price may be paid (i) by cash or check acceptable to the Administrator, (ii) to the extent permied by the Administrator, through a broker-assisted cashless exercise program acceptable to the Administrator, (iii) by such other means, if any, as may be acceptable to the Administrator, or (iv) by any combinaon of the foregoing permissible forms of payment. In the event that the Stock Opon is exercised by a person other than the Oponee, the Company will be under no obligaon to deliver shares hereunder unless and unl it is sasﬁed as to the authority of the Opon Holder to exercise the Stock Opon and compliance with applicable securies laws. The latest date on which the Stock Opon or any poron thereof may be exercised will be the 10th anniversary of the Date of Grant (the “Final Exercise Date”); provided, however, if at such me the Oponee is prohibited by applicable law from exercising the Stock Opon, the Final Exercise Date will be automacally extended to thirty (30) days following the date the Oponee is no longer prohibited from exercising the Stock Opon. If the Stock Opon is not exercised by the Final Exercise Date the Stock Opon or any remaining poron thereof will thereupon immediately terminate. (c) Treatment of the Stock Opon Upon Cessaon of Employment. If the Oponee’s Employment ceases, the Stock Opon, to the extent not already vested will be immediately forfeited, and any vested poron of the Stock Opon that is then outstanding will be treated as follows: (i) Subject to clauses (ii) and (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment, will remain exercisable unl the earlier of (A) the date that is three months following the date of such cessaon of Employment, or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(i) will thereupon immediately terminate. (ii) Subject to clauses (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment due to death, will remain exercisable unl the earlier of (A) the ﬁrst anniversary of the Oponee’s death or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(ii) will thereupon immediately terminate. (iii) If the Oponee’s Employment is terminated by the Company and its subsidiaries in connecon with an act or failure to act constung Cause (as the Administrator, in its sole discreon, may determine), or such terminaon occurs in circumstances that in the determinaon of the Administrator would have entled the Company and its subsidiaries to terminate the Oponee’s Employment for Cause, the Stock Opon (whether 4. Forfeiture; Recovery of Compensaon. or not vested) will immediately terminate and be forfeited upon such terminaon. (a) (b) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Stock Opon at any me if the Oponee is not in compliance with all applicable provisions of this Agreement and the Plan. By accepng the Stock Opon, the Oponee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Stock Opon, under the Stock Opon to any Stock acquired under the Stock Opon or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 8 of this Agreement. 5. Transfer of Stock Opon. The Stock Opon may not be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 6. Withholding. The exercise of this Stock Opon will give rise to “wages” subject to withholding. The Oponee expressly acknowledges and agrees that the Oponee’s rights hereunder, including the right to be issued shares upon exercise, are subject to the Oponee promptly paying to the Company in cash (or by such other means as may be acceptable to the Administrator in its discreon) all taxes required to be withheld. No shares will be transferred pursuant to the exercise of this Stock Opon unless and unl the person exercising this Stock Opon has remied to the Company an amount in cash suﬃcient to sasfy any federal, state, or local withholding tax requirements, or has made other arrangements sasfactory to the Company with respect to such taxes. The Oponee authorizes the Company and its subsidiaries to withhold such amount from any amounts otherwise owed to the Oponee, but nothing in this sentence shall be construed as relieving the Oponee of any liability for sasfying his or her obligaon under the preceding provisions of this Secon. 7. Eﬀect on Employment. Neither the grant of the Stock Opon, nor the issuance of Shares upon exercise of the Stock Opon, will give the Oponee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Oponee at any me, or aﬀect any right of such Oponee to terminate his or her Employment at any me. 8. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Oponee. By exercising all or any part of the Stock Opon, the Oponee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 9. Acknowledgements. The Oponee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Oponee. The Stock Opon evidenced by this Agreement is a non-statutory opon (that is, an opon that does not qualify as an incenve stock opon under Secon 422 of the Code) and is granted to the Oponee in connecon with the Oponee’s employment by or service to the Company and its qualifying subsidiaries. For purposes of the immediately preceding sentence, “qualifying subsidiary” means a subsidiary of the Company as to which the Company has a “controlling interest” as described in Treas. Regs. §1.409A-1(b)(5)(iii)(E)(1). [The remainder of this page is intenonally le blank] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized officer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Executive Officer Title: Dated: Acknowledged and Agreed: By_______________________ Name: Number of Restricted Stock Units subject to Award: Date of Grant: Exhibit 10.32 ULTRAGENYX PHARMACEUTICAL INC. 2023 INCENTIVE PLAN RESTRICTED STOCK UNIT AGREEMENT (EMPLOYEES) This agreement (this “Agreement”) evidences an award (the “Award”) of restricted stock units (the “Restricted Stock Units”) granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Grantee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Restricted Stock Units. The Company grants to the Grantee on the date set forth above (the “Date of Grant”) an award consisng of the right to receive on the terms provided herein and in the Plan, one share of Stock with respect to each Restricted Stock Unit forming part of the Award, in each case, subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. 3. Vesng. Unless earlier terminated, forfeited, relinquished or expired, the Restricted Stock Units shall vest as follows: 1/4th of the underlying shares shall vest on the ﬁrst (1st) anniversary of the Date of Grant (the "Anniversary Date"); thereaer, 25% of the underlying shares shall vest each year as measured from the Anniversary Date. 4. Delivery of Stock. The Company shall deliver to the Grantee as soon as praccable upon the vesng of the Restricted Stock Units or any poron thereof, but in all events no later than March 15th of the year following the year in which such Restricted Stock Units vest, one share of Stock with respect to each such vested Restricted Stock Unit, subject to the terms of the Plan and this Agreement. 5. Dividends; Other Rights. The Award shall not be interpreted to bestow upon the Grantee any equity interest or ownership in the Company or any Aﬃliate prior to the date on which the Company delivers shares of Stock to the Grantee (if any). The Grantee is not entled to vote any shares of Stock by reason of the granng of this Award or to receive or be credited with any dividends declared and payable on any share of Stock prior to the date on which any such share is delivered to the Grantee hereunder. The Grantee shall have the rights of a shareholder only as to those shares of Stock, if any, that are actually delivered under this Award. 6. Forfeiture; Recovery of Compensaon. (a) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Award at any me if the Grantee is not in compliance with all applicable provisions of this Agreement and the Plan. (b) By accepng the Award the Grantee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Award, under the Award to any Stock acquired under the Award or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 10 of this Agreement. 7. Nontransferability. Neither the Award nor the Restricted Stock Units may be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 8. Certain Tax Maers. (a) The Grantee expressly acknowledges and agrees that the Grantee’s rights hereunder, including the right to be issued shares of Stock upon the vesng of the Restricted Stock Units (or any poron thereof), are subject to the Grantee’s promptly paying, or in respect of any later requirement of withholding being liable promptly to pay at such me as such withholdings are due, to the Company in cash (or by such other means as may be acceptable to the Administrator in its discreon) all taxes required to be withheld, if any (the “Tax Withholding Obligaon”). No shares of Stock will be transferred pursuant to the vesng of the Restricted Stock Units (or any poron thereof) unless and unl the Grantee or the person then holding the Award has remied to the Company an amount in cash suﬃcient to sasfy any federal, state, or local withholding tax requirements then due and has commied (and by accepng this Award the Grantee shall be deemed to have commied) to pay in cash all tax withholdings required at any later me in respect of the transfer of such shares, or has made other arrangements sasfactory to the Company with respect to such taxes. The Grantee also authorizes the Company and its subsidiaries to withhold such amount from any amounts otherwise owed to the Grantee, but nothing in this sentence shall be construed as relieving the Grantee of any liability for sasfying his or her obligaons under the preceding provisions of this Secon. (b) The Grantee expressly acknowledges that the Grantee’s acceptance of this Agreement constutes the Grantee’s instrucon and authorizaon to the Company and any brokerage ﬁrm determined acceptable to the Company for such purpose to sell on the Grantee’s behalf a whole number of shares from those shares of Stock issuable to the Grantee as the Company determines to be appropriate to generate cash proceeds suﬃcient to sasfy the applicable Tax Withholding Obligaon, and to transfer the proceeds from the sale of such Stock from the Grantee’s securies account established with the brokerage service provider for the selement of the Grantee’s vested Restricted Stock Units to any account held in the name of the Company. Such shares will be sold on the date of vesng or as soon thereaer as praccable. Grantee will be responsible for all brokers’ fees and other costs of sale, which fees and costs may be deducted from the proceeds of the foregoing sale of Stock, and Grantee agrees to indemnify and hold the Company and any brokerage ﬁrm selling such Stock harmless from any losses, costs, damages, or expenses relang to any such sale. To the extent the proceeds of such sale exceed Grantee’s Tax Withholding Obligaon, such excess cash will be deposited into the securies account established with the brokerage service provider for the selement of Grantee’s vested Restricted Stock Units. Grantee acknowledges that the Company or its designee is under no obligaon to arrange for such sale at any parcular price, and that the proceeds of any such sale may not be suﬃcient to sasfy Grantee’s Tax Withholding Obligaon. Accordingly, Grantee agrees to pay to the Company as soon as praccable, including through addional payroll withholding, any amount of the Tax Withholding Obligaon that is not sasﬁed by the sale of shares described above. Unless otherwise authorized by the Administrator in its sole discreon, the sale of Stock will be the primary method used by the Company to sasfy the applicable Tax Withholding Obligaon. (c) The Grantee expressly acknowledges that because this Award consists of an unfunded and unsecured promise by the Company to deliver Stock in the future, subject to the terms hereof, it is not possible to make a so-called “83(b) elecon” with respect to the Award. 9. Eﬀect on Employment. Neither the grant of the Award, nor the issuance of shares of Stock upon vesng of the Award, will give the Grantee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Grantee at any me, or aﬀect any right of such Grantee to terminate his or her Employment at any me. 10. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Grantee. By accepng the Award, the Grantee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 11. Acknowledgments. The Grantee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Grantee. IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized oﬃcer. [The remainder of this page is intenonally le blank.] ULTRAGENYX PHARMACEUTICAL INC. /s/ Emil Kakkis Emil Kakkis, M.D., Ph.D. Chief Execuve Oﬃcer Dated: Acknowledged and Agreed: By Exhibit 10.33 Name: Number of Shares of Stock subject to Stock Opon: Price Per Share: Date of Grant: Vesng Start Date: U P I. 2023 I P N- S O A (D) This agreement (this “Agreement”) evidences a stock opon granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Oponee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Stock Opon. The Company grants to the Oponee on the date set forth above (the “Date of Grant”) an opon (the “Stock Opon”) to purchase, on the terms provided herein and in the Plan, up to the number of shares of Stock set forth above (the “Shares”) with an exercise price per Share as set forth above, in each case subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. The following terms have the following meanings: (a) “Beneﬁciary” means, in the event of the Oponee’s death, the beneﬁciary named in the wrien designaon (in form acceptable to the Administrator) most recently ﬁled with the Administrator by the Oponee prior to the Oponee’s death and not subsequently revoked, or, if there is no such designated beneﬁciary, the executor or administrator of the Oponee’s estate. An eﬀecve beneﬁciary designaon will be treated as having been revoked only upon receipt by the Administrator, prior to the Oponee’s death, of an instrument of revocaon in form acceptable to the Administrator. (b) “Opon Holder” means the Oponee or, if as of the relevant me the Stock Opon has passed to a Beneﬁciary, the Beneﬁciary. 3. Vesng; Method of Exercise; Treatment of the Stock Opon Upon Cessaon of Employment. (a) Vesng. As used herein with respect to the Stock Opon or any poron thereof, the term “vest” means to become exercisable and the term “vested” as applied to any outstanding Stock Opon means that the Stock Opon is then exercisable, subject in each case to the terms of the Plan. Unless earlier terminated, forfeited, relinquished or expired, the Stock Opon will vest as to all of the Shares inially subject to the Stock Opon on the earlier of (i) the ﬁrst anniversary of the Date of Grant or (ii) the date of the Company's annual meeng of stockholders ﬁrst held aer the Date of Grant. Notwithstanding the foregoing, Shares subject to the Stock Opon shall not (b) vest on any vesng date unless the Oponee has remained in connuous Employment from the Date of Grant through such vesng date. Exercise of the Stock Opon. No poron of the Stock Opon may be exercised unl such poron vests. Each elecon to exercise any vested poron of the Stock Opon will be subject to the terms and condions of the Plan and shall be in wring, signed by the Opon Holder (or in such other form as is acceptable to the Administrator). Each such wrien exercise elecon must be received by the Company at its principal oﬃce or by such other party as the Administrator may prescribe and be accompanied by payment in full as provided in the Plan. The exercise price may be paid (i) by cash or check acceptable to the Administrator, (ii) to the extent permied by the Administrator, through a broker-assisted cashless exercise program acceptable to the Administrator, (iii) by such other means, if any, as may be acceptable to the Administrator, or (iv) by any combinaon of the foregoing permissible forms of payment. In the event that the Stock Opon is exercised by a person other than the Oponee, the Company will be under no obligaon to deliver shares hereunder unless and unl it is sasﬁed as to the authority of the Opon Holder to exercise the Stock Opon and compliance with applicable securies laws. The latest date on which the Stock Opon or any poron thereof may be exercised will be the 10th anniversary of the Date of Grant (the “Final Exercise Date”); provided, however, if at such me the Oponee is prohibited by applicable law from exercising the Stock Opon, the Final Exercise Date will be automacally extended to thirty (30) days following the date the Oponee is no longer prohibited from exercising the Stock Opon. If the Stock Opon is not exercised by the Final Exercise Date the Stock Opon or any remaining poron thereof will thereupon immediately terminate. (c) Treatment of the Stock Opon Upon Cessaon of Employment. If the Oponee’s Employment ceases, the Stock Opon, to the extent not already vested will be immediately forfeited, and any vested poron of the Stock Opon that is then outstanding will be treated as follows: (i) Subject to clauses (ii) and (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment, will remain exercisable unl the earlier of (A) the date that is 24 months following the date of such cessaon of Employment, or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(i) will thereupon immediately terminate. (ii) Subject to clauses (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment due to death, will remain exercisable unl the earlier of (A) the ﬁrst anniversary of the Oponee’s death or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(ii) will thereupon immediately terminate. (iii) If the Oponee’s Employment is terminated by the Company and its subsidiaries in connecon with an act or failure to act constung Cause (as the Administrator, in its sole discreon, may determine), or such terminaon occurs in circumstances that in the determinaon of the Administrator would have entled the Company and its subsidiaries to terminate the Oponee’s Employment for Cause, the Stock Opon (whether 4. Forfeiture; Recovery of Compensaon. or not vested) will immediately terminate and be forfeited upon such terminaon. (a) (b) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Stock Opon at any me if the Oponee is not in compliance with all applicable provisions of this Agreement and the Plan. By accepng the Stock Opon, the Oponee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Stock Opon, under the Stock Opon to any Stock acquired under the Stock Opon or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 8 of this Agreement. 5. Transfer of Stock Opon. The Stock Opon may not be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 6. Withholding. The Oponee shall be responsible for sasfying and paying all taxes arising from or due in connecon with the Opon, its exercise or a disposion of Shares acquired upon exercise of the Opon. The Company shall have no liability or obligaon related to the foregoing. 7. Eﬀect on Service. Neither the grant of the Stock Opon, nor the issuance of Shares upon exercise of the Stock Opon, will give the Oponee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Oponee at any me, or aﬀect any right of such Oponee to terminate his or her Employment at any me. 8. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Oponee. By exercising all or any part of the Stock Opon, the Oponee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 9. Acknowledgements. The Oponee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Oponee. The Stock Opon evidenced by this Agreement is a non-statutory opon (that is, an opon that does not qualify as an incenve stock opon under Secon 422 of the Code) and is granted to the Oponee in connecon with the Oponee’s employment by or service to the Company and its qualifying subsidiaries. For purposes of the immediately preceding sentence, “qualifying subsidiary” means a subsidiary of the Company as to which the Company has a “controlling interest” as described in Treas. Regs. §1.409A-1(b)(5)(iii)(E)(1). [The remainder of this page is intenonally le blank] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized officer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Executive Officer Title: Dated: Acknowledged and Agreed: By_______________________ Exhibit 10.34 Name: Number of Restricted Stock Units subject to Award: Date of Grant: U P I. 2023 I P R S U A (D) This agreement (this “Agreement”) evidences an award (the “Award”) of restricted stock units (the “Restricted Stock Units”) granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Grantee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Restricted Stock Units. The Company grants to the Grantee on the date set forth above (the “Date of Grant”) an award consisng of the right to receive on the terms provided herein and in the Plan, one share of Stock with respect to each Restricted Stock Unit forming part of the Award, in each case, subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. 3. Vesng. Unless earlier terminated, forfeited, relinquished or expired, the Restricted Stock Units shall vest as follows: all of the underlying shares shall vest on the earlier of (i) the ﬁrst anniversary of the Date of Grant or (ii) the date of the Company's annual meeng of stockholders ﬁrst held aer the Date of Grant. 4. Delivery of Stock. The Company shall deliver to the Grantee as soon as praccable upon the vesng of the Restricted Stock Units or any poron thereof, but in all events no later than March 15 of the year following the year in which such Restricted Stock Units vest, one share of Stock with respect to each such vested Restricted Stock Unit, subject to the terms of the Plan and this Agreement. th 5. Dividends; Other Rights. The Award shall not be interpreted to bestow upon the Grantee any equity interest or ownership in the Company or any Aﬃliate prior to the date on which the Company delivers shares of Stock to the Grantee (if any). The Grantee is not entled to vote any shares of Stock by reason of the granng of this Award or to receive or be credited with any dividends declared and payable on any share of Stock prior to the date on which any such share is delivered to the Grantee hereunder. The Grantee shall have the rights of a shareholder only as to those shares of Stock, if any, that are actually delivered under this Award. 6. Forfeiture; Recovery of Compensaon. (a) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Award at any me if the Grantee is not in compliance with all applicable provisions of this Agreement and the Plan. (b) By accepng the Award the Grantee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Award, under the Award to any Stock acquired under the Award or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 10 of this Agreement. 7. Nontransferability. Neither the Award nor the Restricted Stock Units may be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 8. Certain Tax Maers. (a) The Grantee shall be responsible for sasfying and paying all taxes arising from or due in connecon with the Restricted Stock Units or with the shares of Stock issued upon vesng of the Restricted Stock Units. The Company shall have no liability or obligaon related to the foregoing. (b) The Grantee expressly acknowledges that because this Award consists of an unfunded and unsecured promise by the Company to deliver Stock in the future, subject to the terms hereof, it is not possible to make a so-called “83(b) elecon” with respect to the Award. 9. Eﬀect on Service. Neither the grant of the Award, nor the issuance of shares of Stock upon vesng of the Award, will give the Grantee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Grantee at any me, or aﬀect any right of such Grantee to terminate his or her Employment at any me. 10. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Grantee. By accepng the Award, the Grantee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 11. Acknowledgments. The Grantee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Grantee. [The remainder of this page is intenonally le blank.] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized oﬃcer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Execuve Oﬃcer Title: Dated: Acknowledged and Agreed: By_______________________ Name: Number of Shares of Stock subject to Stock Opon: Price Per Share: Date of Grant: Vesng Start Date: Exhibit 10.35 U P I. 2023 I P N- S O A (D) This agreement (this “Agreement”) evidences a stock opon granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Oponee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Stock Opon. The Company grants to the Oponee on the date set forth above (the “Date of Grant”) an opon (the “Stock Opon”) to purchase, on the terms provided herein and in the Plan, up to the number of shares of Stock set forth above (the “Shares”) with an exercise price per Share as set forth above, in each case subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. The following terms have the following meanings: (a) “Beneﬁciary” means, in the event of the Oponee’s death, the beneﬁciary named in the wrien designaon (in form acceptable to the Administrator) most recently ﬁled with the Administrator by the Oponee prior to the Oponee’s death and not subsequently revoked, or, if there is no such designated beneﬁciary, the executor or administrator of the Oponee’s estate. An eﬀecve beneﬁciary designaon will be treated as having been revoked only upon receipt by the Administrator, prior to the Oponee’s death, of an instrument of revocaon in form acceptable to the Administrator. (b) “Opon Holder” means the Oponee or, if as of the relevant me the Stock Opon has passed to a Beneﬁciary, the Beneﬁciary. 3. Vesng; Method of Exercise; Treatment of the Stock Opon Upon Cessaon of Employment. (a) Vesng. As used herein with respect to the Stock Opon or any poron thereof, the term “vest” means to become exercisable and the term “vested” as applied to any outstanding Stock Opon means that the Stock Opon is then exercisable, subject in each case to the terms of the Plan. Unless earlier terminated, forfeited, relinquished or expired, the Stock Opon will vest as to 1/36th of the Shares inially subject to the Stock Opon monthly, so that the Stock Opon will fully vest on the third (3rd) anniversary of the Date of Grant. Notwithstanding the foregoing, Shares subject to (b) the Stock Opon shall not vest on any vesng date unless the Oponee has remained in connuous Employment from the Date of Grant through such vesng date. Exercise of the Stock Opon. No poron of the Stock Opon may be exercised unl such poron vests. Each elecon to exercise any vested poron of the Stock Opon will be subject to the terms and condions of the Plan and shall be in wring, signed by the Opon Holder (or in such other form as is acceptable to the Administrator). Each such wrien exercise elecon must be received by the Company at its principal oﬃce or by such other party as the Administrator may prescribe and be accompanied by payment in full as provided in the Plan. The exercise price may be paid (i) by cash or check acceptable to the Administrator, (ii) to the extent permied by the Administrator, through a broker-assisted cashless exercise program acceptable to the Administrator, (iii) by such other means, if any, as may be acceptable to the Administrator, or (iv) by any combinaon of the foregoing permissible forms of payment. In the event that the Stock Opon is exercised by a person other than the Oponee, the Company will be under no obligaon to deliver shares hereunder unless and unl it is sasﬁed as to the authority of the Opon Holder to exercise the Stock Opon and compliance with applicable securies laws. The latest date on which the Stock Opon or any poron thereof may be exercised will be the 10th anniversary of the Date of Grant (the “Final Exercise Date”); provided, however, if at such me the Oponee is prohibited by applicable law from exercising the Stock Opon, the Final Exercise Date will be automacally extended to thirty (30) days following the date the Oponee is no longer prohibited from exercising the Stock Opon. If the Stock Opon is not exercised by the Final Exercise Date the Stock Opon or any remaining poron thereof will thereupon immediately terminate. (c) Treatment of the Stock Opon Upon Cessaon of Employment. If the Oponee’s Employment ceases, the Stock Opon, to the extent not already vested will be immediately forfeited, and any vested poron of the Stock Opon that is then outstanding will be treated as follows: (i) Subject to clauses (ii) and (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment, will remain exercisable unl the earlier of (A) the date that is 24 months following the date of such cessaon of Employment, or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(i) will thereupon immediately terminate. (ii) Subject to clauses (iii) below and Secon 4 of this Agreement, the Stock Opon, to the extent vested immediately prior to the cessaon of the Oponee’s Employment due to death, will remain exercisable unl the earlier of (A) the ﬁrst anniversary of the Oponee’s death or (B) the Final Exercise Date, and except to the extent previously exercised as permied by this Secon 3(c)(ii) will thereupon immediately terminate. (iii) If the Oponee’s Employment is terminated by the Company and its subsidiaries in connecon with an act or failure to act constung Cause (as the Administrator, in its sole discreon, may determine), or such terminaon occurs in circumstances that in the determinaon of the Administrator would have entled the Company and its subsidiaries to terminate the Oponee’s Employment for Cause, the Stock Opon (whether 4. Forfeiture; Recovery of Compensaon. or not vested) will immediately terminate and be forfeited upon such terminaon. (a) (b) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Stock Opon at any me if the Oponee is not in compliance with all applicable provisions of this Agreement and the Plan. By accepng the Stock Opon, the Oponee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Stock Opon, under the Stock Opon to any Stock acquired under the Stock Opon or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 8 of this Agreement. 5. Transfer of Stock Opon. The Stock Opon may not be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 6. Withholding. The Oponee shall be responsible for sasfying and paying all taxes arising from or due in connecon with the Opon, its exercise or a disposion of Shares acquired upon exercise of the Opon. The Company shall have no liability or obligaon related to the foregoing. 7. Eﬀect on Service. Neither the grant of the Stock Opon, nor the issuance of Shares upon exercise of the Stock Opon, will give the Oponee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Oponee at any me, or aﬀect any right of such Oponee to terminate his or her Employment at any me. 8. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Oponee. By exercising all or any part of the Stock Opon, the Oponee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 9. Acknowledgements. The Oponee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Oponee. The Stock Opon evidenced by this Agreement is a non-statutory opon (that is, an opon that does not qualify as an incenve stock opon under Secon 422 of the Code) and is granted to the Oponee in connecon with the Oponee’s employment by or service to the Company and its qualifying subsidiaries. For purposes of the immediately preceding sentence, “qualifying subsidiary” means a subsidiary of the Company as to which the Company has a “controlling interest” as described in Treas. Regs. §1.409A-1(b)(5)(iii)(E)(1). [The remainder of this page is intenonally le blank] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized officer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Executive Officer Title: Dated: Acknowledged and Agreed: By_______________________ Exhibit 10.36 Name: Number of Restricted Stock Units subject to Award: Date of Grant: U P I. 2023 I P R S U A (D) This agreement (this “Agreement”) evidences an award (the “Award”) of restricted stock units (the “Restricted Stock Units”) granted by Ultragenyx Pharmaceucal Inc. (the “Company”) to the undersigned (the “Grantee”) pursuant to and subject to the terms of the Ultragenyx Pharmaceucal Inc. 2023 Incenve Plan (as amended from me to me, the “Plan”), which is incorporated herein by reference. 1. Grant of Restricted Stock Units. The Company grants to the Grantee on the date set forth above (the “Date of Grant”) an award consisng of the right to receive on the terms provided herein and in the Plan, one share of Stock with respect to each Restricted Stock Unit forming part of the Award, in each case, subject to adjustment pursuant to Secon 7(b) of the Plan in respect of transacons occurring aer the date hereof. 2. Meaning of Certain Terms. Except as otherwise deﬁned herein, all capitalized terms used herein have the same meaning as in the Plan. 3. Vesng. Unless earlier terminated, forfeited, relinquished or expired, the Restricted Stock Units shall vest as follows: 1/3 of the underlying shares shall vest on each anniversary of the Date of Grant so that the Restricted Stock Units will fully vest on the third (3rd) anniversary of the Date of Grant. 4. Delivery of Stock. The Company shall deliver to the Grantee as soon as praccable upon the vesng of the Restricted Stock Units or any poron thereof, but in all events no later than March 15 of the year following the year in which such Restricted Stock Units vest, one share of Stock with respect to each such vested Restricted Stock Unit, subject to the terms of the Plan and this Agreement. th 5. Dividends; Other Rights. The Award shall not be interpreted to bestow upon the Grantee any equity interest or ownership in the Company or any Aﬃliate prior to the date on which the Company delivers shares of Stock to the Grantee (if any). The Grantee is not entled to vote any shares of Stock by reason of the granng of this Award or to receive or be credited with any dividends declared and payable on any share of Stock prior to the date on which any such share is delivered to the Grantee hereunder. The Grantee shall have the rights of a shareholder only as to those shares of Stock, if any, that are actually delivered under this Award. 6. Forfeiture; Recovery of Compensaon. (a) The Administrator may cancel, rescind, withhold or otherwise limit or restrict the Award at any me if the Grantee is not in compliance with all applicable provisions of this Agreement and the Plan. (b) By accepng the Award the Grantee expressly acknowledges and agrees that his or her rights, and those of any permied transferee of the Award, under the Award to any Stock acquired under the Award or proceeds from the disposion thereof, are subject to Secon 6(a)(v) of the Plan (including any successor provision). Nothing in the preceding sentence shall be construed as liming the general applicaon of Secon 10 of this Agreement. 7. Nontransferability. Neither the Award nor the Restricted Stock Units may be transferred except as expressly permied under Secon 6(a)(iii) of the Plan. 8. Certain Tax Maers. (a) The Grantee shall be responsible for sasfying and paying all taxes arising from or due in connecon with the Restricted Stock Units or with the shares of Stock issued upon vesng of the Restricted Stock Units. The Company shall have no liability or obligaon related to the foregoing. (b) The Grantee expressly acknowledges that because this Award consists of an unfunded and unsecured promise by the Company to deliver Stock in the future, subject to the terms hereof, it is not possible to make a so-called “83(b) elecon” with respect to the Award. 9. Eﬀect on Service. Neither the grant of the Award, nor the issuance of shares of Stock upon vesng of the Award, will give the Grantee any right to be retained in the employ or service of the Company or any of its Aﬃliates, aﬀect the right of the Company or any of its Aﬃliates to discharge or discipline such Grantee at any me, or aﬀect any right of such Grantee to terminate his or her Employment at any me. 10. Provisions of the Plan. This Agreement is subject in its enrety to the provisions of the Plan, which are incorporated herein by reference. A copy of the Plan as in eﬀect on the Date of Grant has been furnished to the Grantee. By accepng the Award, the Grantee agrees to be bound by the terms of the Plan and this Agreement. In the event of any conﬂict between the terms of this Agreement and the Plan, the terms of the Plan shall control. 11. Acknowledgments. The Grantee acknowledges and agrees that (a) this Agreement may be executed in two or more counterparts, each of which shall be an original and all of which together shall constute one and the same instrument, (b) this agreement may be executed and exchanged using facsimile, portable document format (PDF) or electronic signature, which, in each case, shall constute an original signature for all purposes hereunder and (c) such signature by the Company will be binding against the Company and will create a legally binding agreement when this Agreement is countersigned by the Grantee. [The remainder of this page is intenonally le blank.] IN WITNESS WHEREOF, the Company has caused this Agreement to be executed by its duly authorized oﬃcer. ULTRAGENYX PHARMACEUTICAL INC. By: /s/ Emil Kakkis Name: Emil Kakkis, M.D., Ph.D. Chief Execuve Oﬃcer Title: Dated: Acknowledged and Agreed: By_______________________ Signiﬁcant Subsidiaries of Ultragenyx Pharmaceucal Inc. Exhibit 21.1 Name of Subsidiary Ultragenyx Holdco LLC Rare Delaware Inc. GeneTx Biotherapeucs LLC Ultragenyx UK Ltd Amlogenyx Inc. Ultragenyx Europe GmbH Ultragenyx Germany GmbH Ultragenyx Brasil Farmacêuca Ltda Ultragenyx Argenna SRL Ultragenyx Netherlands B.V. Ultragenyx France SAS Ultragenyx Colombia SAS Ultragenyx Canada Inc. Ultragenyx México, S. de R.L. de C.V. Ultragenyx Japan K.K. Ultragenyx Chile Limitada Jurisdicon of Incorporaon Delaware Delaware Delaware United Kingdom Delaware Switzerland Germany Brazil Argenna Netherlands France Colombia Canada Mexico Japan Chile Exhibit 23.1 We consent to the incorporaon by reference in the following Registraon Statements: CONSENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM (1) Registraon Statements (Form S-8 Nos. 333-194773, 333-201843, 333-209729, 333-216110, 333-223124, 333-229746, 333-236428, 333-253007, 333- 262751, 333-269840, and 333-272518) pertaining to the 2011 Equity Incenve Plan, as amended, 2014 Incenve Plan, as amended, 2014 Employee Stock Purchase Plan, as amended and restated, 2023 Incenve Plan, and Employee Inducement Plan, as amended of Ultragenyx Pharmaceucal Inc., (2) Registraon Statement (Form S-8 No. 333-221381) pertaining to the Dimension Therapeucs, Inc. 2015 Stock Opon and Incenve Plan and the Dimension Therapeucs, Inc. 2013 Stock Plan, both as assumed by Ultragenyx Pharmaceucal Inc., and (3) Registraon Statement (Form S-3 No. 333-253008) and related Prospectus of Ultragenyx Pharmaceucal Inc. for the registraon of common stock, preferred stock, debt securies, warrants and units; of our reports dated February 21, 2024, with respect to the consolidated ﬁnancial statements of Ultragenyx Pharmaceucal Inc. and the eﬀecveness of internal control over ﬁnancial reporng of Ultragenyx Pharmaceucal Inc. included in this Annual Report (Form 10-K) of Ultragenyx Pharmaceucal Inc. for the year ended December 31, 2023. /s/ Ernst & Young LLP San Mateo, California February 21, 2024 Exhibit 31.1 CERTIFICATION PURSUANT TO SECTION 302 OF THE SARBANES-OXLEY ACT OF 2002 I, Emil D. Kakkis, cerfy that: 1. 2. 3. 4. I have reviewed this Annual Report on Form 10-K of Ultragenyx Pharmaceucal Inc.; Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report; Based on my knowledge, the ﬁnancial statements, and other ﬁnancial informaon included in this report, fairly present in all material respects the ﬁnancial condion, results of operaons and cash ﬂows of the registrant as of, and for, the periods presented in this report; I am responsible for establishing and maintaining disclosure controls and procedures (as deﬁned in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over ﬁnancial reporng (as deﬁned in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have: a) b) c) d) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material informaon relang to the registrant, including its consolidated subsidiaries, is made known to us by others within those enes, parcularly during the period in which this report is being prepared; Designed such internal control over ﬁnancial reporng, or caused such internal control over ﬁnancial reporng to be designed under our supervision, to provide reasonable assurance regarding the reliability of ﬁnancial reporng and the preparaon of ﬁnancial statements for external purposes in accordance with generally accepted accounng principles; Evaluated the eﬀecveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the eﬀecveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluaon; and Disclosed in this report any change in the registrant’s internal control over ﬁnancial reporng that occurred during the registrant’s most recent ﬁscal quarter (the registrant’s fourth ﬁscal quarter in the case of an annual report) that has materially aﬀected, or is reasonably likely to materially aﬀect, the registrant’s internal control over ﬁnancial reporng; and 5. I have disclosed, based on our most recent evaluaon of internal control over ﬁnancial reporng, to the registrant’s auditors and the audit commiee of the registrant’s board of directors (or persons performing the equivalent funcons): a) b) All signiﬁcant deﬁciencies and material weaknesses in the design or operaon of internal control over ﬁnancial reporng which are reasonably likely to adversely aﬀect the registrant’s ability to record, process, summarize and report ﬁnancial informaon; and Any fraud, whether or not material, that involves management or other employees who have a signiﬁcant role in the registrant’s internal control over ﬁnancial reporng. Dated: February 21, 2024 /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D. President and Chief Execuve Oﬃcer (Principal Execuve Oﬃcer) Exhibit 31.2 CERTIFICATION PURSUANT TO SECTION 302 OF THE SARBANES-OXLEY ACT OF 2002 I, Howard Horn, cerfy that: 1. 2. 3. 4. I have reviewed this Annual Report on Form 10-K of Ultragenyx Pharmaceucal Inc.; Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report; Based on my knowledge, the ﬁnancial statements, and other ﬁnancial informaon included in this report, fairly present in all material respects the ﬁnancial condion, results of operaons and cash ﬂows of the registrant as of, and for, the periods presented in this report; I am responsible for establishing and maintaining disclosure controls and procedures (as deﬁned in Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over ﬁnancial reporng (as deﬁned in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have: 1. 2. 3. 4. Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material informaon relang to the registrant, including its consolidated subsidiaries, is made known to us by others within those enes, parcularly during the period in which this report is being prepared; Designed such internal control over ﬁnancial reporng, or caused such internal control over ﬁnancial reporng to be designed under our supervision, to provide reasonable assurance regarding the reliability of ﬁnancial reporng and the preparaon of ﬁnancial statements for external purposes in accordance with generally accepted accounng principles; Evaluated the eﬀecveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the eﬀecveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluaon; and Disclosed in this report any change in the registrant’s internal control over ﬁnancial reporng that occurred during the registrant’s most recent ﬁscal quarter (the registrant’s fourth ﬁscal quarter in the case of an annual report) that has materially aﬀected, or is reasonably likely to materially aﬀect, the registrant’s internal control over ﬁnancial reporng; and 5. I have disclosed, based on our most recent evaluaon of internal control over ﬁnancial reporng, to the registrant’s auditors and the audit commiee of the registrant’s board of directors (or persons performing the equivalent funcons): 1. 2. All signiﬁcant deﬁciencies and material weaknesses in the design or operaon of internal control over ﬁnancial reporng which are reasonably likely to adversely aﬀect the registrant’s ability to record, process, summarize and report ﬁnancial informaon; and Any fraud, whether or not material, that involves management or other employees who have a signiﬁcant role in the registrant’s internal control over ﬁnancial reporng. Dated: February 21, 2024 /s/ Howard Horn Howard Horn Execuve Vice President, Chief Financial Oﬃcer, Corporate Strategy (Principal Financial Oﬃcer) Exhibit 32.1 CERTIFICATION PURSUANT TO SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002 (18 U.S.C. SECTION 1350) In connecon with the accompanying Annual Report of Ultragenyx Pharmaceucal Inc. (the “Company”) on Form 10-K for the year ended December 31, 2023 (the “Report”), I, Emil D. Kakkis, M.D., Ph.D., as President and Chief Execuve Oﬃcer of the Company, and Howard Horn, as Execuve Vice President, Chief Financial Oﬃcer, Corporate Strategy of the Company, cerfy, pursuant to 18 U.S.C. Secon 1350, as adopted pursuant to Secon 906 of the Sarbanes- Oxley Act of 2002, that: (1) The Report fully complies with the requirements of Secon 13(a) or 15(d) of the Securies Exchange Act of 1934; and (2) The informaon contained in the Report fairly presents, in all material respects, the ﬁnancial condion and results of operaons of the Company. Dated: February 21, 2024 Dated: February 21, 2024 /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D. President and Chief Execuve Oﬃcer (Principal Execuve Oﬃcer) /s/ Howard Horn Howard Horn Execuve Vice President, Chief Financial Oﬃcer, Corporate Strategy (Principal Financial Oﬃcer) ULTRAGENYX PHARMACEUTICAL INC. CLAWBACK POLICY Exhibit 97.1 This Clawback Policy (this “Policy”) has been adopted by the Board of Directors (the “Board”) of Ultragenyx Pharmaceucal Inc. (the “Company”) eﬀecve October 2, 2023 (the “Eﬀecve Date”) and replaces the Company’s Clawback Policy dated December 13, 2017 in its enrety. This Policy is administered by the Compensaon Commiee (the “Commiee”) of the Board, subject to raﬁcaon by the independent members of the Board with respect to applicaon of this Policy to the Company’s Chief Execuve Oﬃcer, and is intended to comply with, and as applicable to be administered and interpreted consistent with, and subject to the excepons set forth in, Lisng Rule 5608 adopted by the Nasdaq Stock Market to implement Rule 10D-1 under the Securies Exchange Act of 1934, as amended (collecvely, “Rule 10D-1”). Mandatory Recoupment In the event the Company is required to prepare an accounng restatement of the Company’s ﬁnancial statements (including any such correcon that is material to the previously issued ﬁnancial statements, or that would result in a material misstatement if the error were corrected in the current period or le uncorrected in the current period) due to material non-compliance with any ﬁnancial reporng requirement under the federal securies laws (as applicable, a “Restatement”), the Company will recover on a reasonably prompt basis the amount of any Incenve-Based Compensaon Received by a Covered Execuve during the Recovery Period that exceeds the amount that otherwise would have been Received had it been determined based on the restated ﬁnancial statements. If the Commiee determines the amount of Incenve-Based Compensaon Received by a Covered Execuve during a Recovery Period exceeds the amount that would have been Received if determined or calculated based on the Company’s restated ﬁnancial results, such excess amount of Incenve-Based Compensaon shall be subject to recoupment by the Company pursuant to this Policy. For Incenve-Based Compensaon based on stock price or total shareholder return, where the amount of erroneously awarded compensaon is not subject to mathemacal recalculaon directly from the informaon in an accounng restatement, the Commiee will determine the amount based on a reasonable esmate of the eﬀect of the accounng restatement on the relevant stock price or total shareholder return. In all cases, the calculaon of the excess amount of Incenve-Based Compensaon to be recovered will be determined on a pre-tax basis. The Company will maintain and will provide to The Nasdaq Stock Market documentaon of all determinaons and acons taken in complying with the Mandatory Recoupment provisions of this Policy. Discreonary Recoupment In addion to the mandatory recoupment (required under Rule 10D-1) set forth above, in the event that the Commiee determines, in its sole discreon, that an act or omission of a Covered Execuve contributed to the circumstances requiring the Restatement and that such act or omission involved Fraud or Intenonal Misconduct, then the Commiee may recover all (not just the excess amount) Incenve-Based Compensaon as well as Other Incenve Compensaon, in each case, Received by such Covered Execuve. Deﬁnions For purposes of this Policy: • “Incenve-Based Compensaon” means any compensaon granted, earned or vested based in whole or in part on the Company’s aainment of a ﬁnancial reporng measure that was Received by a person (i) on or aer the Eﬀecve Date and aer the person began service as a Covered Execuve, and (ii) who served as a Covered Execuve at any me during the performance period for the Incenve-Based Compensaon. A ﬁnancial reporng measure is (A) any measure that is determined and presented in accordance with the accounng principles used in preparing the Company’s ﬁnancial statements and any measure derived wholly or in part from such a measure, and (B) any measure based in whole or in part on the Company’s stock price or total shareholder return. “Covered Execuve” means any “execuve oﬃcer” of the Company as deﬁned under Rule 10D-1. “Fraud or Intenonal Misconduct” includes reckless conduct (including any highly unreasonable act or omission, involving not merely simple, or even inexcusable negligence, but an extreme departure from the standards of ordinary care, and that is either known to the Covered Execuve or is so obvious the Covered Execuve must have been aware of it), but is not intended to include (i) negligent conduct or grossly negligent conduct not arising to such standard or (ii) conduct in good faith and in a manner the Covered Execuve reasonably believed to be in, or not opposed to, the best interests of the Company (including the Covered Execuve’s good faith scienﬁc or medical judgments). “Other Incenve Compensaon” means any incenve compensaon (other than Incenve-Based Compensaon), including, but not limited to, service- or me-based equity awards and bonuses and performance-based equity awards and bonuses that are not based on a ﬁnancial reporng measure, that was Received by a person (i) on or aer the Eﬀecve Date and aer the person began service as a Covered Execuve, and (ii) who served as a Covered Execuve at any me during the vesng or service period or performance period, as applicable, for the Other Incenve Compensaon. Incenve-Based Compensaon is deemed to be “Received” in the ﬁscal period during which the relevant ﬁnancial reporng measure is aained, regardless of when the compensaon is actually paid or awarded. Other Incenve Compensaon is deemed to be “Received” in the ﬁscal period during which any applicable performance measure is aained or any service- or me-based requirement is sasﬁed, regardless of when the compensaon is actually paid or awarded. “Recovery Period” means the three completed ﬁscal years immediately preceding the date that the Company is required to prepare the accounng restatement described in this Policy, as determined pursuant to Rule 10D-1, and any transion period of less than nine months that is within or immediately following such three ﬁscal years. • • • • • Recovery The Company may eﬀect any recovery pursuant to this Policy by requiring payment of such amount(s) to the Company, by set-oﬀ, by reducing future compensaon, or by such other means or combinaon of means as the Commiee determines to be appropriate. The Company need not recover the excess amount of Incenve-Based Compensaon if and to the extent that the Commiee determines that such recovery is impraccable, subject to and in accordance with any applicable excepons under the Nasdaq Stock Market lisng rules and not required under Rule 10D-1, including if the Commiee determines that the direct expense paid to a third party to assist in enforcing this Policy would exceed the amount to be recovered aer making a reasonable aempt to recover such amounts. The Company is authorized to take appropriate steps to implement this Policy with respect to Incenve-Based Compensaon and Other Incenve Compensaon arrangements with Covered Execuves. Any determinaons made by the Commiee under this Policy shall be ﬁnal and binding on all aﬀected individuals. 2 Addional Recoupment Rights Any right of recoupment or recovery pursuant to this Policy is in addion to, and not in lieu of, any other remedies or rights of recoupment that may be available to the Company pursuant to the terms of any other policy, any employment agreement or plan or award terms, and any other legal remedies available to the Company; provided that the Company shall not recoup amounts pursuant to such other policy, terms or remedies to the extent it is recovered pursuant to this Policy. The Company shall not indemnify any Covered Execuve against the loss of any Incenve-Based Compensaon or Other Incenve Compensaon pursuant to this Policy. 3

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