Regeneron Pharmaceuticals
Annual Report 2016

Plain-text annual report

A N N U A L R E P O R T G R OWT H T H R O U G H I N N O VAT I O N MENU >C O N T E N T S REGENERON AT A GL ANCE SHAREHOLDER LE T TER MARK E TED PRODUC TS L ATE-STAGE PIPELINE ADDITIONA L PIPELINE PROGR AMS GROW TH CITIZENSHIP FORWARD-LOOK ING STATEMENTS CORPOR ATE INFORMATION REFERENCES 3 4 7 12 15 20 22 28 29 30 REGENERON AT A GLANCE 2 0 1 6 A N N U A L R E P O R T 3 < MENU >< MENU >DEAR FELLOW SHAREHOLDERS, In 2016, we reaffirmed our core strategy of growth through innovation and continued to advance our mission of consistently and repeatedly bringing important new medicines to patients in need. Turning science into important drugs is one of the most difficult activities Turning to our currently marketed medicines, we continue to bring EYLEA® an organization can undertake. Despite thousands of biopharmaceutical (aflibercept) Injection, our market-leading therapy for the treatment of serious companies in the United States and billions in R&D spend, only 22 novel vision-threatening diseases, to more and more indicated patients. In 2016, drugs were approved by the U.S. Food and Drug Administration (FDA) in EYLEA global net sales were $5.2 billion, including $3.3 billion in U.S. net 2016. Of these, only eight were first in class, and even fewer targeted sales. We continue to work to improve outcomes in serious retinal diseases major diseases affecting millions of people. With this background, it is quite and have an ongoing Phase 3 trial with EYLEA in diabetic retinopathy, as well a testament to the Regeneron team that, by the end of 2017, we anticipate as a combination program evaluating EYLEA co-formulated with nesvacumab, having five new medicines approved since 2011, all of which are first- or an investigational ANG-2 antibody. second-in-class therapies. We laid important groundwork last year that has positioned us for a demonstrated gradual sales growth in 2016, reaching $116 million in global potentially transformational year in 2017, with two important new drug net sales. This growth was hampered by significant launches. Dupixent® (dupilumab) Injection was approved on March 28, access challenges and a desire from payers Praluent® (alirocumab) Injection, our therapy for uncontrolled LDL cholesterol, studies in eosinophilic esophagitis. 2017, by the FDA and the launch is ongoing. Moderate-to-severe atopic and physicians to see positive dermatitis is a serious inflammatory disease with limited treatment options. outcomes data. We expect to Patients suffer with widespread rash, debilitating itching, and other complete our 18,000-patient challenges. We believe Dupixent, which the FDA had designated a Breakthrough Therapy, represents an important scientific advance and, most importantly, new hope for patients in need. We also recently ODYSSEY OUTCOMES study by the end of 2017. Together with our resubmitted our U.S. application for Kevzara® (sarilumab) for the treatment collaborators at Sanofi, of moderately to severely active rheumatoid arthritis, and expect an FDA decision later in 2017. we continue to defend our position By the end of 2017, we anticipate having five new medicines approved since 2011, all of which are first- or second-in-class therapies. 2 0 1 6 A N N U A L R E P O R T 4 in the ongoing patent litigation related to Praluent. We believe the controlling We also have a late-stage program ongoing for fasinumab, our antibody to law and facts support our position and look forward to a timely resolution of Nerve Growth Factor (NGF) for osteoarthritis pain and chronic lower back this matter. pain, and in 2016, we entered a major new global collaboration with Teva for the development of this product candidate, which will help us advance this Our pipeline continues to grow with potential innovations across a number program. Our late-stage pipeline is rounded out with suptavumab, our of serious diseases. Dupilumab, in particular, has the potential to represent antibody to respiratory syncytial virus (RSV), a serious respiratory infection in a pipeline in a single compound as the therapy targets a key signaling infants, and our PD-1 antibody, REGN2810, for the treatment of non-small cell pathway that is believed to drive a number of allergic diseases. We expect lung cancer (NSCLC) and a serious skin cancer. top-line Phase 3 results for dupilumab in patients with asthma, followed by a potential U.S. regulatory submission in this indication by year-end 2017. We Our early-to-mid-stage programs also continue to make important progress. are also studying dupilumab in late-stage trials of patients with nasal polyps, Programs include evinacumab, our Angptl-3 antibody for homozygous familial pediatric asthma, and pediatric atopic dermatitis, in addition to earlier-stage hypercholesterolemia, an inherited lipid disorder; additional immuno-oncology candidates, including a bi-specific antibody for blood cancers; and an Activin A antibody for a rare and extremely serious disease known as Fibrodysplasia Ossificans Progressiva. We continue to prioritize ongoing investment in technology and innovation, which we believe will position us to bring needed new medicines to patients for many years to come. One of these efforts is the Regeneron Genetics Center (RGC), which in just a little over three years after launch has sequenced more than 150,000 consented individuals. In March 2017, the RGC embarked on an important collaboration in the United Kingdom with the goal of sequencing all the participants in the UK Biobank, the world’s most comprehensive health resource, which includes samples and medical records from 500,000 volunteer participants. Importantly, the RGC efforts have already identified exciting new targets for drug development. < MENU >< MENU >Turning science into important drugs is one of the most difficult activities Turning to our currently marketed medicines, we continue to bring EYLEA® an organization can undertake. Despite thousands of biopharmaceutical (aflibercept) Injection, our market-leading therapy for the treatment of serious companies in the United States and billions in R&D spend, only 22 novel vision-threatening diseases, to more and more indicated patients. In 2016, drugs were approved by the U.S. Food and Drug Administration (FDA) in EYLEA global net sales were $5.2 billion, including $3.3 billion in U.S. net 2016. Of these, only eight were first in class, and even fewer targeted sales. We continue to work to improve outcomes in serious retinal diseases major diseases affecting millions of people. With this background, it is quite and have an ongoing Phase 3 trial with EYLEA in diabetic retinopathy, as well a testament to the Regeneron team that, by the end of 2017, we anticipate as a combination program evaluating EYLEA co-formulated with nesvacumab, having five new medicines approved since 2011, all of which are first- or an investigational ANG-2 antibody. second-in-class therapies. We laid important groundwork last year that has positioned us for a demonstrated gradual sales growth in 2016, reaching $116 million in global potentially transformational year in 2017, with two important new drug net sales. This growth was hampered by significant launches. Dupixent® (dupilumab) Injection was approved on March 28, access challenges and a desire from payers 2017, by the FDA and the launch is ongoing. Moderate-to-severe atopic and physicians to see positive dermatitis is a serious inflammatory disease with limited treatment options. outcomes data. We expect to Patients suffer with widespread rash, debilitating itching, and other complete our 18,000-patient challenges. We believe Dupixent, which the FDA had designated a Breakthrough Therapy, represents an important scientific advance and, most importantly, new hope for patients in need. We also recently of moderately to severely active rheumatoid arthritis, and expect an FDA decision later in 2017. ODYSSEY OUTCOMES study by the end of 2017. Together with our we continue to defend our position resubmitted our U.S. application for Kevzara® (sarilumab) for the treatment collaborators at Sanofi, in the ongoing patent litigation related to Praluent. We believe the controlling We also have a late-stage program ongoing for fasinumab, our antibody to law and facts support our position and look forward to a timely resolution of Nerve Growth Factor (NGF) for osteoarthritis pain and chronic lower back this matter. pain, and in 2016, we entered a major new global collaboration with Teva for the development of this product candidate, which will help us advance this Our pipeline continues to grow with potential innovations across a number program. Our late-stage pipeline is rounded out with suptavumab, our of serious diseases. Dupilumab, in particular, has the potential to represent antibody to respiratory syncytial virus (RSV), a serious respiratory infection in a pipeline in a single compound as the therapy targets a key signaling infants, and our PD-1 antibody, REGN2810, for the treatment of non-small cell pathway that is believed to drive a number of allergic diseases. We expect lung cancer (NSCLC) and a serious skin cancer. top-line Phase 3 results for dupilumab in patients with asthma, followed by a potential U.S. regulatory submission in this indication by year-end 2017. We Our early-to-mid-stage programs also continue to make important progress. are also studying dupilumab in late-stage trials of patients with nasal polyps, Programs include evinacumab, our Angptl-3 antibody for homozygous familial pediatric asthma, and pediatric atopic dermatitis, in addition to earlier-stage hypercholesterolemia, an inherited lipid disorder; additional immuno-oncology Praluent® (alirocumab) Injection, our therapy for uncontrolled LDL cholesterol, studies in eosinophilic esophagitis. We continue to prioritize ongoing investment in technology and innovation, which we believe will position us to bring needed new medicines to patients for many years to come. candidates, including a bi-specific antibody for blood cancers; and an Activin A antibody for a rare and extremely serious disease known as Fibrodysplasia Ossificans Progressiva. We continue to prioritize ongoing investment in technology and innovation, which we believe will position us to bring needed new medicines to patients for many years to come. One of these efforts is the Regeneron Genetics Center (RGC), which in just a little over three years after launch has sequenced more than 150,000 consented individuals. In March 2017, the RGC embarked on an important collaboration in the United Kingdom with the goal of sequencing all the participants in the UK Biobank, the world’s most comprehensive health resource, which includes samples and medical records from 500,000 volunteer participants. Importantly, the RGC efforts have already identified exciting new targets for drug development. 2 0 1 6 A N N U A L R E P O R T 5 < MENU >< MENU >As we have grown to employ over 5,500 people, we have also grown physically — commitment to support this program, which plays a critical role in the we continue to expand our manufacturing facilities in Rensselaer, New York, and development of a strong science talent pipeline for generations to come and in Raheen, Ireland, and we also purchased an office building near our Tarrytown, elevating the place of science in our society. New York facility, which will help expand the footprint of our headquarters in Westchester County, New York. Also, in early 2017, we completed a new lease We invite you to read about our 2016 accomplishments, financial performance financing for our Tarrytown corporate headquarters. As a result of this and corporate citizenship efforts in our online annual report and in our 2016 transaction, we have obtained an option to buy the facility at the end of the Annual Report on Form 10-K, which are available on the Investor Relations five-year lease term and are poised to benefit from immediate cash savings and portion of our website. increased flexibility for future growth. Finally, in 2016, we were thrilled to expand our long-standing dedication to on our mission of developing transformative medicines for patients. We are very much looking forward to a successful 2017 and continuing to deliver science education with a major philanthropic commitment to inspire future innovators. We became only the third sponsor in 75 years of the nation’s oldest and most prestigious high school science competition, now known as the Sincerely, Regeneron Science Talent Search. This program was previously sponsored by Intel, and before that, by Westinghouse. We have made a 10-year, $100 million Len, George, and Roy Leonard S. Schleifer, MD, PhD President and Chief Executive Officer George D. Yancopoulos, MD, PhD President and Chief Scientific Officer P. Roy Vagelos, MD Chairman of the Board 2 0 1 6 A N N U A L R E P O R T 6 < MENU >< MENU >M A R K E T E D P R O D U CTS M A K E G R E AT M E D I C I N E T H E N D O I T A G A I N A N D A G A I N 2 0 1 6 A N N U A L R E P O R T 7 < MENU >< MENU >EYLEA® (AFLIBERCEPT) INJECTION AND RETINAL DISEASE PROGRAMS Market-leading anti-VEGF approved in more than 100 countries for the treatment of key blindness-causing retinal conditions including wet age-related macular degeneration (AMD) and diabetic macular edema (DME). EYLEA global net sales exceeded $5 billion in 2016. In the United States, EYLEA net sales increased 24% to $3.32 billion for the full year 2016 from $2.68 billion for the full year 2015. Outside of the United States, where our collaborator Bayer HealthCare commercializes EYLEA, net sales were $1.87 billion in 2016, compared to $1.41 billion in 2015. Regeneron recognized $649 million from its share of net profit outside the United States in 2016, compared to $467 million in 2015. “We’re proud that EYLEA has helped many patients over the last several years. We continue to work on new innovations for people with serious vision-threatening diseases in an effort to further improve outcomes for these patients.” — Robert L. Vitti, MD, Vice President and Head of Ophthalmology In 2017, we continue to enroll patients in our ongoing Phase 3 study of EYLEA in non-proliferative diabetic retinopathy, a common eye disease that impacts many people with diabetes. In addition to this new indication, we are exploring EYLEA in combination with nesvacumab, an anti-angiopoietin 2 antibody, in two fully enrolled Phase 2 trials — RUBY in DME and ONYX in wet AMD. In 2016, we discontinued the development of another EYLEA combination therapy, aflibercept + rinucumab, an anti–platelet-derived growth factor receptor beta (anti-PDGFR-beta) antibody, which did not demonstrate improvement in best corrected visual acuity (BCVA) compared to aflibercept monotherapy in our Phase 2 CAPELLA study. Though pre-clinical data for the co-formulation of aflibercept and nesvacumab are more supportive, EYLEA sets a very high efficacy bar in the treatment of these disease indications. EYLEA U.S. SALES: 24% INCREASE $3.32 bn $2.68 bn $1.74 bn 2014 2015 2016 EYLEA EX-U.S. SALES: 33% INCREASE $1.87 bn $1.41 bn $1.04 bn 2014 2015 2016 Sales increases represent year-over-year growth from 2015 to 2016. 2 0 1 6 A N N U A L R E P O R T 8 < MENU >< MENU >PRALUENT® (ALIROCUMAB) INJECTION Monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) available in two doses, allowing for dose adjustment based on patients’ LDL-C–lowering needs. Praluent completed its first full year on the market in 2016, with $116 million in global net sales. Praluent is a PCSK9 inhibitor approved by the FDA as adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease in adults who require additional lowering of LDL-C (often referred to as “bad cholesterol”). The effect of Praluent on cardiovascular morbidity and mortality has not been determined. The ongoing ODYSSEY OUTCOMES clinical trial program, which is evaluating the potential of Praluent to prevent heart attacks, stroke and cardiac death, reached full enrollment in 2015, with more than 18,000 patients at over 2,000 study centers. Two prespecified interim analyses were performed by an independent Data Monitoring Committee in 2016 — the first, a futility analysis when 50% of cardiovascular events had occurred, and the second analysis, for both futility and overwhelming efficacy, when 75% of cardiovascular events had occurred. The trial continued as planned following both analyses, and we expect to complete the study in late 2017. We continue to be involved in patent litigation with Amgen related to Praluent. In 2016, a District Court jury ruled against us, upholding the validity of Amgen’s patents. In early 2017, the District Court granted a permanent injunction requested by Amgen, preventing the marketing, selling, or commercial manufacturing of Praluent in the United States. We have appealed both of these decisions to the U.S. Court of Appeals for the Federal Circuit, which hears all biopharmaceutical patent litigation appeals, and the court has stayed (suspended) the permanent injunction for Praluent that was granted by the District Court, pending appeal. This stay ensures that Praluent will continue to be available to patients during the ongoing appeal process. We strongly believe that the controlling law and facts support our position that Amgen’s asserted patent claims are invalid. We look forward to pursuing our appeal over the coming months. “After I suffered a major heart attack and was at risk for another one, I was afraid I would not be here for the future of my two children. Now that my bad cholesterol is under control, I feel like I have my life back!” — Peggy, Praluent patient 2 0 1 6 A N N U A L R E P O R T 9 < MENU > < MENU >DUPIXENT® (DUPILUMAB) INJECTION First-in-class monoclonal antibody that treats moderate-to-severe atopic dermatitis (AD) by blocking IL-4 and IL-13, two key cytokines involved in allergic diseases. “I so appreciate all the researchers who worked on bringing Dupixent to atopic dermatitis patients like me. I now feel confident spending time with my family, continuing my music career and living my life to the fullest.” — Lisa, harpist and Dupixent patient Dupixent has been approved in the United States and is under regulatory review in the European Union for the treatment of atopic dermatitis (AD). It is also being studied in other allergic conditions including asthma, nasal polyps, and eosinophilic esophagitis. In March of 2017, Dupixent was approved by the FDA for the treatment of moderate-to-severe AD in adults whose disease is not adequately controlled with topical prescription therapies or for whom those therapies are not advisable. Dupixent can be used with or without topical corticosteroids. With our collaborator Sanofi, we launched the product to the commercial market shortly following approval. We are excited to provide this first-in-class medicine to adult patients who, up until the approval of Dupixent, had no FDA-approved biologic therapies to treat their uncontrolled moderate-to-severe AD. Additionally, in December of 2016, the European Medicines Agency (EMA) accepted for review the Marketing Authorization Application (MAA) for Dupixent for the treatment of moderate-to-severe AD in adults who are candidates for systemic therapy. We expect a decision from the EMA later in 2017. In 2016, we reported positive data from three Phase 3 trials of Dupixent (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, and LIBERTY AD CHRONOS) in adult patients with moderate-to-severe AD. In these studies, treatment with Dupixent as monotherapy or as concomitant treatment with topical medications significantly improved measures of overall disease severity, skin clearing, and itching. We are also studying dupilumab in pediatric patients with moderate-to-severe AD, and have been granted Breakthrough Therapy designation by the FDA for a subset of pediatric patients with moderate-to-severe AD. We began a Phase 3 trial in adolescents (aged 12 to 17 years) with moderate-to-severe AD in the first quarter of 2017, and we expect to initiate a trial in children (aged 6 to 11 years) with severe AD later in 2017. Our second pivotal study for the treatment of asthma, LIBERTY ASTHMA QUEST, is fully enrolled, with data expected in the second half of 2017. We plan to submit a U.S. regulatory filing for dupilumab in this indication by year-end 2017. In the second quarter of 2017, we anticipate beginning enrollment of a Phase 3 trial in uncontrolled, persistent asthma in children (aged 6 to 11 years). Progress continues on our other indications as well. We have begun enrolling patients with nasal polyps in two Phase 3 trials, and expect to begin enrolling patients with food allergies in a Phase 2 trial in the second half of 2017. We also expect Phase 2 data from our ongoing trial in patients with eosinophilic esophagitis in the second half of 2017. 2 0 1 6 A N N U A L R E P O R T 1 0 < MENU > < MENU >KEVZARA® (SARILUMAB) INJECTION IL-6R antibody under U.S. and EU regulatory review for the treatment of rheumatoid arthritis (RA). Kevzara has been approved in Canada. In 2016, we reported positive data from the Phase 3 SARIL-RA-MONARCH monotherapy study, which met its primary endpoint by demonstrating that Kevzara was superior to Humira® (adalimumab) in improving signs and symptoms in adults with active RA who were inadequate responders to, intolerant of, or inappropriate candidates for methotrexate. It was the first time a subcutaneously delivered IL-6 receptor blocker demonstrated superiority over adalimumab monotherapy in RA. In 2016, the EMA accepted for review the MAA for sarilumab, and an application for marketing approval for sarilumab was submitted in Japan. In the United States, we, along with our collaborator Sanofi, submitted the U.S. Biologics License Application (BLA) for Kevzara in November 2015, and were assigned a Prescription Drug User Fee Act (PDUFA) date of October 30, 2016. On October 28, 2016, we received a Complete Response Letter (CRL) from the FDA related to a Sanofi manufacturing facility. In early 2017, after the facility completed a successful FDA re-inspection, we resubmitted the Kevzara BLA. We expect an FDA decision in the second quarter of 2017. Finally, in February 2017, Kevzara received approval and was launched in the commercial market in Canada for the treatment of moderately to severely active RA in adults who have had an inadequate response or intolerance to one or more biologic or non-biologic disease-modifying antirheumatic drugs (DMARDs). “RA impacts every aspect of my life and when its uncontrolled it makes me feel like I can’t do anything I love. I’m so glad people continue to develop new treatments so I can go back to doing the things I love – playing with my five grandchildren, quilting, and cooking.” — Michelle, seamstress and RA clinical trial patient 2 0 1 6 A N N U A L R E P O R T 1 1 < MENU > < MENU >LAT E - STA G E P I P E L I N E N E V E R STO P A S K I N G W H Y 2 0 1 6 A N N U A L R E P O R T 1 2 < MENU >< MENU >PIPELINE (as of April 2017) Regeneron has fifteen fully human monoclonal antibodies in clinical development that were developed using our proprietary VelocImmune ® technology. PHASE 1 REGN1908-1909 Feld1 Antibody Allergic disease REGN2810* PD-1 Antibody Cancer REGN1979 CD20XCD3 Antibody Cancer (also in combination with REGN2810) REGN3470-3471-3479 Antibody to Ebola virus Ebola virus infection PHASE 2 DUPILUMAB* IL-4R Antibody Eosinophilic esophagitis SARILUMAB* IL-6R Antibody Juvenile idiopathic arthritis EVINACUMAB Angptl3 Antibody Homozygous familial hypercholesterolemia FASINUMAB† NGF Antibody Pain due to chronic lower back pain TREVOGRUMAB GDF8 Antibody (in combination with REGN2477) REGN2477 Activin A Antibody Fibrodysplasia ossificans progressiva (also in combination with trevogrumab) REGN3500* IL-33 Antibody Inflammatory diseases REGN3767* LAG-3 Antibody Cancer (also in combination with REGN2810) * in collaboration with Sanofi ^ in collaboration with Bayer HealthCare ex-U.S. † in collaboration with Mitsubishi Tanabe Pharma Corporation (Asia) and Teva NESVACUMAB + AFLIBERCEPT^ Ang2 Antibody + Aflibercept Wet age-related macular degeneration, diabetic macular edema REGN2810* PD-1 Antibody Advanced cutaneous squamous cell carcinoma PHASE 3 ALIROCUMAB* PCSK9 Antibody Hypercholesterolemia SARILUMAB* IL-6R Antibody Rheumatoid arthritis DUPILUMAB* IL-4R Antibody Atopic dermatitis in children, asthma in adults and children, nasal polyps AFLIBERCEPT VEGF-Trap Diabetic retinopathy without diabetic macular edema SUPTAVUMAB RSV Antibody Respiratory syncytial virus infection FASINUMAB† NGF Antibody Pain due to osteoarthritis 2 0 1 6 A N N U A L R E P O R T 1 3 < MENU >< MENU >SUPTAVUMAB Fully human monoclonal antibody being investigated for the prevention of serious lower respiratory tract infections associated with respiratory syncytial virus (RSV). In 2016, we continued enrollment of the Phase 3 NURSERY-preterm trial that is evaluating the efficacy, safety, pharmacokinetics (PK) and immunogenicity of suptavumab in infants born at a gestational age of 35 weeks or less who are younger than 6 months. We expect to report topline data from this trial in the second half of 2017. FASINUMAB Nerve growth factor–targeting antibody being evaluated for novel, non-opioid approach to certain chronic pain conditions. In 2016, we announced a global collaboration to develop and commercialize fasinumab with Teva, a leading global pharmaceutical company with expertise in pain therapeutics. Under a previously announced collaboration agreement with Regeneron, Mitsubishi Tanabe Pharma Corporation (MTPC) has exclusive development and commercial rights to fasinumab in Japan, Korea, and nine other Asian countries. We believe both Teva and MTPC will be strong partners in potentially bringing fasinumab to the market and those patients in need. We launched a large Phase 3 clinical program studying fasinumab for pain due to osteoarthritis (OA) in 2016 and continue to enroll patients. The FDA placed our Phase 2 trial in chronic lower back pain (CLBP) on hold in the fourth quarter of 2016, following the observation of a case of rapidly progressing OA in a patient who was receiving high-dose fasinumab and had a history of advanced OA of the knee. This event prompted an unplanned interim analysis of the study, which had completed 70% of its targeted enrollment and showed clear evidence of efficacy and improvement in pain scores for all dosing groups. Following communications with the FDA, we plan to continue development of fasinumab in CLBP without advanced OA. In collaboration with Teva, we expect to initiate a Phase 3 trial in 2017. “An RSV infection can be serious and very frightening for parents of infants and young children — we’re evaluating a therapeutic candidate to see if it has the potential to prevent these infections before they start.” — Leah Lipsich, PhD, Vice President, Strategic Program Direction 80% of people with OA report some degree of movement limitation2 OA affects more than 30 MILLION adults in the U.S.1 Back pain is the MOST COMMON type of pain among adults in the U.S.3* 2 0 1 6 A N N U A L R E P O R T 1 4 *Includes low back pain, severe headache or migraine and neck pain. < MENU >< MENU >A D D I T I O N A L P I P E L I N E P R O G R A M S O U R G R E AT E ST D I S C O V E R I E S H AV E Y E T TO B E D E F I N E D 2 0 1 6 A N N U A L R E P O R T 15 < MENU >< MENU >IMMUNO-ONCOLOGY Our portfolio in this rapidly developing field grew in 2016, through both new product candidates and new indications for existing candidates, supported by our ongoing collaboration with Sanofi. Our growing clinical-stage immuno-oncology pipeline now includes three antibodies: a PD-1 inhibitor, a CD20xCD3 bi-specific antibody, and an antibody to LAG3. In 2016, we presented Phase 1 data from our PD-1 program, which helped us determine the therapeutic dose for our ongoing, potentially pivotal Phase 2 trial in cutaneous squamous cell carcinoma. This study is currently enrolling patients. In 2017, we plan to initiate a Phase 3 study in non-small cell lung cancer, as well as a potentially pivotal study in basal cell carcinoma. We also presented interim data from our CD20xCD3 bi-specific program in 2016. The CD20xCD3 antibody is currently in clinical trials both as a monotherapy and as a combination therapy with our PD-1 antibody. We are also conducting studies of REGN3767, our antibody to LAG3, both as a monotherapy and as a combination therapy with our PD-1 antibody. A number of additional immuno-oncology antibodies are expected to enter the clinic in 2017 and 2018, and we continue to pursue business development opportunities with novel immuno-oncology approaches that have potential to be combined with antibodies. 2 0 1 6 A N N U A L R E P O R T 1 6 < MENU >< MENU > RARE DISEASES We are expanding our research into rare diseases, where serious unmet medical needs provide the opportunity to deliver on our mission of turning science into life-changing medicine. Our most clinically advanced rare disease antibody, evinacumab, an antibody to Angptl-3, is in clinical development for the treatment of homozygous familial hypercholesterolemia (HoFH), which is the most severe form of hypercholesterolemia. Patients with this disease are at a significantly higher risk of serious cardiac events, including heart attack and stroke. In the first half of 2016, we presented positive interim data from a Phase 2 proof-of-concept study of evinacumab in patients with HoFH. We also entered REGN2477, our antibody to Activin A, into clinical development for the treatment of fibroplasia ossificans progressiva (FOP). FOP is a progressive, severely disabling, and ultimately fatal disease in which muscles, ligaments, tendons, and other connective tissues are transformed into bone. We entered the drug into a Phase 1 study in healthy volunteers in 2016, and expect to move into a Phase 2 trial in 2017. We also initiated a Phase 1 study of REGN2477 in combination with REGN1033, our antibody to GDF8, in 2016. REGN2477 has been granted orphan drug designation status by the FDA. In pre-clinical development we have a number of indications and programs identified, including transthyretin-related amyloidosis (TTR), juvenile X-Linked retinoschisis, and a C5 complement inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). We are working to advance these programs further in 2017. 2 0 1 6 A N N U A L R E P O R T 1 7 < MENU >< MENU >RAPID RESPONSE + INFECTIOUS DISEASE Regeneron’s rapid response capabilities leverage our core VelociSuite® technologies to significantly compress the time required for discovery and pre-clinical validation of potential treatments for emerging infectious diseases. In 2016, work continued on our antibodies to the Ebola virus (REGN3470-3471-3479), where we began a Phase 1 study in healthy volunteers in the first half of 2016, and the antibody was granted orphan designation status by the FDA. This program is in development with the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services. In pre-clinical development, we also have antibodies to Middle Eastern respiratory virus (MERS) and the Zika virus. 2 0 1 6 A N N U A L R E P O R T 1 8 < MENU >< MENU >REGENERON GENETICS CENTER The Regeneron Genetics Center (RGC) is one of the world’s largest genetic sequencing initiatives, providing important insights into target identification and clinical development. The Regeneron Genetics Center (RGC) is a leader in human genetics research. Our RGC scientists have sequenced more than 150,000 consented individuals, entered into more than 30 academic collaborations, and have continuously supported our clinical development efforts. We expect these efforts to help us discover new targets, indications and biomarkers that could better predict drug response, and help de-risk the process of bringing new medicines into the clinic. We ended 2016 with two simultaneous publications in Science, one of which provided the first overall description of the Geisinger-Regeneron Genetics Center (RGC) collaboration known as DiscovEHR, and the other demonstrated the underdiagnosis and undertreatment of familial hypercholesterolemia (FH) through pairing genetic variants causing FH with their de-identified medical histories. In March 2017, we announced a major new RGC initiative with UK Biobank and GSK, in which we will be sequencing 500,000 individuals in the UK Biobank’s health resource. We expect new and important publications and continued RGC progress in 2017. 2 0 1 6 A N N U A L R E P O R T 1 9 < MENU >< MENU >G R OWT H B E A N E N G I N E O F I N V E N T I O N 2 0 1 6 A N N U A L R E P O R T 2 0 < MENU >< MENU >GROWTH Be an engine of invention. In 2016, we continued to grow, adding both employees and other important assets. As a result of this transaction, we have obtained an option to buy the facility at the Our manufacturing facilities in Rensselaer and Raheen both grew — in Rensselaer end of the five-year lease term and are poised to benefit from immediate cash we expanded our product manufacturing operations, and in Raheen we continued savings and increased flexibility for future growth. Finally, we welcomed our 5,000th construction and hired new employees for the site. We also expanded our Regeneron employee in 2016. Each employee helps us continually deliver on our headquarters, purchasing an office building near our Tarrytown facility, and in early mission to help patients with serious diseases, and reminds us that our people are 2017, we completed new lease financing for our Tarrytown corporate headquarters. what make Regeneron great. REVENUE $4.860 bn $4.104 bn $2.820 bn FULL-TIME EMPLOYEES 5,400* 4,300 18 % increase 2,925 26 % increase R&D INVESTMENT† $2.052 bn $1.621 bn $1.271 bn 27% increase 2014 2015 2016 2014 2015 2016 2014 2015 2016 *700 hold a PhD and/or MD or PharmD degree. †Generally Accepted Accounting Principles R&D Expenses 2 0 1 6 A N N U A L R E P O R T 2 1 < MENU >< MENU >C I T I Z E N S H I P M A K I N G A D I F F E R E N C E B E YO N D O U R LA B S 2 0 1 6 A N N U A L R E P O R T 2 2 < MENU >< MENU >FOCUSED ON CREATING A BETTER TOMORROW In addition to our dedication to patients and the development of life-transforming medicines, we are committed across the organization to our four pillars of citizenship: FOSTERING the future of scientific innovation CULTIVATING sustainable communities SUPPORTING patient communities NURTURING our high-engagement high-integrity culture 2 0 1 6 A N N U A L R E P O R T 2 3 < MENU >< MENU >FOSTERING THE FUTURE OF SCIENTIFIC INNOVATION We believe in future scientists’ power to advance societal progress, solve our most pressing global challenges, and create a healthier tomorrow. REGENERON SCIENCE TALENT SEARCH In 2016, Regeneron became the new sponsor of the Science Talent Search (STS), a program of the Society for Science & the Public, and our nation’s most prestigious science and math competition for high school seniors. This 76-year-old program was previously sponsored by Westinghouse and then by Intel. We made a 10-year, $100-million commitment, and nearly doubled the competition’s overall award distribution to $3.1 million annually. We are committed to expanding and diversifying the Science Technology Engineering and Math (STEM) talent pool, and have consequently earmarked $30 million for Society programs aiming to increase access to STEM education and resources for underrepresented populations. In addition to the Regeneron STS, we focus our STEM education efforts across three areas of impact: WESTINGHOUSE (1942-1998) INTEL (1998-2016) ATTRACTING EXCELLENCE WIDENING THE POOL AMPLIFYING A MOVEMENT Progress thrives when the brightest minds go into science. We support these sharp young students by Recruiting a more diverse STEM workforce As a company founded with the starts with awareness and equity. We focus goal of transforming lives through on capacity-building programs that bridge science, we are committed to access to quality science education and promoting the important role of funding programs such as the address systemic change in science science in our society. We are Regeneron-Westchester instruction. The BioBus, STEM Teaching sharing our deep commitment to Science and Engineering Fair, Fellowship and Science News in High science education and leading a Regeneron Prize for Creative Schools are just a few of the ways we drive movement to drive greater Innovation and high school deeper interest in science, support collective action across our industry, research mentorship programs. scientific literacy, and facilitate discovery. communities, and country. 2,190 hours of teacher development 4,000 high school subscriptions to Science News 298 Regeneron interns ~1,700 Regeneron STS entrants 4,062 hours of science instruction aboard the BioBus (made possible by Regeneron funding) 2 0 1 6 A N N U A L R E P O R T 24 < MENU >< MENU >CULTIVATING SUSTAINABLE COMMUNITIES We proudly expand on our mission to improve human life with our efforts to strengthen our communities through environmental and social action. COMMUNITY INVOLVEMENT ENVIRONMENTAL SUSTAINABILITY At Regeneron, volunteering is an essential part of the employee experience. We empower our people to give back and create meaningful change in our communities through Regeneron In the Community, our company volunteer As we continue to grow, environmental stewardship and responsible growth remain at our core. In 2013, we set five-year targets in four major focus areas to measure and monitor our environmental progress. With just two years remaining, program. Not only do our employees donate their time, talent and leadership to we are on track to meet or exceed each of these goals. With our evolving global help tackle some of our communities’ most pressing problems, but their collaborations and new product development efforts, we remain committed to involvement also inspires communal action. monitoring and reducing the environmental impact of our business. 1,263 volunteers 5,697 hours 650 organizations supported, including our Matching Gifts Program 91% of employees feel good about the ways we contribute to the community — Great Places to Work® Survey PROGRESS ON FIVE-YEAR GOALS, 2013-2016: CARBON* Reduced our greenhouse gas emissions per employee by 31%, exceeding our expanded 2018 goal of 30% WASTE 68% of our waste avoids the landfill, moving toward our 2018 goal of 90% ELECTRICITY* Reduced our consumption per employee by 2%, moving toward our 2018 goal of 10% HAZARDOUS CHEMICAL WASTE At 53% reduction per lab employee, we are just short of our 2018 goal of 60% *Carbon and Electricity baselines are reported based on the original Carbon Disclosure Project (CDP) reporting year; 2013 information noted above corresponds to June 2013 — May 2014 reporting year. 2 0 1 6 A N N U A L R E P O R T 2 5 < MENU >< MENU >SUPPORTING PATIENT COMMUNITIES Regeneron is committed to supporting patients with serious diseases and ensuring that patients are able to access the medicines they need. BRINGING ATTENTION TO A DEBILITATING DISEASE The Understand AD national initiative aims to increase awareness and understanding of atopic dermatitis (AD), in partnership with the National Eczema Association (NEA) and the Dermatology Nurses’ Association (DNA). The most common form of eczema, AD is a chronic inflammatory disease with symptoms often appearing as a rash on the skin. The initiative offers a glimpse into the daily struggle of life with AD and connects people to helpful resources such as the NEA. EDUCATION & AWARENESS FOR CHOLESTEROL MANAGEMENT In 2016, Regeneron and Sanofi committed to support the American Heart Association’s cholesterol education program, Check.Change.Control.Cholesterol, which aims to drive millions of Americans to better cholesterol management. The three-year program will engage patients, caregivers and healthcare practitioners, and provide valuable educational resources to communities across the country. PARTNERING TO FIGHT A RARE DISEASE Fibrodysplasia ossificans progressiva (FOP) is an exceedingly rare disease in which bone forms in the muscle and connective tissue. Over time, people living with FOP gradually lose the ability to move and even breathe as their rib cage loses flexibility. When Regeneron discovered that the protein Activin-A played a role in triggering FOP, we made it a priority to reach out to the small but strong FOP community to understand their daily struggles and treatment expectations. Since then, organizations such as the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) and the National Organization for Rare Disorders (NORD) have been integral to informing the development of our investigational candidate REGN2477 and to helping us keep patient needs front and center in our efforts. We’ve also given back to the FOP community with grants and by sharing our genetically modified FOP mouse model with other scientists to advance basic and translational research. Through these mutually supportive relationships, we have come together with the FOP community to fight this devastating disease. OUR MEDICINES: ENSURING ACCESS AND EDUCATION 2 0 1 6 A N N U A L R E P O R T 2 6 < MENU >< MENU >NURTURING OUR HIGH-ENGAGEMENT, HIGH-INTEGRITY CULTURE Creating a one-of-a-kind culture of collaboration and holding ourselves to the highest ethical standards are essential to our company vision. We believe in the power of original thinking. As a company built on breakthrough ideas, we foster collaboration, curiosity, openness, and inspiration from within — and we do it with an unwavering commitment to ethics. Each of us plays an active role in transforming people’s lives through our work, and we pursue this goal with passion and vigor, never losing focus on integrity. Regeneron’s people make us who we are, and we are truly more than a company — we’re a community. 93% of employees say – Great Places to Work® Survey “I’m proud to tell others I work here” “Our culture is rooted in doing the right thing, even when it may not be easy. In the long run, acting ethically and with integrity is essential to the safety of our patients and to our business success.” — Leonard S. Schleifer, MD, PhD, President and CEO #1 Biopharma Employer, Science 3RD Most Innovative Company, Forbes 3RD CONSECUTIVE YEAR 100 Best Companies to Work For, Fortune WORLD’S BEST World’s Best CEOs, Barron’s R+D Team of the Year, Scrip 2 0 1 6 A N N U A L R E P O R T 2 7 < MENU >< MENU >FORWARD-LOOKING STATEMENTS This Annual Report includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. (“Regeneron” or the “Company”), and actual events or results may differ materially from these forward-looking statements. Words such as “anticipate,” “expect,” “intend,” “plan,” “believe,” “seek,” “estimate,” variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of Regeneron’s products, product candidates, and research and clinical programs now underway or planned, including without limitation EYLEA® (aflibercept) Injection, PRALUENT® (alirocumab) Injection, DUPIXENT® (dupilumab) Injection, KEVZARA® (sarilumab) Injection, fasinumab, suptavumab (REGN2222), REGN2810 (antibody to programmed cell death protein 1), Regeneron’s earlier-stage product candidates, Regeneron’s immuno-oncology program, and the use of human genetics in Regeneron’s research process; the extent to which the results from Regeneron’s research programs or preclinical testing may lead to advancement of product candidates to clinical trials or therapeutic applications; unforeseen safety issues resulting from the administration of products and product candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s product candidates in clinical trials; the likelihood and timing of possible regulatory approval and commercial launch of Regeneron’s late-stage product candidates and new indications for marketed products, including without limitation EYLEA, PRALUENT, DUPIXENT, KEVZARA, fasinumab, suptavumab, and REGN2810; risks associated with intellectual property of other parties and pending or future litigation relating thereto, including without limitation the patent litigation relating to Praluent, the permanent injunction granted by the United States District Court for the District of Delaware that, if upheld on appeal, would prohibit Regeneron and Sanofi from marketing, selling, or commercially manufacturing Praluent in the United States, the outcome of any appeals regarding such injunction, the ultimate outcome of such litigation, and the impact any of the foregoing may have on Regeneron’s business, prospects, operating results, and financial condition; the likelihood and timing of achieving any of the anticipated milestones described in this Annual Report; ongoing regulatory obligations and oversight impacting Regeneron’s marketed products (such as EYLEA, PRALUENT, and DUPIXENT), research and clinical programs, and business, including those relating to patient privacy; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron’s ability to continue to develop or commercialize Regeneron’s products and product candidates; competing drugs and product candidates that may be superior to Regeneron’s products and product candidates; uncertainty of market acceptance and commercial success of Regeneron’s products and product candidates; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; the ability of Regeneron’s collaborators, suppliers, or other third parties to perform filling, finishing, packaging, labelling, distribution, and other steps related to Regeneron’s products and product candidates; coverage and reimbursement determinations by third-party payers, including Medicare and Medicaid; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its sales or other financial projections or guidance and changes to the assumptions underlying those projections or guidance; and the potential for any license or collaboration agreement, including Regeneron’s agreements with Sanofi, Bayer, and Teva Pharmaceutical Industries Ltd. (or their respective affiliated companies, as applicable), to be cancelled or terminated without any further product success. A more complete description of these and other material risks can be found in Regeneron’s filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the fiscal year ended December 31, 2016, including in the section thereof captioned “Item 1A. Risk Factors.” Any forward-looking statements are made based on management’s current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update publicly any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise. 2 0 1 6 A N N U A L R E P O R T 2 8 < MENU >< MENU >CORPORATE INFORMATION Common Stock and Related Matters Our Common Stock is traded on The NASDAQ Global Select Market under the symbol “REGN.” Our Class A Stock is not publicly quoted or traded. The following table sets forth, for the periods indicated, the range of high and low sales prices for the Common Stock as reported by The NASDAQ Global Select Market. 2014 First Quarter Second Quarter Third Quarter Fourth Quarter HIGH $352.49 $320.00 $369.31 $437.64 LOW $262.97 $269.50 $285.06 $320.06 2015 First Quarter Second Quarter Third Quarter Fourth Quarter HIGH $495.50 $544.00 $605.93 $592.59 LOW $393.00 $433.47 $435.52 $448.10 2016 First Quarter Second Quarter Third Quarter Fourth Quarter HIGH $532.91 $433.93 $443.99 $452.96 LOW $348.96 $329.09 $348.43 $325.35 As of April 13, 2017, there were 193 shareholders of record of our Common Stock and 18 shareholders of record of our Class A Stock. The closing sales price for the Common Stock on that date was $370.37. We have never paid cash dividends and do not anticipate paying any in the foreseeable future. SEC Form 10-K A copy of our 2016 Annual Report on Form 10-K filed with the Securities and Exchange Commission (which accompanies and forms part of this 2016 Annual Report to Shareholders) is available without charge from the Regeneron Investor Relations Department. 2017 Annual Shareholder Meeting The 2017 Annual Shareholder Meeting will be held on Friday, June 9, 2017, at 10:30 a.m. at the Westchester Marriott Hotel, 670 White Plains Road, Tarrytown, New York 10591. Shareholders’ Inquiries Inquiries relating to stock transfer or lost certificates and notices of changes of address should be directed to our Transfer Agent, American Stock Transfer & Trust Co., 6201 15th Avenue, Brooklyn, New York 11219, (800) 937-5449, . General information regarding the Company, recent press releases and SEC filings are available on our website at or can be obtained by contacting our Investor Relations Department at (914) 847-7741. Corporate Office 777 Old Saw Mill River Road Tarrytown, New York 10591-6707 (914) 847-7400 Transfer Agent and Registrar American Stock Transfer & Trust Co. 6201 15th Avenue Brooklyn, New York 11219 Independent Registered Public Accounting Firm PricewaterhouseCoopers LLP REGENERON®, Science to Medicine® and the following are registered trademarks of Regeneron Pharmaceuticals, Inc.: ARCALYST®, EYLEA®, VelociGene®, and VelocImmune®. Praluent®, Dupixent®, and Kevzara® are registered trademarks of Sanofi. 2 0 1 6 A N N U A L R E P O R T 2 9 < MENU >< MENU > REFERENCES 1. Osteoarthritis Fact Sheet. CDC Website. Available at: . Accessed March 30, 2017. 2. Semanik P, Chang RW, Dunlop DD. PMR. 2012;4(50):S37–S44. 3. National Center for Health Statistics. Health, United States, 2015. Hyattsville, MD, 2016. 2 0 1 6 A N N U A L R E P O R T 3 0 < MENU < MENU 

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