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Ardelyx, Inc.

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FY2021 Annual Report · Ardelyx, Inc.
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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
____________________________________________________

FORM 10-K
____________________________________________________

(Mark One)

x

o

ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(D) OF THE SECURITIES EXCHANGE ACT OF 1934

TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(D) OF THE SECURITIES EXCHANGE ACT OF 1934

FOR THE FISCAL YEAR ENDED DECEMBER 31, 2021

OR

FOR THE TRANSITION PERIOD FROM                     TO                     
COMMISSION FILE NUMBER 001-36485
____________________________________________________

ARDELYX, INC.

(EXACT NAME OF REGISTRANT AS SPECIFIED IN ITS CHARTER)
____________________________________________________

DELAWARE

(STATE OR OTHER JURISDICTION OF

INCORPORATION OR ORGANIZATION)

26-1303944

(I.R.S. EMPLOYER

IDENTIFICATION NO.)

400 FIFTH AVE., SUITE 210, WALTHAM, MASSACHUSETTS 02451
(ADDRESS OF PRINCIPAL EXECUTIVE OFFICES, INCLUDING ZIP CODE)

(510) 745-1700
(REGISTRANT’S TELEPHONE NUMBER, INCLUDING AREA CODE)
____________________________________________________

Securities registered pursuant to Section 12(b) of the Act:

Title of Each Class

Common Stock, par value $0.0001 per share

Trading Symbol(s)

ARDX

Name of Each Exchange on Which Registered

The Nasdaq Global Market

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes o No x

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes o  No x

Securities registered pursuant to Section 12(g) of the Act: None
____________________________________________________

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 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 x No o

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation 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 x No o
Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See the
definition of “large accelerated filer”, “accelerated filer”, “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer

Non-accelerated filer

x

o

Accelerated filer

Small reporting company

Emerging growth company

o

o

o

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. o
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section
404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. x

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes o No x
The aggregate market value of the Registrant’s common stock held by non-affiliates of the Registrant as of the last business day of the Registrant’s most recently completed second fiscal quarter,
June 30, 2021, based on the last reported sales price of the Registrant’s common stock on the Nasdaq Global Market of $7.58 per share was $768,831,274.
The number of shares of Registrant’s Common Stock outstanding as of February 23, 2022, was 130,294,254.

DOCUMENTS INCORPORATED BY REFERENCE:

Portions of the Registrant’s Definitive Proxy Statement for its 2022 Annual Meeting of Stockholders, which will be filed with the Commission within 120 days of December 31, 2021, the close of
the Registrant’s 2021 fiscal year, are incorporated by reference into Part III of this Report.

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ARDELYX, INC.
FORM 10-K FOR THE FISCAL YEAR ENDED December 31, 2021
TABLE OF CONTENTS

Item 1.

Item 1A.

Item 1B.

Item 2.

Item 3.

Item 4.

Item 5.

Item 6.

Item 7.

Business

Risk Factors

Unresolved Staff Comments

Properties

Legal Proceedings

Mine Safety Disclosures

PART I

PART II

Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

[Reserved]

Management’s Discussion and Analysis of Financial Condition and Results of Operations

Item 7A.

Quantitative and Qualitative Disclosures About Market Risk

Financial Statements and Supplementary Data

Changes in and Disagreements with Accountants on Accounting and Financial Disclosure

Controls and Procedures

Other Information

Disclosure Regarding Foreign Jurisdictions that Prevent Inspection

PART III

Directors, Executive Officers and Corporate Governance

Executive Compensation

Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters

Certain Relationships and Related Transactions, and Director Independence

Principal Accounting Fees and Services

PART IV

Exhibits, Financial Statement Schedules

Form 10-K Summary

Item 8.

Item 9.

Item 9A.

Item 9B.

Item 9C.

Item 10.

Item 11.

Item 12.

Item 13.

Item 14.

Item 15.

Item 16.

Signatures

Page

3

18

52

52

52

53

54

54

54

67

69

102

102

104

104

105

105

105

105

105

106

106

109

NOTE REGARDING FORWARD-LOOKING STATEMENTS

Unless  the  context  requires  otherwise,  in  this  Annual  Report  on  Form  10-K  the  terms  “Ardelyx”,  “we,”  “us,”  “our”  and  “the  Company”  refer  to
Ardelyx, Inc.

This Annual Report on Form 10-K contains forward-looking statements that involve risks and uncertainties. Any statements contained herein that are not
statements of historical facts may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by terminology
such as “aim,” “anticipate,” “assume,” “believe,” “continue,” “could,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “predict,”
“potential,”  “positioned,”  “seek,”  “should,”  “target,”  “will,”  “would,”  and  other  similar  expressions  that  are  predictions  of  or  indicate  future  events  and
future trends, or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements
about:

•

our expectations regarding our plans to commence the commercialization of IBSRELA (tenapanor) in the U.S. for the treatment of irritable bowel
syndrome with constipation (“IBS-C”) in April 2022;

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•

•

•

•

•

•

•

•

•

our expectations regarding the timing of our receipt of a decision from the Office of New Drugs (“OND”) with respect to our appeal of the Appeal
Denied Letter (“ADL”) received from the Office of Cardiology, Hematology, Endocrinology and Nephrology (“OCHEN”) of the United States
("U.S.) Food and Drug Administration (“FDA”) relating to our New Drug Application (“NDA”) for tenapanor for the control of serum phosphorus
in adult patients with chronic kidney disease (“CKD”) on dialysis (the “Hyperphosphatemia Indication”);

our  expectations  regarding  our  plans  for  our  participation  in  the  commercialization  of  XPHOZAH (tenapanor)  for  the  control  of  serum
phosphorus in adult patients with CKD on dialysis in the U.S., if approved;

® 

our  expectations  regarding  our  Japanese  collaboration  partner’s  plans  to  file  a  marketing  authorization  application  with  the  Japanese
Pharmaceuticals and Medical Devices Agency (“PMDA”) in the second half of 2022;

our expectations regarding the potential market size and the size of the patient populations for IBSRELA and XPHOZAH;

our plans with respect to RDX013 and RDX020;

the implementation of our business model and strategic plans for our business, product candidates and technology;

estimates of our expenses, future revenue, capital requirements, our needs for additional financing and our ability to obtain additional capital;

our financial performance; and

developments and projections relating to our competitors and our industry.

Factors that could cause actual results or conditions to differ from those anticipated by these and other forward-looking statements include those more fully
described  in  the  “ITEM  1A.  RISK  FACTORS”  section  and  elsewhere  in  this  Annual  Report  on  Form  10-K.  Except  as  required  by  law,  we  assume  no
obligation to update any forward-looking statement publicly, or to revise any forward-looking statement to reflect events or developments occurring after
the date of this Annual Report on Form 10-K, even if new information becomes available in the future. Thus, you should not assume that our silence over
time means that actual events are bearing out as expressed or implied in any such forward-looking statement.

SUMMARY OF PRINCIPAL RISKS ASSOCIATED WITH OUR BUSINESS

• We have a limited operating history, have incurred significant losses since our inception and will incur losses in the future, which makes it difficult

for us to assess our future viability.

• Although our financial statements have been prepared on a going concern basis, our current level of cash and investments alone is not sufficient to

meet our operating plans for the next twelve months, raising substantial doubt regarding our ability to continue as a going concern.

• We will require substantial additional financing to achieve our goals, including our goals of commercializing IBSRELA beginning in April 2022
and pursuing a formal dispute resolution (“FDR”) process in response to the CRL received from the FDA relating to our NDA for tenapanor for
the Hyperphosphatemia Indication and the inability to access necessary capital when needed on acceptable terms, or at all, could force us to delay,
limit, reduce or terminate our efforts to commercialize IBSRELA or to seek and obtain tenapanor for the Hyperphosphatemia Indication.

• Our failure to meet the continued listing requirements of The Nasdaq Global Market ("Nasdaq") could result in a de-listing of our common stock.
On February 28, 2022, we received a letter from Nasdaq indicating that we have failed to comply with the minimum bid price requirement of
Nasdaq  Listing  Rule  5550(a)(2).  Nasdaq  Listing  Rule  5550(a)(2)  requires  that  companies  listed  on  the  Nasdaq  Capital  Market  maintain  a
minimum closing bid price of at least $1.00 per share. Under Nasdaq Listing Rule 5810(c)(3)(A), we have a 180 calendar day grace period to
regain compliance by meeting the continued listing standard. To regain compliance, the closing bid price of the Company’s common stock must
meet or exceed $1.00 per share for a minimum of ten consecutive business days during this grace period. We are monitoring the bid price of our
common stock and will consider options available to us to achieve compliance. There can be no assurances that we will be successful in restoring
our compliance with the Nasdaq listing requirements.

• We have never generated any revenue from product sales and may never be profitable.

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• We are substantially dependent on the successful launch and commercialization of IBSRELA for IBS-C, and there is no guarantee that we will
achieve sufficient market acceptance for IBSRELA; secure adequate coverage and reimbursement for IBSRELA; or generate sufficient revenue
from product sales of IBSRELA .

• Our success is also dependent upon our ability to obtain regulatory approval for tenapanor for the control of serum phosphorus in adult patients

with CKD on dialysis, and there can be no assurances that we will be successful in obtaining such regulatory approval.

•

•

Even if we are successful in obtaining regulatory approval for tenapanor for control of serum phosphorus in adult patients with CKD on dialysis,
the expense and time required to do so could adversely impact our ability to successfully commercialize XPHOZAH for the Hyperphosphatemia
Indication.

IBSRELA, and/or XPHOZAH, if approved and commercialized, may cause undesirable side effects or have other properties that could limit the
commercial success of the product.

• We  have  no  prior  experience  in  the  marketing,  sale  and  distribution  of  pharmaceutical  products;  and  there  are  significant  risks  in  building  and

managing a sales organization.

•

Third-party  payor  coverage  and  reimbursement  status  of  newly-commercialized  products  are  uncertain.  Failure  to  obtain  or  maintain  adequate
coverage and reimbursement for IBSRELA and XPHOZAH, if approved, could limit our ability to market those products and decrease our ability
to generate revenue.

• We rely completely on third parties to manufacture IBSRELA, XPHOZAH and RDX013. If they are unable to comply with applicable regulatory
requirements,  unable  to  source  sufficient  raw  materials,  experience  manufacturing  or  distribution  difficulties  or  are  otherwise  unable  to
manufacture sufficient quantities to meet demand, our commercialization of IBSRELA, and XPHOZAH, if approved and commercialized, and our
development efforts for tenapanor or RDX013 may be materially harmed.

• Our operating activities may be restricted as a result of covenants related to the indebtedness under our loan and security agreement and we may

be required to repay the outstanding indebtedness in an event of default, which could have a materially adverse effect on our business.

NOTE REGARDING TRADEMARKS

®

®

ARDELYX , IBSRELA , and XPHOZAH are trademarks of Ardelyx. All other trademarks, trade names and service marks appearing in this Annual
Report on Form 10-K are the property of their respective owners.

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ITEM 1.    BUSINESS

Company Overview

We  are  a  biopharmaceutical  company  founded  with  a  mission  to  discover,  develop  and  commercialize  innovative  first-in-class  medicines  that  meet
significant unmet medical needs. This includes adult patients with irritable bowel syndrome with constipation (“IBS-C”), adult patients with chronic kidney
disease  (“CKD”)  on  dialysis  suffering  from  elevated  serum  phosphorus,  or  hyperphosphatemia;  and  adult  patients  with  CKD  and/or  heart  failure  with
elevated serum potassium, or hyperkalemia.

Since  commencing  operations  in  October  2007,  substantially  all  our  efforts  have  been  dedicated  to  our  research  and  development  (“R&D”)  activities,
including  developing  tenapanor  and  developing  our  proprietary  drug  discovery  and  design  platform.  We  have  not  generated  any  revenues  from  product
sales. As of December 31, 2021, we had an accumulated deficit of $712.9 million.

We expect to continue to incur substantial operating losses for the foreseeable future as we prepare for commercialization of IBSRELA  (tenapanor)  in
April of this year, seek to gain approval for XPHOZAH (tenapanor) for the control of serum phosphorus in adult patients with CKD on dialysis; prepare
for the potential commercialization of XPHOZAH, if approved; incur manufacturing and development cost for, tenapanor; and incur development costs for
RDX013.  To  date,  we  have  funded  our  operations  from  the  sale  and  issuance  of  common  stock  and  convertible  preferred  stock,  funds  from  our
collaboration partnerships, which includes license fees, milestones and product supply revenue, as well as funds from our loan agreements with our lenders.

® 

®

Our Product Pipeline

IBSRELA for IBS-C

Our  unique  discovery  platform  and  deep  understanding  of  the  primary  mechanism  of  sodium  transport  in  the  intestine  resulted  in  our  discovery  and
development  of  IBSRELA,  a  first-in-class,  FDA  approved,  sodium  hydrogen  exchanger  3  ("NHE3")  inhibitor  for  the  treatment  of  IBS-C  in  adults.
IBSRELA  acts  locally  in  the  gut  and  is  minimally  absorbed.  By  inhibiting  NHE3,  IBSRELA  exerts  a  triple  action  mechanism.  First,  it  blocks  dietary
sodium absorption, leading to increased intestinal transit time and softer stool to address constipation. Second, it decreases intestinal permeability to reduce
abdominal pain, and, third, it decreases visceral hypersensitivity to reduce abdominal pain. The triple action mechanism of IBSRELA is differentiated from
existing therapies and has been shown to provide significant improvement in abdominal pain, bloating, and constipation – with a quick onset of action and
sustained  efficacy.  In  clinical  trials,  treatment  with  IBSRELA  has  been  demonstrated  to  result  in  improved  quality  of  life  versus  placebo  and  patient
treatment satisfaction.

We plan to launch IBSRELA in the U.S. in April 2022.

IBS-C is a gastrointestinal disorder characterized by both abdominal pain and altered bowel movements, estimated to affect 11 million people in the U.S.
IBS-C is associated with significantly impaired quality of life, reduced productivity, and substantial economic burden. The introduction of new agents over
the last decade has led to an established prescription ("RX") treated market with 9,000 writers accounting for 50% of the RXs. Despite the active use of
GCC agonist therapies, 83% of Health Care Providers ("HCPs") report a significant unmet need for new therapies, and report that approximately 35% of
the patients currently under their care do not adequately respond to the available treatments. When presented with the IBSRELA product profile, 75% of
HCPs respond favorably, with the efficacy profile and novel method of action rated as the most compelling aspects of the product profile.

In  preparation  for  our  commercial  launch  of  IBSRELA,  we  have  built  a  commercial  organization  highly  experienced  in  launching  novel  therapies  into
specialty  areas.  The  established  nature  of  the  market,  limited  number  of  players,  concentration  of  prescribers,  recognized  unmet  need,  and  favorable
response to the novel mechanism IBSRELA product profile enable a targeted promotional effort centered on the 9,000 health care providers that account
for 50% of IBS-C prescriptions. Central to the go to market strategy is a highly experienced specialty sales force, many with existing relationships across
their GI target base, full company engagement, and innovative peer-to-peer and digital initiatives leveraging the rapidly evolving market dynamics in how
HCPs receive information and interact with industry.

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With a concentrated promotional focus on patients currently being managed for IBS-C by high writing HCPs - in contrast to the DTC centered, market
building approach taken by the existing GCC agonists - competition for IBSRELA will come largely from the four prescription products indicated for IBS-
C: Linzess (linaclotide); Amitiza (lubiprostone); Trulance (plecanatide) and Zelnorm (tegaserod). Additionally, over the counter products are commonly
used to treat the constipation component of IBS-C, both alone, and in combination with the IBS-C indicated RX therapies.

We have established commercial agreements with Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. (“Fosun Pharma”) in China and Knight
Therapeutics, Inc. (“Knight”) in Canada for IBSRELA for IBS-C. Knight is currently marketing IBSRELA in Canada.

Development Candidate XPHOZAH: A New Approach for The Control of Serum Phosphorus in Adult Patients with CKD on Dialysis

XPHOZAH  is  a  first-in-class  medicine  being  developed  for  the  control  of  serum  phosphorus  in  adult  patients  with  CKD  on  dialysis.  XPHOZAH  has  a
unique mechanism of action and acts locally in the gut to inhibit NHE3. This results in the tightening of the epithelial cell junctions, thereby significantly
reducing paracellular uptake of phosphate, the primary pathway of phosphate absorption. If approved, XPHOZAH would be the first therapy for phosphate
management that blocks phosphorus absorption at the primary site of uptake. It is not a phosphate binder.

In June 2020, we submitted a new drug application ("NDA") to the U.S. Food and Drug Administration (“FDA”) for tenapanor for the control of serum
phosphorus in adult patients with CKD on dialysis. The NDA was supported by three Phase 3 trials involving over 1,000 adult patients that evaluated the
use of tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis, with two trials evaluating tenapanor as monotherapy and one
trial  evaluating  tenapanor  as  part  of  a  dual  mechanism  approach  with  phosphate  binders.  All  three  Phase  3  trials  met  their  primary  and  key  secondary
endpoints.

On July 28, 2021, we received a Complete Response Letter ("CRL") from the FDA’s Division of Cardiology and Nephrology (the “Division”) regarding
our NDA for tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis. According to the CRL, while the Division agrees “that
the  submitted  data  provide  substantial  evidence  that  tenapanor  is  effective  in  reducing  serum  phosphorus  in  adult  patients  with  CKD  on  dialysis,”  the
Division characterizes the magnitude of the treatment effect as “small and of unclear clinical significance.” Following an End-of-Review Type A meeting
(“End of Review Meeting”) in October 2021, with the Division, we submitted a Formal Dispute Resolution Request (“FDRR”) in December 2021 to the
Office of Cardiology, Hematology, Endocrinology and Nephrology (“OCHEN”). The FDRR was focused on demonstrating that the data submitted in the
NDA supported the clinical significance of the treatment effect of tenapanor.

On February 4, 2022, we received an Appeal Denied Letter (“ADL”) from OCHEN. On February 18, 2022, we submitted an appeal of the ADL to the
FDA’s Center for Drug Evaluation and Research, Office of New Drugs (“OND”). If accepted, we expect a decision on the appeal to the OND in April 2022.
While  the  CRL  noted  that  in  order  for  the  NDA  to  be  approved,  we  need  to  conduct  an  additional  adequate  and  well-controlled  trial  demonstrating  a
clinically relevant treatment effect on serum phosphorus or an effect on the clinical outcome thought to be caused by hyperphosphatemia in adult patients
with CKD on dialysis, the ADL provided a potential additional path forward involving the resubmission of the NDA (without conducting an additional
trial) with a number of new analyses of each of our Phase 3 clinical trials; an assessment of tenapanor’s benefits and risks; and a proposal of how to label
tenapanor for prescribers. There can be no assurances that the Formal Dispute Resolution (“FDR”) process will result in approval of our NDA, or in a clear
path to resubmission of our NDA that is achievable in terms of clinical endpoints, time and cost.

RDX013 Program: Small Molecule for Treating Hyperkalemia

We  are  also  advancing  a  small  molecule  potassium  secretagogue  program,  RDX013,  for  the  potential  treatment  of  hyperkalemia.  Hyperkalemia  is  a
common  problem  in  patients  with  heart  and  kidney  disease,  particularly  in  patients  taking  customary  blood  pressure  medications  known  as  renin-
angiotensin-aldosterone  system  (“RAAS”)  inhibitors.  RDX013  is  a  novel  mechanism  agent  designed  to  target  the  underlying  biological  mechanisms  of
potassium secretion to lower elevated potassium. While currently available therapies are all ion exchange agents, RDX013 is a first in class secretagogue
with  demonstrated  proof  of  concept  in  a  Phase  2  dose  ranging  study  evaluating  the  safety  and  pharmacodynamics  of  RDX013  in  adult  patients  with
hyperkalemia.  The  next  steps  for  RDX013  will  be  determined  based  on  final  analyses  of  the  Phase  2  results,  continued  formulation  development,  and
sufficient financial resources.

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RDX020 Program: Small molecule for Treating Metabolic Acidosis

We  have  an  ongoing  discovery  program  targeting  the  inhibition  of  bicarbonate  exchange  inhibitor  for  the  treatment  of  metabolic  acidosis,  a  highly
prevalent comorbidity in CKD patients that is strongly correlated with disease progression and adverse outcomes. We have identified lead compounds that
are potent, selective and proprietary inhibitors of bicarbonate secretion. Our research organization was eliminated as part of our October 2021 restructuring,
and therefore, we currently expect to continue to advance this discovery program utilizing third-party resources managed by internal non-clinical expertise.

Our Commercial Strategy

We have developed a portfolio of novel products to address unmet medical needs across gastrointestinal and cardiorenal therapeutic areas and intend to
commercialize  our  products  in  the  United  States.  We  have  established  a  high-quality  commercial  organization  highly  experienced  in  bringing  novel
products to our customers, including patients, payors and healthcare providers. Our commercial capabilities, including marketing, access, patient services
and  sales  are  designed  to  support  our  commercialization  of  IBSRELA,  and  will  enable  the  commercialization  of  XPHOZAH,  if  approved.  We  have
executed ex-U.S. collaborations with established industry leaders to efficiently bring XPHOZAH for hyperphosphatemia and IBSRELA for IBS-C to adult
patients in specific territories outside of the Unites States.

We continue to evaluate our strategy for the commercialization of IBSRELA and XPHOZAH in other ex-U.S. territories.

Collaboration Partners

We have exclusive rights to tenapanor in the U.S. and we have established agreements with Kyowa Kirin Co., Ltd. ("KKC”) in Japan, Fosun Pharma in
China and Knight in Canada for the development and commercialization of tenapanor for certain indications in their respective territories.

Knight has exclusive rights for the development, commercialization and distribution of tenapanor in Canada for hyperphosphatemia and IBS-C. In March
2021, Knight announced the commercial availability of IBSRELA in Canada, following its approval by Health Canada in April 2020. Under the terms of
the  agreement  with  Knight,  we  received  a $2.3  million  nonrefundable,  one-time  upfront  payment  in  March  2018  and  are  eligible  to  receive  additional
development and commercialization milestone payments worth up to $17.4 million. We are also eligible to receive royalties throughout the term of the
agreement, and a transfer price for manufacturing services.

KKC  has  exclusive  rights  for  the  development,  commercialization  and  distribution  of  tenapanor  in  Japan  for  cardiorenal  indications.  In  April  2021,  we
announced that KKC had commenced four phase 3 clinical trials in Japan evaluating tenapanor for hyperphosphatemia. The phase 3 clinical trials consist of
a  multi-center,  randomized,  double-blind,  placebo-controlled,  parallel-group  comparative  study;  a  phosphate  binder-combination  parallel-group
comparative study; an open-label, single-arm study evaluating adult hyperphosphatemia patients on peritoneal dialysis; and a long-term study evaluating
serum phosphorus in adult patients who switch from one or more phosphate binders to tenapanor. KKC has publicly announced its plans to file a marketing
authorization application with the Japanese Pharmaceuticals and Medical Devices Agency (“PMDA”) in the second half of 2022. Under the terms of the
agreement with KKC, we received a $30.0 million upfront payment from KKC, and we may be entitled to receive up to $55.0 million in total development
milestones,  of  which  $10.0  million  has  been  received  and  recognized  as  revenue  as  of  December  31,  2021,  and  approximately  ¥8.5  billion  for
commercialization milestones, or approximately $73.9 million at the currency exchange rate on December 31, 2021, as well as high-teen royalties on net
sales throughout the term of the agreement.

Fosun Pharma has exclusive rights for the development and commercialization for the development, commercialization and distribution of tenapanor in
China  for  both  hyperphosphatemia  and  IBS-C.  Under  the  terms  of  the  Fosun  Agreement,  we  received  $12.0  million  in  upfront  license,  and  we  may  be
entitled to additional development and commercialization milestones of up to $110.0 million, as well as reimbursement of cost plus a reasonable overhead
for the supply of product and tiered royalties on net sales ranging from the mid-teens to 20%.

Corporate Restructurings

On July 29, 2021, our Board of Directors approved, and on August 2, 2021, we began implementing a restructuring plan to better align our workforce and
anticipated commercial and development spend with our capital resources and the needs of our business following the receipt of the CRL for tenapanor for
the  control  of  serum  phosphorus  in  adult  patients  with  CKD  on  dialysis.  Under  the  restructuring  plan,  we  reduced  our  workforce  by  83  employees
(approximately 33%). Impacted employees

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received cash payments equal to their base pay for a notice period of sixty (60) days and Company funded COBRA premiums through such notice period.

Following the conclusion of our End of Review Meeting with the FDA, in October 2021, we began to implement an additional restructuring plan to further
reduce operating costs and better align our workforce with the needs of our business. Under the restructuring plan, we planned to reduce our workforce by
approximately 100 of our remaining employees (approximately 60%). The impacted employees received notice that their positions would be eliminated on
December 15, 2021.

On November 30, 2021, we announced plans to launch IBSRELA, our approved treatment for IBS-C in adults. In connection with the planned launch of
IBSRELA, which we currently expect to occur in April 2022, we retained 28 of the employees whose positions were originally planned to be eliminated as
part of the restructuring plan, thereby reducing the number of employees impacted by the restructuring plan to 72. The restructuring plan, which resulted in
the elimination of our research organization was substantially completed in December 2021.

Employees who were impacted by the restructurings were eligible to receive severance benefits and Company funded COBRA premiums, contingent upon
an impacted employee’s execution (and non-revocation, where applicable) of a separation agreement, which included a general release of claims against us.
In  connection  with  the  restructurings,  we  have  incurred  restructuring  charges  of  $6.2  million,  which  were  recorded  during  the  twelve  months  ended
December 31, 2021, related to one-time employee termination benefits, including severance payments and other employee-related costs. Of these charges,
$2.7  million  was  recorded  in  research  and  development  expenses,  and  $3.5  million  was  recorded  in  general  and  administrative  expense  in  the
accompanying statements of operations and comprehensive loss. Most of the cash payments related to the reduction in workforce were disbursed during the
twelve months ended December 31, 2021. We have reported the remaining estimated liability of $0.5 million as accrued compensation and benefits in our
Balance Sheet as of December 31, 2021.

CORPORATE DEVELOPMENT

In July 2020, we filed a Form S-3 registration statement, which became effective in August 2020, containing (i) a base prospectus for the offering, issuance
and sale by us of up to a maximum aggregate offering price of $250.0 million of our common stock, preferred stock, debt securities, warrants and/or units,
from  time  to  time  in  one  or  more  offerings;  and  (ii)  a  prospectus  supplement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a  maximum  aggregate
offering  price  of  $100.0  million  of  our  common  stock  that  may  be  issued  and  sold,  from  time  to  time,  under  an  Open  Market  Sales  Agreement  with
Jefferies LLC, as sales agent, deemed to be “at-the-market offerings” (the "2020 Open Market Sales Agreement"). Pursuant to the 2020 Open Market Sales
Agreement, Jefferies, as sales agent, received a commission of up to 3.0% of the gross sales price for shares of common stock sold under the 2020 Open
Market Sales Agreement. We sold a cumulative total of 23.3 million shares and received gross proceeds of $100.0 million at a weighted average sales price
of approximately $4.30 per share under the 2020 Open Market Sales Agreement.

In  August  2021,  we  filed  an  additional  prospectus  supplement  under  the  Registration  Statement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a
maximum  aggregate  offering  price  of  $150.0  million  of  our  common  stock  that  may  be  issued  and  sold,  from  time  to  time,  under  an  additional  sales
agreement  we  entered  into  with  Jefferies  (the  "2021  Open  Market  Sales  Agreement"),  pursuant  to  which  we  may,  from  time  to  time,  sell  up  to  $150.0
million in shares of our common stock through Jefferies. We are not required to sell shares under the 2021 Open Market Sales Agreement. Pursuant to the
2021 Open Market Sales Agreement, Jefferies, as our sales agent, receives a commission of up to 3.0% of the gross sales price for shares of common stock
sold under the 2021 Open Market Sales Agreement. As of December 31, 2021, we have sold 15.7 million shares and received gross proceeds of $25.0
million at a weighted average sales price of approximately $1.60 per share under the 2021 Open Market Sales Agreement.

In  December  2019,  we  completed  an  underwritten  public  offering  of  23.0  million  shares  of  common  stock,  resulting  in  the  receipt  of  aggregate  gross
proceeds  of  approximately  $143.8  million,  less  underwriting  discounts,  commissions  and  offering  expenses  totaling  approximately  $8.9  million,  which
resulted in net proceeds of approximately $134.9 million.

In November 2019, we enhanced our strategic partnership with KKC by entering into a Stock Purchase Agreement, pursuant to which we sold to KKC an
aggregate of 2.9 million shares of our common stock for aggregate gross proceeds of approximately $20.0 million.

As of December 31, 2021, we had cash, cash equivalents and investments totaling $116.7 million.

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INTELLECTUAL PROPERTY

Our commercial success depends in part on our ability to obtain and maintain proprietary protection for our drug candidates, manufacturing and process
discoveries, and other know-how, to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.
Our policy is to seek to protect our intellectual property by, among other methods, filing U.S. and foreign patent applications related to our proprietary
technology and inventions that are important to the development and operation of our business. We also rely on trade secrets and careful monitoring of our
proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

The  patent  positions  of  biopharmaceutical  companies  like  us  are  generally  uncertain  and  involve  complex  legal,  scientific  and  factual  questions.  In
addition,  the  coverage  claimed  in  a  patent  application  can  be  significantly  reduced  before  the  patent  is  issued,  and  its  scope  can  be  reinterpreted  after
issuance. Consequently, we do not know whether any of our product candidates will be protectable or remain protected by enforceable patents. We cannot
predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of our issued
patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third
parties. If third parties prepare and file patent applications in the United States that also claim technology or therapeutics to which we have rights, we may
have to participate in interference proceedings in the U.S. Patent and Trademark Office (the “USPTO”) to determine priority of invention, which would
result in substantial costs to us even if the eventual outcome is favorable to us.

The term of individual patents depends upon the legal term of the patents in countries in which they are obtained. In most countries, including the United
States, the patent term is generally 20 years from the earliest date of filing a non-provisional patent application in the applicable country. In the U.S., a
patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in
examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common
inventor and having an earlier expiration date.

In addition, in the United States, the Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of a U.S. patent as partial
compensation for the patent term lost during the FDA regulatory review process occurring while the patent is in force. A patent extension cannot extend the
remaining term of a patent beyond a total of 14 years from the date of product approval, and only one patent applicable to each regulatory review period
may  be  extended  and  only  those  claims  covering  the  approved  drug,  a  method  for  using  it  or  a  method  for  manufacturing  it  may  be  extended.  Similar
provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.

We may rely, in some circumstances, on trade secrets to protect our technology. Although we take steps to protect our proprietary information and trade
secrets,  including  through  contractual  means  with  our  employees  and  consultants,  third  parties  may  independently  develop  substantially  equivalent
proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully
protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaboration partners, sponsored researchers and other
advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that
all confidential information concerning the business or financial affairs developed or made known to the individual during the course of the individual’s
relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements
provide  that  all  inventions  conceived  by  the  individual,  and  which  are  related  to  our  current  or  planned  business  or  research  and  development  or  made
during the normal working hours, on our premises or using our equipment or proprietary information, are our exclusive property.

Tenapanor Patents

Our tenapanor patent portfolio is wholly owned by us. This portfolio includes five issued U.S. patents, three issued Israeli patents, two issued patents in
each of European Patent Organization, Japan, Korea, Hong Kong and Mexico and one issued patent in each of the following territories: Australia, Brazil,
India, and China. These issued patents cover the composition and certain methods of using tenapanor and are predicted, without extension or adjustment, to
expire in December 2029. The portfolio further includes patents covering the use of tenapanor for the control of serum phosphorus that have been issued in
the U.S., Europe, Japan, China, Australia, Gulf Co-op countries, Hong Kong, Israel, Korea, Mexico, New Zealand, Russia and Taiwan and is pending in
other countries. These patents are predicted, without extension or adjustment, to expire in April 2034.

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Additional U.S. and international patent applications are pending covering additional methods of treatment with tenapanor, and composition of matter and
methods of using compounds that we believe may be follow on compounds to tenapanor.

Other Program Patents

We have patent applications pending in the U.S. and internationally that cover the compositions and methods of using compounds in our RDX013 program.

MANUFACTURING

To  date,  we  have  relied  upon  third-party  contract  manufacturing  organizations  (“CMOs”)  to  manufacture  both  the  active  pharmaceutical  ingredient  and
final drug product dosage forms of our potential drug candidates used as clinical trial material. We expect that we will continue to rely upon CMOs for the
manufacture of commercial product for IBSRELA, our clinical trial materials and for our commercial product requirements for XPHOZAH, when and if
regulatory approval is received. Our license agreements with Knight, and Fosun Pharma require us to supply final drug product dosage forms of tenapanor
for  their  use  in  the  development  and  commercialization  of  tenapanor  in  each  of  their  respective  territories.  We  are  further  obligated  to  supply  active
pharmaceutical ingredient to KKC to support their development and commercialization of tenapanor in Japan. We expect that we will use CMOs to satisfy
our supply obligations to our collaboration partners.

GOVERNMENT REGULATION

The  FDA  and  comparable  regulatory  authorities  in  state  and  local  jurisdictions  and  in  other  countries  impose  substantial  and  burdensome  requirements
upon companies involved in the clinical development, manufacture, marketing and distribution of drugs. These agencies and other federal, state and local
entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping,
approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling, and export and import of our product candidates.

In  the  United  States,  the  FDA  regulates  drug  products  under  the  Federal  Food,  Drug,  and  Cosmetic  Act  (the  “FFDCA”)  and  the  FDA’s  implementing
regulations. If we fail to comply with applicable FDA or other requirements at any time during the drug development process, the approval process or after
approval, we may become subject to administrative or judicial sanctions. These sanctions could include the FDA’s refusal to approve pending applications,
license  suspension  or  revocation,  withdrawal  of  an  approval,  warning  or  untitled  letters,  product  recalls,  product  seizures,  total  or  partial  suspension  of
production or distribution, injunctions, fines, civil penalties or criminal prosecution. Any FDA enforcement action could have a material adverse effect on
us. FDA approval is required before any new unapproved drug or dosage form, including a new use of a previously approved drug, can be marketed in the
United States.

The process required by the FDA before a drug may be marketed in the United States generally involves:

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•

•

•

•

completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies, some performed in accordance with the
FDA’s current Good Laboratory Practice (“GLP”) regulations;

submission  to  the  FDA  of  an  Investigational  New  Drug  (“IND”)  application  which  must  become  effective  before  human  clinical  trials  in  the
United States may begin;

approval by an independent institutional review board, (“IRB”) or ethics committee at each clinical trial site before each trial may be initiated;

performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice ("GCP") regulations to establish the
safety and efficacy of the drug candidate for each proposed indication;

submission to the FDA of a new drug application (“NDA”);

satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with
current Good Manufacturing Practice (“cGMP”) regulations;

satisfactory completion of a potential review by an FDA advisory committee, if applicable; and

FDA review and approval of the NDA prior to any commercial marketing, sale or commercial shipment of the drug.

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The  preclinical  and  clinical  testing  and  approval  process  requires  substantial  time,  effort  and  financial  resources,  and  we  cannot  be  certain  that  any
approvals  for  our  product  candidates  will  be  granted  on  a  timely  basis,  if  at  all.  Nonclinical  tests  include  laboratory  evaluation  of  product  chemistry,
formulation,  stability  and  toxicity,  as  well  as  animal  studies  to  assess  the  characteristics  and  potential  safety  and  efficacy  of  the  product.  The  results  of
preclinical tests, together with manufacturing information, analytical data and a proposed clinical trial protocol and other information, are submitted as part
of an IND to the FDA. Additional preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after
receipt by the FDA, unless the FDA, within the 30-day period, raises concerns or questions relating to the IND and places the clinical trial on a clinical
hold, including concerns that human research subjects will be exposed to unreasonable health risks. In such a case, the IND sponsor and the FDA must
resolve  any  outstanding  concerns  before  the  clinical  trial  can  begin.  A  separate  submission  to  an  existing  IND  must  also  be  made  for  each  successive
clinical trial conducted during product development.

Clinical trials involve the administration of the investigational drug to human subjects under the supervision of qualified investigators. Clinical trials are
conducted  under  protocols  detailing,  among  other  things,  the  objectives  of  the  clinical  trial,  the  parameters  to  be  used  in  monitoring  safety  and  the
effectiveness criteria to be used. Each protocol must be submitted to the FDA as part of the IND.

An independent IRB or ethics committee for each medical center proposing to conduct a clinical trial must also review and approve a plan for any clinical
trial before it can begin at that center and the IRB must monitor the clinical trial until it is completed. The FDA, the IRB, or the sponsor may suspend or
discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk. Clinical
testing also must satisfy extensive GCP requirements, including the requirements for informed consent.

All  clinical  research  performed  in  the  United  States  in  support  of  an  NDA  must  be  submitted  in  advance  by  the  FDA  under  the  IND  regulations  and
procedures  described  above.  However,  a  sponsor  who  wishes  to  conduct  a  clinical  trial  outside  the  United  States  may,  but  need  not,  obtain  FDA
authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the
clinical trial to the FDA in support of an NDA so long as the clinical trial is conducted in compliance with GCP and if the FDA is able to validate the data
from the study through an onsite inspection, if necessary. GCP includes review and approval by an independent ethics committee, such as an IRB, and
obtaining and documenting the freely given informed consent of each subject before study initiation. If the applicant seeks approval of an NDA solely on
the basis of foreign data, the FDA will only accept such data if they are applicable to the U.S. population and U.S. medical practice, the studies have been
performed by clinical investigators of recognized competence, and the data may be considered valid without the need for an on-site inspection by the FDA,
or if the FDA considers such an inspection to be necessary, the FDA is able to validate the data through an on-site inspection or through other appropriate
means.

Clinical Trials

The  clinical  investigation  of  a  new  drug  is  typically  conducted  in  three  or  four  phases,  which  may  overlap  or  be  combined,  and  generally  proceed  as
follows.

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•

•

•

Phase 1: Clinical trials are initially conducted in a limited population of subjects to test the drug candidate for safety, dose tolerance, absorption,
metabolism, distribution and excretion in healthy humans or, on occasion, in patients with severe problems or life-threatening diseases to gain an
early indication of its effectiveness.

Phase  2:  Clinical  trials  are  generally  conducted  in  a  limited  patient  population  to  evaluate  dosage  tolerance  and  appropriate  dosage,  identify
possible adverse effects and safety risks, and evaluate preliminarily the efficacy of the drug for specific targeted indications in patients with the
disease or condition under study.

Phase 3: Clinical trials are typically conducted when Phase 2 clinical trials demonstrate that a dose range of the product candidate is effective and
has  an  acceptable  safety  profile.  Phase  3  clinical  trials  are  commonly  referred  to  as  “pivotal”  studies,  which  typically  denotes  a  study  which
presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a drug. Phase 3 clinical trials
are  generally  undertaken  with  large  numbers  of  patients,  such  as  groups  of  several  hundred  to  several  thousand,  to  further  evaluate  dosage,  to
provide  substantial  evidence  of  clinical  efficacy  and  to  further  test  for  safety  in  an  expanded  and  diverse  patient  population  at  multiple,
geographically-dispersed clinical trial sites.

Phase 4: In some cases, the FDA may condition approval of an NDA for a product candidate on the sponsor’s agreement to conduct additional
clinical trials after NDA approval. In other cases, a sponsor may voluntarily conduct

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additional  clinical  trials  post  approval  to  gain  more  information  about  the  drug.  Such  post  approval  trials  are  typically  referred  to  as  Phase  4
clinical trials.

Concurrent with clinical trials, companies usually complete additional nonclinical studies and must also develop additional information about the chemistry
and physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with GMP requirements.
The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, the manufacturer must
develop methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and
tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

The FDA, the IRB or the clinical trial sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research
subjects are being exposed to an unacceptable health risk.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety
monitoring board or committee. This group provides authorization for whether or not a trial may move forward at designated check points based on access
to certain data from the study. We may also suspend or terminate a clinical trial based on evolving business objectives and/or competitive climate.

New Drug Applications

The  results  of  preclinical  studies  and  of  the  clinical  trials,  together  with  other  detailed  information,  including  extensive  manufacturing  information  and
information  on  the  composition  of  the  drug,  are  submitted  to  the  FDA  in  the  form  of  an  NDA  requesting  approval  to  market  the  drug  for  one  or  more
specified indications. The FDA reviews an NDA to determine, among other things, whether a drug is safe and effective for its intended use.

Under the Prescription Drug User Fee Act, the FDA has a goal of responding to standard review NDAs for new molecular entities within ten months after
the 60-day filing review period, or six months after the 60-day filing review period for priority review NDAs and for non-new molecular entities, within ten
months of receipt of standard review NDAs and six month of receipt for priority review NDAs, but this timeframe is often extended by FDA requests for
additional  information  or  clarification.  The  FDA  may  refer  the  application  to  an  advisory  committee  for  review,  evaluation  and  recommendation  as  to
whether  the  application  should  be  approved.  The  FDA  is  not  bound  by  the  recommendation  of  an  advisory  committee,  but  it  generally  follows  such
recommendations.

Before  approving  an  application,  the  FDA  may  inspect  the  facility  or  the  facilities  at  which  the  finished  drug  product,  and  sometimes  the  active
pharmaceutical ingredient (“API”) is manufactured, and will not approve the drug unless cGMP compliance is satisfactory. The FDA may also inspect the
sites  at  which  the  clinical  trials  were  conducted  to  assess  their  compliance  and  will  not  approve  the  drug  unless  compliance  with  GCP  requirements  is
satisfactory.

After the FDA evaluates the NDA and conducts inspections of manufacturing facilities where the drug product and/or its API will be produced, if deemed
necessary, it may issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific
prescribing  information  for  specific  indications.  A  Complete  Response  Letter  indicates  that  the  review  cycle  of  the  application  is  complete,  and  the
application is not ready for approval. A Complete Response Letter may require additional clinical data and/or an additional pivotal Phase 3 clinical trial(s),
and/or other significant, expensive and time-consuming requirements related to clinical trials, preclinical studies or manufacturing. Even if such additional
information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval. The FDA could also approve the NDA
with a Risk Evaluation and Mitigation Strategy (“REMS”) if it is determined that a REMS is necessary to ensure that the drug’s benefits outweigh its risks
and a REMS to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted
distribution  methods,  patient  registries  and  other  risk  minimization  tools.  The  FDA  also  may  condition  approval  on,  among  other  things,  changes  to
proposed  labeling,  development  of  adequate  controls  and  specifications,  or  a  commitment  to  conduct  one  or  more  post-market  studies  or  clinical  trials.
Such  post-market  testing  may  include  Phase  4  clinical  trials  and  surveillance  to  further  assess  and  monitor  the  product’s  safety  and  effectiveness  after
commercialization. The FDA has the authority to prevent or limit further marketing of a drug based on the results of these post-marketing programs. Once
the  FDA  approves  an  NDA,  or  supplement  thereto,  the  FDA  may  withdraw  the  approval  if  ongoing  regulatory  requirements  are  not  met  or  if  safety
problems are identified after the drug reaches the market.

Drugs may be marketed only for the FDA approved indications and in accordance with the provisions of the approved labeling. Further, if there are any
modifications to the drug, including changes in indications, labeling, or manufacturing

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processes  or  facilities,  the  applicant  may  be  required  to  submit  and  obtain  FDA  approval  of  a  new  NDA  or  NDA  supplement,  which  may  require  the
applicant to develop additional data or conduct additional preclinical studies and clinical trials.

The testing and approval processes require substantial time, effort and financial resources, and each may take several years to complete. The FDA may not
grant approval on a timely basis, or at all. Even if we believe a clinical trial has demonstrated safety and efficacy of one of our drug candidates for the
proposed indication, the results may not be satisfactory to the FDA. Nonclinical and clinical data may be interpreted by the FDA in different ways, which
could  delay,  limit  or  prevent  regulatory  approval.  We  may  encounter  difficulties  or  unanticipated  costs  in  our  efforts  to  secure  necessary  governmental
approvals which could delay or preclude us from marketing drugs. The FDA may limit the indications for use or place other conditions on any approvals
that  could  restrict  the  commercial  application  of  the  drugs.  After  approval,  certain  changes  to  the  approved  drug,  such  as  adding  new  indications,
manufacturing changes, or additional labeling claims are subject to further FDA review and approval. Depending on the nature of the change proposed, an
NDA supplement must be filed and approved before the change may be implemented.

Other Regulatory Requirements

Any drugs manufactured or distributed by us or our collaboration partners pursuant to FDA approvals would be subject to continuing regulation by the
FDA, including recordkeeping requirements and reporting of adverse experiences associated with the drug. Drug manufacturers and their subcontractors
are required to register their establishments with the FDA and certain state agencies and are subject to periodic announced and unannounced inspections by
the  FDA  and  certain  state  agencies  for  compliance  with  ongoing  regulatory  requirements,  including  cGMP,  which  impose  certain  procedural  and
documentation  requirements  upon  us  and  our  third-party  manufacturers.  Failure  to  comply  with  the  statutory  and  regulatory  requirements  can  subject  a
manufacturer to possible legal or regulatory action, such as warning or untitled letters, suspension of manufacturing, seizure of product, injunctive action or
possible civil penalties. We cannot be certain that we or our present or future third-party manufacturers or suppliers will be able to comply with the cGMP
regulations and other ongoing FDA regulatory requirements. If we or our present or future third-party manufacturers or suppliers are not able to comply
with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a drug from distribution or withdraw approval of the
NDA for that drug.

The FDA closely regulates the post-approval marketing and promotion of drugs, including standards and regulations for direct-to-consumer advertising,
off-label promotion, industry-sponsored scientific and educational activities and promotional activities involving the Internet. A company can make only
those claims relating to safety and efficacy that are in the final label or consistent with the final label. Failure to comply with these requirements can result
in,  among  other  things,  adverse  publicity,  warning  or  untitled  letters,  corrective  advertising  and  potential  civil  and  criminal  penalties.  Physicians  may
prescribe legally available drugs for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA.
Such  off-label  uses  are  common  across  medical  specialties.  Physicians  may  believe  that  such  off-label  uses  are  the  best  treatment  for  many  patients  in
varied  circumstances.  The  FDA  does  not  regulate  the  behavior  of  physicians  in  their  choice  of  treatments.  The  FDA  does,  however,  impose  stringent
restrictions on manufacturers’ communications regarding off-label use.

Hatch-Waxman Act

Under  the  Price  Competition  and  Patent  Term  Restoration  Act,  or  Hatch-Waxman  Act,  Section  505  of  the  FFDCA  describes  three  types  of  marketing
applications that may be submitted to the FDA to request marketing authorization for a new drug. A Section 505(b)(1) NDA is an application that contains
full reports of investigations of safety and efficacy. A Section 505(b)(2) NDA is an application that contains full reports of investigations of safety and
efficacy but where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for
which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. This regulatory pathway
enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product, or published literature, in support of its
application.  Section  505(j)  establishes  an  abbreviated  approval  process  for  a  generic  version  of  approved  drug  products  through  the  submission  of  an
Abbreviated New Drug Application (“ANDA”). An ANDA provides for marketing of a generic drug product that has the same active ingredients, dosage
form,  strength,  route  of  administration,  labeling,  performance  characteristics  and  intended  use,  among  other  things,  to  a  previously  approved  product.
ANDAs are termed “abbreviated” because they are generally not required to include nonclinical (animal) and clinical (human) data to establish safety and
efficacy. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent to, or performs in the same manner as, the innovator
drug through in vitro, in vivo, or other testing. The generic version must deliver the same amount of active ingredients into a subject’s bloodstream in the
same amount of time as the innovator drug and can often be substituted by pharmacists under prescriptions written for the reference listed drug. In seeking
approval for a drug through an NDA, applicants are required to list with the FDA each patent with claims that cover the

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applicant’s drug or a method of using the drug. Upon approval of a drug, each of the patents listed in the application for the drug is then published in the
FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. Drugs listed in the Orange Book can, in
turn, be cited by potential competitors in support of approval of an ANDA or 505(b)(2) NDA.

Upon submission of an ANDA or a 505(b)(2) NDA, an applicant must certify to the FDA that (1) no patent information on the drug product that is the
subject  of  the  application  has  been  submitted  to  the  FDA;  (2)  such  patent  has  expired;  (3)  the  date  on  which  such  patent  expires;  or  (4)  such  patent  is
invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. Generally, the ANDA or
505(b)(2) NDA cannot be approved until all listed patents have expired, except where the ANDA or 505(b)(2) NDA applicant challenges a listed patent
through the last type of certification, also known as a Paragraph IV certification. 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 or 505(b)(2) NDA application will not be approved until all of the listed patents claiming the
referenced product have expired.

If  the  ANDA  or  505(b)(2)  NDA  applicant  has  provided  a  Paragraph  IV  certification  to  the  FDA,  the  applicant  must  send  notice  of  the  Paragraph  IV
certification to the NDA holder and patent owners once the application has been accepted for filing by the FDA. The NDA and patent holders may then
initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification. If the Paragraph IV certification is challenged by an NDA
holder or the patent owner(s), the FDA may not approve that application until the earlier of 30 months from the receipt of the notice of the Paragraph IV
certification, the expiration of the patent, when the infringement case concerning each such patent was favorably decided in the applicant’s favor or settled,
or such shorter or longer period as may be ordered by a court. This prohibition is generally referred to as the 30-month stay. In instances where an ANDA
or  505(b)(2)  NDA  applicant  files  a  Paragraph  IV  certification,  the  NDA  holder  or  patent  owner(s)  regularly  take  action  to  trigger  the  30-month  stay,
recognizing that the related patent litigation may take many months or years to resolve. Thus, approval of an ANDA or 505(b)(2) NDA could be delayed
for  a  significant  period  of  time  depending  on  the  patent  certification  the  applicant  makes  and  the  reference  drug  sponsor’s  decision  to  initiate  patent
litigation.

The  Hatch-Waxman  Act  establishes  periods  of  regulatory  exclusivity  for  certain  approved  drug  products,  during  which  the  FDA  cannot  approve  (or  in
some cases accept) an ANDA or 505(b)(2) application that relies on the branded reference drug. For example, the holder of an NDA, including a 505(b)
(2)  NDA,  may  obtain  five  years  of  exclusivity  upon  approval  of  a  new  drug  containing  a  new  chemical  entity  (“NCE”)  that  has  not  been  previously
approved by the FDA. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety,
which  is  the  molecule  or  ion  responsible  for  the  therapeutic  activity  of  the  drug  substance.  During  the  exclusivity  period,  the  FDA  may  not  accept  for
review an ANDA or a 505(b)(2) NDA submitted by another company that contains the previously approved active moiety. However, an ANDA or 505(b)
(2) NDA may be submitted after four years if it contains a Paragraph IV certification of patent invalidity or non-infringement.

The Hatch-Waxman Act also provides three years of marketing exclusivity to the holder of an NDA (including a 505(b)(2) NDA) for a particular condition
of approval, or change to a marketed product, such as a new formulation for a previously approved product, if one or more new clinical studies (other than
bioavailability or bioequivalence studies) was essential to the approval of the application and was conducted/sponsored by the applicant. This three-year
exclusivity  period  protects  against  FDA  approval  of  ANDAs  and  505(b)(2)  NDAs  for  the  specific  condition  of  the  new  drug’s  approval.  As  a  general
matter, the three-year exclusivity does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for generic versions of the original, unmodified
drug product. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA; however, an applicant submitting a full NDA
would  be  required  to  conduct  or  obtain  a  right  of  reference  to  all  of  the  preclinical  studies  and  adequate  and  well-controlled  clinical  trials  necessary  to
demonstrate safety and efficacy.

Fraud and Abuse Laws

In  the  U.S.  the  research,  manufacturing,  distribution,  sale  and  promotion  of  drug  products  and  medical  devices  are  potentially  subject  to  regulation  by
various federal, state and local authorities in addition to the FDA, including the Centers for Medicare & Medicaid Services (“CMS”) other divisions of the
U.S. Department of Health and Human Services (e.g., the Office of Inspector General), the U.S. Department of Justice, state Attorneys General, and other
state  and  local  government  agencies.  These  laws  include  but  are  not  limited  to,  the  Anti-Kickback  Statute,  the  federal  False  Claims  Act,  the  federal
Physician Payments Sunshine Act, and other state and federal laws and regulations.

The Anti-Kickback Statute makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and
willfully solicit, receive, offer, or pay any remuneration that is intended to induce the referral of business, including the purchase, order, or prescription of a
particular drug, for which payment may be made under a federal

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healthcare program, such as Medicare or Medicaid. Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil
money penalties, and exclusion from participation in federal healthcare programs. In addition, a person or entity does not need to have actual knowledge of
the statute or specific intent to violate it in order to have committed a violation.

The  federal  False  Claims  Act  prohibits  anyone  from  knowingly  presenting,  or  causing  to  be  presented,  for  payment  to  federal  programs  (including
Medicare and Medicaid) claims for items or services, including drugs, that are false or fraudulent, claims for items or services not provided as claimed, or
claims for medically unnecessary items or services. Although we would not submit claims directly to payors, manufacturers can be held liable under these
laws  if  they  are  deemed  to  “cause”  the  submission  of  false  or  fraudulent  claims  by,  for  example,  providing  inaccurate  billing  or  coding  information  to
customers  or  promoting  a  product  off-label.  In  addition,  our  future  activities  relating  to  the  reporting  of  wholesaler  or  estimated  retail  prices  for  our
products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement
for  our  products,  and  the  sale  and  marketing  of  our  products,  are  subject  to  scrutiny  under  this  law.  Moreover,  the  government  may  assert  that  a  claim
including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False
Claims Act. Penalties for a False Claims Act violation include three times the actual damages sustained by the government, plus mandatory civil penalties
for each separate false claim, the potential for exclusion from participation in federal healthcare programs. As well, although the federal False Claims Act is
a civil statute, conduct that results in a False Claims Act violation may also implicate various federal criminal statutes. If the government were to allege that
we were, or convict us of, violating these false claims laws, we could be subject to a substantial fine and may suffer a decline in our stock price. In addition,
private individuals have the ability to bring actions under the federal False Claims Act.

In addition to the laws described above, the Physician Payments Sunshine Act requires certain drug manufacturers to report payments and other transfer of
value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) certain non-physician practitioners (physician
assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, anesthesiologist assistants and certified nurse midwives) and teaching
hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Failure to submit required information
may  result  in  significant  civil  monetary  penalties,  and  additional  penalties  for  knowing  failures,  for  all  payments,  transfers  of  value  or  ownership  or
investment interests that are not timely, accurately and completely reported in an annual submission. Manufacturers must submit reports by the 90th day of
each subsequent calendar year.

Many  states  have  also  adopted  laws  similar  to  the  federal  laws  discussed  above.  Some  of  these  state  prohibitions  apply  to  the  referral  of  patients  for
healthcare services reimbursed by any insurer, not just federal healthcare programs such as Medicare and Medicaid. There has also been a recent trend of
increased  regulation  of  payments  made  to  physicians  and  other  healthcare  providers.  Certain  states  mandate  implementation  of  compliance  programs,
impose restrictions on drug manufacturers’ marketing practices and/or require the tracking and reporting of pricing and marketing information as well as
gifts, compensation and other remuneration to physicians. Many of these laws contain ambiguities as to what is required to comply with such laws, which
may affect our sales, marketing, and other promotional activities by imposing administrative and compliance burdens on us. In addition, given the lack of
clarity  with  respect  to  these  laws  and  their  implementation,  our  reporting  actions  could  be  subject  to  the  penalty  provisions  of  the  pertinent  state  and
perhaps federal, authorities.

Violations of any of such laws or any other governmental regulations that apply may result in penalties, including, without limitation, administrative, civil
and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, reporting obligations and integrity oversight, exclusion
from participation in federal and state healthcare programs and imprisonment.

Third-Party Coverage and Reimbursement

Sales of pharmaceutical products depend in significant part on the availability of coverage and adequate reimbursement by third-party payors, such as state
and federal governments, including Medicare and Medicaid, and commercial managed care providers. In the United States, no uniform policy of coverage
and  reimbursement  for  drug  products  exists  among  third-party  payors.  Accordingly,  decisions  regarding  the  extent  of  coverage  and  amount  of
reimbursement to be provided for our product candidates, if approved, will be made on a payor by payor basis. As a result, the coverage determination
process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to
each payor separately, with no assurance that coverage and adequate reimbursement will be obtained. Third-party payors may limit coverage to specific
drug products on an approved list, or formulary, which might not include all of the FDA-approved drugs for a particular indication. A decision by a third-
party payor not to cover our product candidates could reduce physician utilization of our products once approved and have a material adverse effect on our
future  sales,  results  of  operations  and  financial  condition.  Moreover,  a  payor’s  decision  to  provide  coverage  for  a  drug  product  does  not  imply  that  an
adequate

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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.

There is increased uncertainty related to insurance coverage and reimbursement for certain drugs, like XPHOZAH, which, if approved, will be marketed
for the control of serum phosphorus in adult patients with CKD on dialysis. In January 2011, CMS implemented a new prospective payment system for
dialysis treatment. Under the ESRD prospective payment system, CMS generally makes a single bundled payment to the dialysis facility for each dialysis
treatment  that  covers  all  items  and  services  routinely  required  for  dialysis  treatments  furnished  to  Medicare  beneficiaries  in  Medicare-certified  ESRD
facilities or at their home, including the cost of certain routine drugs. The inclusion of oral medications without injectable or intravenous equivalents in the
bundled payment was initially delayed until January 1, 2014 and through several subsequent legislative actions was delayed until January 1, 2025. As a
result, absent further legislation or regulation on this matter, beginning in 2025, oral ESRD-related drugs without injectable or intravenous equivalents may
be included in the ESRD bundle and separate Medicare payment for these drugs will no longer be available, as is the case today under Medicare Part D.
While it is too early to project the full impact that bundling may have on XPHOZAH and our business should XPHOZAH be brought into the bundle in
2025, or at any time, we may be unable to sell XPHOZAH, if approved, to dialysis providers on a profitable basis if third-party payors reduce their current
levels of payment, or if our costs of production are higher than levels necessary for an appropriate gross margin after payment of all discounts, rebates
and chargebacks.

Healthcare Reform

In March 2010, Congress passed the Patient Protection and Affordable Care Act, a healthcare reform measure (the “ACA”). The ACA was signed into law
and  substantially  changed  the  way  healthcare  is  financed  by  both  governmental  and  private  insurers,  and  significantly  impacted  the  pharmaceutical
industry.

The ACA contained a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement changes and fraud and
abuse  measures,  which  have  impacted  existing  government  healthcare  programs  and  have  resulted  in  the  development  of  new  programs,  including
Medicare payment for performance initiatives and improvements to the physician quality reporting system and feedback program.

Additionally, the ACA:

•

•

•

•

•

•

increased  the  minimum  level  of  Medicaid  rebates  payable  by  manufacturers  of  brand-name  drugs  from  15.1%  to  23.1%  of  the  average
manufacturer price;

required collection of rebates for drugs paid by Medicaid managed care organizations;

expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals
and by adding new mandatory eligibility categories for certain individuals with income at or below 133% of the federal poverty level, thereby
potentially increasing a manufacturer’s Medicaid rebate liability;

expanded access to commercial health insurance coverage through new state-based health insurance marketplaces, or exchanges;

required manufacturers to participate in a coverage gap discount program, under which they must now agree to offer 70% point-of-sale discounts
off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s
outpatient drugs to be covered under Medicare Part D; and

imposed  a  non-deductible  annual  fee  on  pharmaceutical  manufacturers  or  importers  who  sell  “branded  prescription  drugs”  to  specified  federal
government programs.

Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA. On June 17, 2021, the U.S. Supreme
Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed
by Congress. Thus, the ACA will remain in effect in its current form. Further, prior to the U.S. Supreme Court ruling, President Biden issued an executive
order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace from February 15, 2021
through August 15, 2021. The executive order instructed certain governmental agencies to review and reconsider their existing policies and rules that limit
access  to  healthcare,  including  among  others,  reexamining  Medicaid  demonstration  projects  and  waiver  programs  that  include  work  requirements,  and
policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

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In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted. For example, in August 2011, the
Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into
effect on April 1, 2013, and, due to subsequent legislative amendments, will remain in effect through 2030, with the exception of a temporary suspension
from May 1, 2020 through March 31, 2022 and a 1% reduction from April 1, 2022 through June 30, 2022, unless additional Congressional action is taken.
In  January  2013,  the  American  Taxpayer  Relief  Act,  among  other  things,  further  reduced  Medicare  payments  to  several  providers,  including  hospitals,
imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from
three  to  five  years.  More  recently,  on  March  11,  2021,  President  Biden  signed  the  American  Rescue  Plan  Act  of  2021  into  law,  which  eliminates  the
statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, beginning January 1, 2024.

Recently, there has also been heightened governmental scrutiny over the manner in which drug manufacturers set prices for their marketed products, which
has resulted in several Congressional inquiries and proposed bills designed to, among other things, bring more transparency to product pricing, review the
relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products. By way
of example, the Build Back Better Act, if enacted, would introduce substantial drug pricing reforms, including the establishment of a drug price negotiation
program within the U.S. Department of Health and Human Services that would require manufacturers to charge a negotiated “maximum fair price” for
certain selected drugs or pay an excise tax for noncompliance, and the establishment of rebate payment requirements on manufacturers of certain drugs
payable  under  Medicare  Parts  B  and  D.  If  the  Build  Back  Better  Act  is  not  enacted,  similar  or  other  drug  pricing  proposals  could  appear  in  future
legislation.  Additionally,  individual  states  have  also  become  increasingly  active  in  passing  legislation  and  implementing  regulations  designed  to  control
pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, and to encourage
importation from other countries and bulk purchasing. These new laws and the regulations and policies implementing them, as well as other healthcare
reform measures that may be adopted in the future, may have a material adverse effect on our industry generally and on our ability to successfully develop
and commercialize our products.

Government Price Reporting

Medicaid is a joint federal and state program for low-income and disabled beneficiaries. Medicare is a federal program covering individuals age 65 and
over as well as those with certain disabilities. As a condition of having federal funds being made available for our covered drugs under Medicaid, we intend
to enroll in the Medicaid Drug Rebate Program (“MDRP”), which would require us to pay a rebate to state Medicaid programs for each unit of our covered
drugs dispensed to a Medicaid beneficiary and paid for by a state Medicaid program. Medicaid drug rebates are based on pricing data that we must report
on  a  monthly  and  quarterly  basis  to  the  U.S.  Centers  for  Medicare  &  Medicaid  Services  (“CMS”),  the  federal  agency  that  administers  the  MDRP  and
Medicare programs. For the MDRP, these data include the average manufacturer price (“AMP”) and the best price (“BP”) for each drug. If we become
aware that our MDRP price reporting submission for a prior period was incorrect or has changed as a result of recalculation of the pricing data, we must
resubmit the corrected data for up to three years after those data originally were due. Manufacturers who fail to provide information timely or are found to
have knowingly submitted false information to the government may be subject to civil monetary penalties and other sanctions, including termination from
the MDRP.

Federal  law  requires  that  a  manufacturer  that  participates  in  the  MDRP  also  participate  in  the  Public  Health  Service’s  340B  drug  pricing  program  (the
“340B program”) in order for federal funds to be available for the manufacturer’s drugs under Medicaid and Medicare Part B. We intend to participate in
the 340B program, which is administered by the Health Resources and Services Administration (“HRSA”), and requires us to charge statutorily defined
covered  entities  no  more  than  the  340B  “ceiling  price”  for  the  our  covered  outpatient  drugs  used  in  an  outpatient  setting.  These  340B  covered  entities
include a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as hospitals that
serve a disproportionate share of low-income patients. The 340B ceiling price calculated using a statutory formula, which is based on the AMP and rebate
amount for the covered outpatient drug as calculated under the MDRP. In general, products subject to Medicaid price reporting and rebate liability are also
subject  to  the  340B  ceiling  price  calculation  and  discount  requirement.  We  must  report  340B  ceiling  prices  to  HRSA  on  a  quarterly  basis,  and  HRSA
publishes them to 340B covered entities. HRSA has finalized regulations regarding the calculation of the 340B ceiling price and the imposition of civil
monetary  penalties  on  manufacturers  that  knowingly  and  intentionally  overcharge  covered  entities  for  340B-eligible  drugs.  HRSA  has  also  finalized  an
administrative dispute resolution process through which 340B covered entities may pursue claims against participating manufacturers for overcharges, and
through which manufacturers may pursue claims against 340B covered entities for engaging in unlawful diversion or duplicate discounting of 340B drugs.
In  addition,  legislation  may  be  introduced  that,  if  passed,  would  further  expand  the  340B  program,  such  as  adding  further  covered  entities  or  requiring
participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.

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In  order  to  be  eligible  to  have  drug  products  paid  for  with  federal  funds  under  Medicaid  and  purchased  by  certain  federal  agencies  and  grantees,
manufacturers  must  also  participate  in  the  U.S.  Department  of  Veterans  Affairs  (“VA”)  Federal  Supply  Schedule  (“FSS”)  pricing  program.  Under  the
VA/FSS program, manufacturers must report the Non-Federal Average Manufacturer Price (“Non-FAMP”) for their covered drugs to the VA and charge
certain federal agencies no more than the Federal Ceiling Price, which is calculated based on Non-FAMP using a statutory formula. These four agencies are
the VA, the U.S. Department of Defense, the U.S. Coast Guard, and the U.S. Public Health Service (including the Indian Health Service). Manufacturers
must also pay rebates on products purchased by military personnel and dependents through the TRICARE retail pharmacy program. Manufacturers who
fail to provide timely information or are found to have knowingly submitted false information may be subject to civil monetary penalties.

Individual  states  continue  to  consider  and  have  enacted  legislation  to  limit  the  growth  of  healthcare  costs,  including  the  cost  of  prescription  drugs  and
combination products. A number of states have either implemented or are considering implementation of drug price transparency legislation. Requirements
under  such  laws  include  advance  notice  of  planned  price  increases,  reporting  price  increase  amounts  and  factors  considered  in  taking  such  increases,
wholesale  acquisition  cost  information  disclosure  to  prescribers,  purchasers,  and  state  agencies,  and  new  product  notice  and  reporting.  Such  legislation
could limit the price or payment for certain drugs, and a number of states are authorized to impose civil monetary penalties or pursue other enforcement
mechanisms  against  manufacturers  who  fail  to  comply  with  drug  price  transparency  requirements,  including  the  untimely,  inaccurate,  or  incomplete
reporting of drug pricing information.

Data Privacy and Security Laws

Numerous  state,  federal  and  foreign  laws,  including  consumer  protection  laws  and  regulations,  govern  the  collection,  dissemination,  use,  access  to,
confidentiality  and  security  of  personal  information,  including  health-related  information.  In  the  United  States,  numerous  federal  and  state  laws  and
regulations,  including  data  breach  notification  laws,  health  information  privacy  and  security  laws,  including  the  Health  Insurance  Portability  and
Accountability Act of 1996, as amended, and regulations promulgated thereunder (collectively “HIPAA”), and federal and state consumer protection laws
and regulations (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure, and protection of health-related and other
personal  information  could  apply  to  our  operations  or  the  operations  of  our  partners.  In  addition,  certain  state  laws,  such  as  the  California  Consumer
Privacy Act (“CCPA”) and the California Privacy Rights Act (“CPRA”) govern the privacy and security of personal data, including health-related data in
certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the
same effect, thus complicating compliance efforts. Further, certain foreign laws govern the privacy and security of personal data, including health-related
data. Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.
Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and
can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Other Regulations

We are also subject to numerous federal, state and local laws relating to such matters as safe working conditions, manufacturing practices, environmental
protection, fire hazard control, and disposal of hazardous or potentially hazardous substances. We may incur significant costs to comply with such laws and
regulations now or in the future.

Impact of COVID-19

The global COVID-19 pandemic has impacted the operational decisions of companies worldwide. It also has created and may continue to create significant
uncertainty in the global economy. We have undertaken measures to protect our employees, partners, collaborators, and vendors, some of which impact our
normal operations. To date, we have been able to continue our operations with our workforce, most of whom are working remotely, and our pre-existing
infrastructure that supports secure access to our internal systems. If, however, the COVID-19 pandemic has a substantial impact on the productivity of our
employees, our ability to successfully prepare for and execute the commercial launch of IBSRELA, including our ability to hire and successfully integrate
into the company the new personnel required to prepare for such launch, or our ability to pursue our appeal of the ADL issued by OHCEN following the
issuance of a CRL for our NDA for tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis, the results of our operations and
overall financial performance may be adversely impacted. The extent of the impact from the COVID-19 pandemic on our business will depend largely on
future developments that are highly uncertain and cannot be predicted. For a discussion of risks of COVID-19 relating to our business, see “Item 1A. - Risk
Factors- Risks Related to Our Business- The ongoing COVID-19 pandemic, or any other outbreak of epidemic diseases, or the perception of their effects,
could have a material adverse effect on our business, financial condition,

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results of operations or cash flows.” As of the date of issuance of this financial report, we are not aware of any specific event or circumstance that would
require updates to our estimates and judgments or revisions to the carrying value of our assets or liabilities. These estimates may change as new events
occur and additional information is obtained.

Human Capital

The future success of our company depends on our ability to attract, retain, and further develop top talent. We plan to launch IBSRELA in April 2022 and,
as  a  result,  we  are  building  an  experienced  commercial  team  and  expanding  our  internal  resources  to  support  a  commercial  organization.  During  this
ongoing transition and expansion of our workforce, we remain steadfastly committed to our core values, including our goal to develop and maintain an
inclusive, diverse, and safe workplace with opportunities for our employees to grow and develop in their careers, supported by strong compensation and
benefits.

At December 31, 2021, we had approximately 86 full-time employees, 55 of whom were engaged directly in development and manufacturing, and 31 in
marketing,  sales  and  administrative  activities.  During  2021  our  employee  base  decreased  by  approximately  43,  or  33%,  primarily  as  a  result  of  our
restructurings in August 2021 and October 2021.

Inclusion and Diversity

Our culture is supported by an unwavering commitment to inclusion and diversity. As of December 31, 2021, approximately 63% of our workforce was
female;  43%  of  our  executive  leadership  team  was  female  and  56%  of  our  employees  in  managerial  roles  were  female.  As  of  December  31,  2021,
minorities represented approximately 39% of our workforce, of which 41% of our employees in managerial roles were minorities. We strive to foster a
culture where mutual respect, inclusive behavior, and dignity are core to our individual expectations.

We believe that our success will be significantly impacted by our ability to create and maintain a safe inclusive environment where everyone is empowered
to do their best work—regardless of race, color, national origin, religion, sex, sexual orientation, gender identity and expression, age, or disability. We are
united  by  our  desire  to  serve  our  patients,  and  we  are  proud  financial  sponsors  of  the  California  Life  Sciences  Association  Racial  and  Social  Equity
Initiative, a first step in a unified effort for the life sciences industry in California to do more for the under-served and under-represented, focusing on the
most critical need to address the inequality for Black, Hispanic, Native American and Pacific Islander populations in California.

Core Values

Fostering and maintaining a strong, healthy culture is a key strategic focus. Our core values reflect who we are and the way our employees interact with one
another, our partners and our stockholders. We are dedicated to our core values, recognizing that this dedication will foster an environment where we will
be able to realize our vision of advancing patient care. We are Passionate, aware that with integrity and determination, we make a difference for patients.
We are Fearless, aware that by challenging convention, we truly innovate. We are Dedicated, aware that working tirelessly together, we are greater than the
sum of our parts. We are Inclusive, aware that with respect, grace and humor, we are family. We encourage our employees to live out our core values and to
discuss our core values with potential candidates looking to join our team. We believe that this is an important step in helping our culture stay strong and
unique.

Health, Safety, and Wellness

The health, safety, and wellness of our employees is a priority in which we have always invested, and will continue to do so. These investments and the
prioritization of employee health, safety, and wellness took on particular significance in light of COVID-19. In response to the COVID-19 pandemic, we
implemented  significant  changes  that  we  determined  were  in  the  best  interest  of  our  employees,  as  well  as  the  communities  in  which  we  operate,  in
compliance with government regulations. This included having the vast majority of our employees work from home. We have reopened our facilities and
are currently inviting our employees to return to our facilities in the manner in which they are comfortable. We will continue to monitor infection rates and
severity of disease in those communities in which are facilities are located and will continue to adopt and align our policies to focus on the health, safety
and wellness of our employees, and the needs of our business.

Compensation and Benefits

We recognize that we operate within an industry where there is significant competition for top talent, and we endeavor to provide not only a strong healthy
culture,  but  also  important  compensation  and  benefits  programs  to  help  meet  the  needs  of  our  employees.  In  addition  to  base  compensation,  these
programs, include annual bonuses, stock awards, an Employee Stock Purchase Plan, 401(k), healthcare and insurance benefits, health savings (funded by
the Company) and flexible spending

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accounts,  family  leave,  family  care  resources,  and  flexible  work  schedules,  among  many  others.  As  a  response  to  the  COVID-19  pandemic,  we
implemented payments to assist employees in paying for expenses incurred in working from home.

Ensuring  fair  and  equitable  pay  is  integral  to  our  commitment  to  our  employees.  Our  executive  team  and  Board  of  Directors  strongly  support  this
commitment.  We  conduct  pay  equity  reviews  annually  to  help  us  understand  whether  our  compensation  structure  is  appropriate  and  to  identify  what
improvements can be made.

Corporate Information

We were incorporated in Delaware on October 17, 2007, under the name Nteryx and changed our name to Ardelyx, Inc. in June 2008. We operate in one
business  segment,  which  is  the  development  and  planned  commercialization  of  biopharmaceutical  products.  Our  principal  office  is  located  at  400  Fifth
Avenue, Suite 210, Waltham, Massachusetts 02415. Our telephone number is (510) 745-1700 and our website address is www.ardelyx.com.

We  file  electronically  with  the  Securities  and  Exchange  Commission  (“SEC”)  our  annual  reports  on  Form  10-K,  quarterly  reports  on  Form  10-Q  and
current reports on Form 8-K pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended. We make available on our website at
www.ardelyx.com, free of charge, copies of these reports, as soon as reasonably practicable after we electronically file such material with, or furnish it to,
the  SEC.  The  SEC  maintains  a  website  that  contains  reports,  proxy  and  information  statements,  and  other  information  regarding  issuers  that  file
electronically with the SEC. The address of that website is www.sec.gov.

ITEM 1A.     RISK FACTORS

Our business involves significant risks, some of which are described below. You should carefully consider these risks, as well as other information in this
Annual  Report  on  Form  10-K,  including  our  financial  statements  and  the  notes  thereto  and  “Management’s  Discussion  and  Analysis  of  Financial
Condition and Results of Operations.” The occurrence of any of the events or developments described below could harm our business, financial condition,
results of operations, cash flows, the trading price of our common stock and our growth prospects. Many of the following risks and uncertainties are, and
will be, exacerbated by the COVID-19 pandemic and any worsening of the global business and economic environment as a result. Additional risks and
uncertainties not presently known to us or that we currently deem immaterial may also impair our business operations.

Risks Related to our Financial Condition and Capital Requirements

We have a limited operating history, have incurred significant losses since our inception and we will incur losses in the future, which makes it difficult
to  assess  our  future  viability;  although  our  financial  statements  have  been  prepared  on  a  going  concern  basis,  our  current  level  of  cash  and
investments alone is not sufficient to meet our operating plans for the next twelve months, raising substantial doubt regarding our ability to continue as
a going concern.

    We are a clinical-stage biopharmaceutical company with a limited operating history. Biopharmaceutical product development is a highly speculative
undertaking and involves a substantial degree of risk. To date, we have focused substantially all of our efforts on our research and development activities,
including developing tenapanor and developing our proprietary drug discovery and design platform. To date, we have not commercialized any products or
generated any revenue from the sale of products.

We are not profitable and have incurred losses in each year since our inception in October 2007, and we do not know whether or when we will become
profitable. We continue to incur significant research, development and other expenses related to our ongoing operations. As of December 31, 2021, we had
an accumulated deficit of $712.9 million.

We expect to continue to incur substantial operating losses for the foreseeable future as we prepare for commercialization of IBSRELA  (tenapanor) for the
treatment of irritable bowel syndrome with constipation (“IBS-C”) in April of this year, seek to gain approval for XPHOZAH (tenapanor) for the control
of serum phosphorus in adult patients with chronic kidney disease (“CKD”) on dialysis (the “Hyperphosphatemia Indication”); prepare for the potential
commercialization of XPHOZAH, if approved; incur manufacturing and development cost for, tenapanor; and incur development costs for RDX013.

® 

®

Ernst & Young LLP, our independent registered public accounting firm for the fiscal year ended December 31, 2021, has included an explanatory paragraph
in their opinion that accompanies our audited financial statements as of the year ended December 31, 2021, indicating our current liquidity position raises
substantial doubt about our ability to continue as a going

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concern.  We  plan  to  address  our  operating  cash  flow  requirements  with  our  current  cash  and  investments,  cash  generated  from  the  product  launch  of
IBSRELA,  our  potential  receipt  of  anticipated  milestone  payments  from  our  collaboration  partners,  our  ability  to  access  the  capital  markets,  as  well  as
through the implementation of cash preservation activities to reduce or defer discretionary spending.

There are no assurances that our efforts to meet our operating cash flow requirements will be successful. If our current cash and investments as well as our
plans to meet our operating cash flow requirements are not sufficient to fund necessary expenditures and meet our obligations for at least the next twelve
months, our liquidity, financial condition and business prospects will be materially affected.

    Our prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders’ equity and working
capital. Further, 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 operations may not be a good indication of our future performance.

We  have  substantial  net  operating  loss  and  tax  credit  carryforwards  for  Federal  and  California  income  tax  purposes.  Such  net  operating  losses  and  tax
credits carryforwards may be reduced as a result of certain intercompany restructuring transactions. In addition, the future utilization of such net operating
loss  and  tax  credit  carryforwards  and  credits  will  be  subject  to  limitations,  pursuant  to  Internal  Revenue  Code  Sections  382  and  383,  as  a  result  of
ownership  changes  that  have  occurred  previously  and  additional  limitations  may  be  applicable  as  a  result  of  ownership  changes  that  could  occur  in  the
future.

We will require substantial additional financing to achieve our goals, including our goals of commercializing IBSRELA beginning in April 2022 and
pursuing a formal dispute resolution ("FDR") process in response to the Complete Response Letter (“CRL”) received from the U.S. Food and Drug
Administration  (“FDA”)  relating  to  our  New  Drug  Application  (“NDA”)  for  tenapanor  for  the  Hyperphosphatemia  Indication  and  the  inability  to
access necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our efforts to commercialize
IBSRELA or to seek and obtain approval for tenapanor for the Hyperphosphatemia Indication.

Since our inception, most of our resources have been dedicated to our research and development activities, including developing tenapanor and developing
our proprietary drug discovery and design platform. Following the receipt of the CRL, we implemented two restructuring plans in order to reduce operating
costs  and  to  better  align  our  workforce  with  the  needs  of  our  business.  Notwithstanding  the  restructurings,  we  believe  that  we  will  continue  to  expend
substantial resources for the foreseeable future, including, costs associated with our efforts to commercialize IBSRELA commencing in April 2022, cost
associated  with  our  efforts  to  pursue  approval  for  our  NDA  for  tenapanor  for  the  Hyperphosphatemia  Indication  through  the  FDR  process;  conducting
pediatric clinical trials for IBSRELA and XPHOZAH, if approved, development of RDX013; and manufacturing for IBSRELA and RDX013. Our future
funding requirements will depend on many factors, including, but not limited to:

•

the extent to which we are able to generate product revenue from sales of IBSRELA;

• whether we are successful in our efforts under the FDR process to secure approval for our NDA for tenapanor for the Hyperphosphatemia Indication,
or  to  reach  resolution  with  the  FDA  regarding  a  path  to  address  the  deficiencies  in  the  NDA  noted  in  the  CRL  and  ADL,  and  the  time  and  cost
associated with such path;

•

•

•

•

•

•

•

the sales price and the availability of adequate third-party reimbursement for IBSRELA and XPHOZAH, if approved;

the manufacturing costs of IBSRELA and XPHOZAH;

the selling and marketing costs associated with IBSRELA and XPHOZAH, if approved;

our  ability  to  maintain  our  existing  collaboration  partnerships  and  to  establish  additional  collaboration  partnerships,  in-license/out-license,  joint
ventures or other similar arrangements and the financial terms of such agreements;

the timing, receipt, and amount of sales of, or royalties on, tenapanor, if any;

the cash requirements of any future acquisitions or discovery of product candidates;

any clinical trials we are required to or decide to pursue for tenapanor or RDX013;

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•

•

•

the time and cost necessary to respond to technological and market developments;

the costs of filing, prosecuting, maintaining, defending and enforcing any patent claims and other intellectual property rights, including litigation costs
and the outcome of such litigation, including costs of defending any claims of infringement brought by others in connection with the development,
manufacture or commercialization of tenapanor or any of our product candidates; and

the payment of interest and principal related to our loan and security agreement entered into with SLR Investment Corp. in February 2022.

Additional funds may not be available when we need them on terms that are acceptable to us, or at all. If adequate funds are not available to us on a timely
basis, we may be required to delay, limit, reduce or terminate our commercialization of IBSRELA, our efforts to secure approval for XPHOZAH for the
hyperphosphatemia indication, or clinical trials for tenapanor or RDX013. Additionally, our inability to access capital on a timely basis and on terms that
are  acceptable  to  us  may  force  us  to  restructure  certain  aspects  of  our  business  or  identify  and  complete  one  or  more  strategic  collaborations  or  other
transactions in order to fund the development or commercialization of IBSRELA or XPHOZAH through the use of alternative structures.

Our failure to meet the continued listing requirements of The Nasdaq Global Market could result in a de-listing of our common stock.
If we fail to satisfy the continued listing requirements of The Nasdaq Global Market ("Nasdaq") such as the minimum stockholders’ equity requirement or
the minimum closing bid price requirement, Nasdaq may take steps to de-list our common stock. For example, on February 28, 2022 we received a letter
from Nasdaq indicating that Nasdaq had determined that we had failed to comply with the minimum bid price requirement of Nasdaq Listing Rule 5550(a)
(2). Nasdaq Listing Rule 5550(a)(2) requires that companies listed on the Nasdaq Global Market maintain a minimum closing bid price of at least $1.00 per
share. In accordance with Nasdaq Listing Rule 5810(c)(3)(A), we have been provided with a period of 180 calendar days, or until August 29, 2022, to
regain compliance with the minimum bid price requirement. We are monitoring the bid price of our common stock and will consider options available to us
to achieve compliance. If we fail to maintain compliance with this requirement, or any other of the continued listing requirements of The Nasdaq Global
Market, Nasdaq may take steps to de-list our common stock.

If  Nasdaq  de-lists  our  securities  for  trading  on  the  Nasdaq  or  takes  other  actions  with  respect  to  our  Nasdaq  listing,  we  could  face  significant  adverse
consequences, including:

•    a limited availability of market quotations for our common stock;

•    reduced liquidity with respect to our common stock;

•    reduced trading volume in and market price of our common stock;

•    a limited amount of news and analyst coverage for our company; and

•    a decreased ability to issue additional securities or obtain additional financing in the future.

Such a de-listing would likely have an adverse effect on the price of our common stock and would impair your ability to sell or purchase our common stock
when you wish to do so. We may take actions to avoid such a de-listing or in the event of a de-listing, we may take actions to restore our compliance with
Nasdaq’s listing requirements, but we can provide no assurance that any such action taken by us would allow our common stock to remain listed or to
become listed again, stabilize the market price or improve the liquidity or trading volume of our common stock, prevent our common capitalization and
stockholder’s  equity  from  dropping  below  the  Nasdaq  minimum  requirements,  or  prevent  other  future  non-compliance  with  Nasdaq’s  continued  listing
requirements.

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We have never generated any revenue from product sales and may never be profitable.
We  received  FDA  approval  for  our  NDA  for  tenapanor  for  the  treatment  of  IBS-C  in  adults  in  September  2019,  and  we  currently  expect  to  launch
IBSRELA in April 2022. We have no other products approved for sale and have received a CRL from the FDA for our NDA for the Hyperphosphatemia
Indication and an Appeal Denied Letter (“ADL”) in response to our appeal of the CRL to the FDA Office of Cardiology, Hematology, Endocrinology and
Nephrology  (“OCHEN”).  There  can  be  no  assurances  that  our  NDA  for  tenapanor  for  the  Hyperphosphatemia  Indication  will  be  approved  for  such
indication or any other related indication. We have never generated any revenue from product sales. Our ability to generate revenue from product sales and
achieve profitability depends on our ability to successfully commercialize IBSRELA; obtain approval by the FDA for the Hyperphosphatemia Indication,
and  subsequently  successfully  commercialize  XPHOZAH  for  the  Hyperphosphatemia  Indication;  and  the  ability  of  our  collaboration  partners  to  obtain
regulatory approval to market tenapanor in their respective territories. There can be no assurances that we will generate sufficient product revenue from
sales  of  IBSRELA  and,  if  approved,  XPHOZAH,  to  cover  our  expenses.  Our  ability  to  generate  product  revenue  from  sales  or  pursuant  to  milestone
payments depends heavily on many factors, including but not limited to:

•

•

•

our ability to successfully commercialize IBSRELA;

obtaining market acceptance of IBSRELA as a viable treatment option for IBS-C;

our ability to obtain and sustain an adequate level of coverage and reimbursement for IBSRELA by third-party payors;

• whether we are successful in our efforts under the FDR process to secure approval for our NDA for tenapanor for the Hyperphosphatemia Indication,
or whether we are able during the FDR to reach resolution with the FDA regarding a path to addressing the deficiencies in our NDA noted in the CRL
and ADL that is achievable in terms of clinical study design, time and cost;

•

•

establishing and maintaining supply and manufacturing relationships with third parties that can provide an adequate (in amount and quality) supply of
product to support the market demand for IBSRELA, and, if approved, XPHOZAH;

addressing any competing technological and market developments;

• maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets, and know-how, and our ability to

develop, manufacture and commercialize our product candidates and products without infringing intellectual property rights of others; and

•

attracting, hiring, and retaining qualified personnel.

With respect to our commercialization of IBSRELA, and if we are successful in obtaining regulatory approval to market XPHOZAH, our revenue will be
dependent, in part, upon the size of the markets in the U.S. and the label for which approval is or was granted, accepted price for the product, the ability to
get reimbursement at any price. While there is significant uncertainty related to the insurance coverage and reimbursement of newly approved products in
general  in  the  United  States,  there  is  additional  uncertainty  related  to  insurance  coverage  and  reimbursement  for  drugs,  like  XPHOZAH,  which,  if
approved, will be marketed for the control of serum phosphorus in adult patients with CKD on dialysis or for another other related indication. If we are
successful  in  obtaining  regulatory  approval  to  market  XPHOZAH  for  such  indication,  our  ability  to  generate  and  sustain  future  revenues  from  sales  of
tenapanor for such indication, may be dependent upon whether and when XPHOZAH, along with other oral ESRD related drugs without an injectable or
intravenous equivalent, are bundled into the ESRD prospective payment system, and the manner in which such introduction into the ESRD prospective
payment  system  may  occur.  See  “Third-party  payor  coverage  and  reimbursement  status  of  newly-approved  products  is  uncertain.  Failure  to  obtain  or
maintain adequate coverage and reimbursement for IBSRELA or XPHOZAH, if approved, could limit our ability to market those products and decrease
our ability to generate revenue” below. Additionally, if the number of adult patients for IBSRELA or XPHOZAH, if approved, is not as significant as we
estimate, the indication approved by regulatory authorities for XPHOZAH is narrower than we expect, coverage and reimbursement for either IBSRELA or
XPHOZAH, if approved, are not available in the manner and to the extent we expect, or the reasonably accepted population for treatment is narrowed by
competition, physician choice or treatment guidelines, we may not generate significant revenue from the sale of IBSRELA or XPHOZAH, if approved.
Even if we achieve profitability in the future, we may not be able to sustain profitability in subsequent periods. Our failure to generate adequate revenue
from  product  sales  would  likely  depress  our  market  value  and  could  impair  our  ability  to  raise  capital,  expand  our  business,  discover  or  develop  other
product  candidates  or  continue  our  operations.  A  decline  in  the  value  of  our  common  stock  could  cause  our  stockholders  to  lose  all  or  part  of  their
investment.

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Principal Risks Related to Our Business

We are substantially dependent on the successful launch and commercialization of IBSRELA for IBS-C, and there is no guarantee that we will achieve
sufficient market acceptance for IBSRELA; secure adequate coverage and reimbursement for IBSRELA; or generate sufficient revenue from product
sales of IBSRELA.

In November 2021, we announced plans to launch IBSRELA, our approved treatment for IBS-C in adults. We are investing a significant portion of our
efforts and financial resources to prepare for and fund the commercialization of IBSRELA, which we currently expect to commence in April 2022. Our
ability to successfully launch IBSRELA, and the overall commercial success of IBSRELA will depend on a number of factors, including the following:

•

•

•

•

•

•

•

•

•

•

•

the  ability  of  the  third-party  manufacturers  we  contract  with  to  provide  an  adequate  (in  amount  and  quality)  supply  of  product  to  support  the
launch and market demand for IBSRELA;

our ability to obtain and sustain an adequate level of coverage and reimbursement for IBSRELA by third-party payors;

the effectiveness of IBSRELA as a treatment for adult patients with IBS-C;

the size of the treatable patient population;

the effectiveness of our sales, market access and marketing efforts;

the  adoption  of  IBSRELA  by  physicians  for  the  treatment  of  IBS-C,  depends  upon  whether  physicians  view  IBSRELA  as  a  safe  and  effective
treatment for adult patients with IBS-C;

the  availability,  perceived  advantages,  relative  cost,  relative  safety  and  relative  efficacy  of  IBSRELA  compared  to  alternative  and  competing
treatments; and

the prevalence and severity of adverse side effects of IBSRELA;

our potential involvement in lawsuits in connection with enforcing intellectual property rights in and to IBSRELA;

our  potential  involvement  in  third-party  interference,  opposition,  derivation  or  similar  proceedings  with  respect  to  our  patent  rights  directed  to
IBSRELA, and avoiding other challenges to our patent rights and patent infringement claims; and

a continued acceptable safety and tolerability profile of IBSRELA following approval.

Our potential to achieve revenue from the commercialization of IBSRELA and the amount of such potential revenue is subject to these and other factors,
and  may  be  unpredictable  from  quarter-to-quarter.  If  the  number  of  patients  in  the  market  for  IBSRELA  or  the  price  that  the  market  can  bear  is  not  as
significant as we estimate, or if we are not able to secure adequate physician and patient acceptance of IBSRELA or adequate coverage and reimbursement
for IBSRELA, we may not generate sufficient revenue from sales of IBSRELA. Any failure of IBSRELA to achieve market acceptance, sufficient third-
party coverage or reimbursement, or commercial success for would adversely affect our results of operations.

Our success is also dependent upon our ability to obtain regulatory approval for tenapanor for the control of serum phosphorus in adult patients with
CKD on dialysis, and there can be no assurances that we will be successful in obtaining such regulatory approval.

Our success is also dependent upon our ability to obtain regulatory approval for tenapanor for the control of serum phosphorus in adult patients
with CKD on dialysis. To date, we have invested a significant amount of our efforts and financial resources in the research and development of tenapanor
for the control of serum phosphorus in adult patients with CKD on dialysis. On July 28, 2021, we received a CRL from the’FDA's Division of Cardiology
and Nephrology (the “Division”) regarding our NDA for tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis. According
to the CRL, the FDA has determined that the magnitude of the treatment effect observed in our Phase 3 clinical trials was small and of unclear of clinical
significance. Following an End-of-Review Type A meeting (“End of Review Meeting”) in October 2021, with the Division, we submitted a Formal Dispute
Resolution Request (“FDRR”) in December 2021. The FDRR was focused on demonstrating that the data submitted in the NDA supported the clinical
significance of the treatment effect of tenapanor. On February 4, 2022, we received an ADL from OCHEN. On February 18, 2022, we submitted an appeal
of the ADL to the FDA’s

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Center for Drug Evaluation and Research, Office of New Drugs (“OND”). If accepted, we expect a decision on the appeal to the OND in April 2022. There
can be no assurances that the Formal Dispute Resolution (“FDR”) process will result in approval of our NDA, or in a clear path to resubmission of our
NDA that is achievable in terms of clinical study design, time and cost. As a result, the regulatory approval process for our NDA is highly uncertain. We
may  not  obtain  approval  at  all,  and  if  we  are  able  to  obtain  approval,  the  expense  and  time  to  do  so  could  adversely  impact  our  ability  to  successfully
commercialize XPHOZAH, our business and our results of operations.

Even if we are successful in obtaining regulatory approval for tenapanor for control of serum phosphorus in adult patients with CKD on dialysis, the
expense and time required to do so could adversely impact our ability to successfully commercialize XPHOZAH for the Hyperphosphatemia Indication.

We may not be successful in obtaining approval for tenapanor for the Hyperphosphatemia Indication, and if we are able to obtain approval, the expense and
time to do so could adversely impact our ability to successfully commercialize XPHOZAH for the Hyperphosphatemia Indication, our business and our
results  of  operations.  If  we  are  successful  in  obtaining  approval  for  XPHOZAH  for  the  Hyperphosphatemia  Indication,  the  commercial  success  of
XPHOZAH will depend on a number of factors, including the following:

•

the ability of the third-party manufacturers we contract with to provide an adequate (in amount and quality) supply of product to support the market
demand for both IBSRELA and XPHOZAH;

• whether  or  not  the  content  and  breadth  of  the  label  approved  by  the  FDA  for  XPHOZAH  may  materially  and  adversely  impact  our  ability  to

commercialize the product for the approved indication;

• whether or when XPHOZAH, along with other oral end-stage renal disease (“ESRD”) related drugs without an injectable or intravenous equivalent,
are bundled into the ESRD prospective payment system, and the manner in which such introduction into the ESRD prospective payment system may
occur;

•

•

•

•

•

•

•

•

the prevalence and severity of adverse side effects of XPHOZAH;

acceptance of XPHOZAH as safe, effective and well-tolerated by patients and the medical community, and, the extent to which the issuance of a CRL
by the FDA has impacted the potential acceptance of XPHOZAH as safe, effective and well-tolerated;

our ability to manage the commercialization of IBSRELA and XPHOZAH and the complex pricing and reimbursement negotiations that may arise
with marketing the same product at different doses for separate indications;

the  availability,  perceived  advantages,  relative  cost,  relative  safety  and  relative  efficacy  of  XPHOZAH  compared  to  alternative  and  competing
treatments;

obtaining and sustaining an adequate level of coverage and reimbursement for XPHOZAH by third-party payors;

our potential involvement in lawsuits in connection with enforcing intellectual property rights in and to XPHOZAH;

our potential involvement in third-party interference, opposition, derivation or similar proceedings with respect to our patent rights, and avoiding other
challenges to our patent rights and patent infringement claims; and

a continued acceptable safety and tolerability profile of XPHOZAH following approval.

IBSRELA,  and/or  XPHOZAH,  if  approved  and  commercialized,  may  cause  undesirable  side  effects  or  have  other  properties  that  could  limit  the
commercial success of the product.

Undesirable  side  effects  caused  by  IBSRELA,  and/or  XPHOZAH,  if  approved,  could  cause  us  or  regulatory  authorities  to  interrupt,  delay  or  halt  the
commercialization of the product. To date, the most common adverse reactions reported in at least 2% of patients in IBSRELA-treated patients and at an
incidence greater than placebo in the two Phase 3 trials include: diarrhea, abdominal distension, flatulence and dizziness. Despite our receipt of marketing
approval for IBSRELA and the completion of our Phase 3 clinical program for XPHOZAH, the prevalence and/or severity of these or other side effects
could result in a number of potentially significant negative consequences could occur, including:

•

regulatory authorities may withdraw their approval of the product or seize the product;

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• we or a collaboration partner may be required to recall the product;

•

additional restrictions may be imposed on the marketing of the particular product or the manufacturing processes for the product or any component
thereof,  including  the  imposition  of  a  Risk  Evaluation  and  Mitigation  Strategy  (“REMS”)  which  could  require  creation  of  a  Medication  Guide  or
patient package insert outlining the risks of such side effects for distribution to patients, a communication plan to educate healthcare providers of the
drugs’ risks, as well as other elements to assure safe use of the product, such as a patient registry and training and certification of prescribers;

• we or a collaboration partner may be subject to fines, injunctions or the imposition of civil or criminal penalties;

•

regulatory authorities may require the addition of new labeling statements, such as a “black box” warning or a contraindication;

• we could be sued and held liable for harm caused to patients;

•

•

the product may become less competitive; and

our reputation may suffer.

Any  of  the  foregoing  events  could  prevent  us,  or  a  collaboration  partner,  from  achieving  or  maintaining  market  acceptance  of  IBSRELA,  and/or
XPHOZAH, if approved, and could result in the loss of significant revenue to us, which would materially and adversely affect our results of operations and
business.

We  have  no  prior  experience  in  the  marketing,  sale  and  distribution  of  pharmaceutical  products;  and  there  are  significant  risks  in  building  and
managing a commercial organization.

Prior to the receipt of the CRL for our NDA for the Hyperphosphatemia Indication, we had made significant progress in the establishment of our sales,
marketing,  and  access  organizations.  Many  members  of  those  teams  had  their  positions  eliminated  by  our  restructuring  plans  adopted  in  August  and
October 2021. In November 2021, we announced our plans to commercialize IBSRELA and commenced our efforts to rebuild the critical components of
the  sales,  marketing  and  access  teams  aligned  to  the  IBSRELA  commercial  opportunity.  As  a  company,  we  have  no  prior  experience  in  building  and
managing a commercial organization, or in the marketing, sale and distribution of pharmaceutical products. There can be no assurances that we will be
successful  in  our  efforts  to  hire,  retain,  and  incentivize  qualified  individuals,  generate  sufficient  sales  leads,  provide  adequate  training  to  sales  and
marketing personnel, comply with regulatory requirements applicable to the marketing and sale of drug products and effectively manage a geographically
dispersed sales and marketing team.

If we fail or are delayed in the development of our internal sales, marketing and distribution capabilities, we may need to delay the commercialization of
IBSRELA, or commercialization could be adversely impacted.

Our operating activities may be restricted as a result of covenants related to the indebtedness under our loan and security agreement and we may be
required to repay the outstanding indebtedness in an event of default, which could have a materially adverse effect on our business.

On February 23, 2022, we entered into a loan and security agreement with SLR Investment Corp. (the “Lender”) pursuant to which the Lender agreed to
provide us a $50.0 million term loan facility with a maturity date of March 1, 2027. The loan was funded in the amount of $27.5 million on February 23,
2022 and the remaining $22.5 million may be funded upon the satisfaction of both of the following conditions precedent to funding (i) receipt from the
FDA  of  approval  of  the  NDA  for  tenapanor  for  the  Hyperphosphatemia  Indication  on  or  prior  to  December  31,  2022  and  (ii)  our  achievement  of  a
minimum  of  $30.0  million  in  net  product  revenue  calculated  on  a  trailing  six  month  basis.  Until  we  have  repaid  all  funded  indebtedness,  the  loan  and
security agreement subjects us to various customary covenants, including requirements as to financial reporting and insurance and restrictions on our ability
to dispose of our business or property, to change our line of business, to liquidate or dissolve, to enter into any change in control transaction, to merge or
consolidate with any other entity or to acquire all or substantially all the capital stock or property of another entity, to incur additional indebtedness, to incur
liens on our property, to pay any dividends or other distributions on capital stock other than dividends payable solely in capital stock, to redeem capital
stock, to enter into licensing agreements, to engage in transactions with affiliates, and to encumber our intellectual property. Our business may be adversely
affected by these restrictions on our ability to operate our business.

We  are  permitted  to  make  interest  only  payments  on  the  loan  facility  through  March  2024,  with  principal  repayments  commencing  on  April  1,  2024,
however, we may be required to repay the outstanding indebtedness under the loan facility if an

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event of default occurs under the loan and security agreement. An event of default will occur if, among other things, we fail to make payments under the
loan  and  security  agreement;  we  breach  any  of  our  covenants  under  the  loan  and  security  agreement,  subject  to  specified  cure  periods  with  respect  to
certain breaches; the Lender determines that a material adverse change has occurred; we or our assets become subject to certain legal proceedings, such as
bankruptcy proceedings; we are unable to pay our debts as they become due; or we default on contracts with third parties which would permit the Lender to
accelerate the maturity of such indebtedness or that could have a material adverse change on us. We may not have enough available cash or be able to raise
additional funds through equity or debt financings to repay such indebtedness at the time any such event of default occurs. In this case, we may be required
to delay, limit, reduce or terminate our activities necessary to commercialize IBSRELA, and/or if approved, XPHOZAH, clinical trials for tenapanor or
RDX013, the Lender could also exercise its rights as collateral agent to take possession of and to dispose of the collateral securing the term loans, which
collateral includes substantially all of our property (excluding intellectual property, which is subject to a negative pledge). Our business, financial condition
and results of operations could be materially adversely affected as a result of any of these events.

Third-party  payor  coverage  and  reimbursement  status  of  newly  commercialized  products  are  uncertain.  Failure  to  obtain  or  maintain  adequate
coverage and reimbursement for IBSRELA and XPHOZAH, if approved, could limit our ability to market those products and decrease our ability to
generate revenue.
The  pricing,  coverage  and  reimbursement  of  IBSRELA  and  XPHOZAH,  if  approved,  must  be  adequate  to  support  a  commercial  infrastructure.  The
availability and adequacy of coverage and reimbursement by governmental and private payors are essential for most patients to be able to afford treatments.
Sales of IBSRELA, and XPHOZAH, if approved and commercialized, will depend substantially, both domestically and abroad, on the extent to which the
costs  of  the  product  will  be  paid  for  by  health  maintenance,  managed  care,  pharmacy  benefit,  and  similar  healthcare  management  organizations,  or
reimbursed  by  government  authorities,  private  health  insurers,  and  other  third-party  payors.  If  coverage  and  reimbursement  are  not  available,  or  are
available only to limited levels, we, or our collaboration partners, may not be able to successfully commercialize IBSRELA, or XPHOZAH, if approved.
Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize
a return on our investment.
There  is  significant  uncertainty  related  to  the  insurance  coverage  and  reimbursement  of  newly  approved  products.  In  the  United  States,  the  principal
decisions  about  coverage  and  reimbursement  for  new  drugs  are  typically  made  by  the  Centers  for  Medicare  &  Medicaid  Services  (“CMS”),  an  agency
within the United States Department of Health and Human Services responsible for administering the Medicare program, as CMS 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 substantial degree. It is difficult to predict what CMS will decide with respect to reimbursement for products such as ours.
There is increased uncertainty related to insurance coverage and reimbursement for drugs, like XPHOZAH for the Hyperphosphatemia Indication, which, if
approved, will be marketed for the control of serum phosphorus in adult patients with CKD on dialysis or for another other related indication. In January
2011, CMS implemented a new prospective payment system for dialysis treatment. Under the ESRD prospective payment system, CMS generally makes a
single  bundled  payment  to  the  dialysis  facility  for  each  dialysis  treatment  that  covers  all  items  and  services  routinely  required  for  dialysis  treatments
furnished to Medicare beneficiaries in Medicare-certified ESRD facilities or at their home, including the cost of certain routine drugs. The inclusion of oral
medications  without  injectable  or  intravenous  equivalents  in  the  bundled  payment  was  initially  delayed  until  January  1,  2014,  and  through  several
subsequent legislative actions was delayed until January 1, 2025. As a result, absent further legislation or regulation on this matter, beginning in 2025, oral
ESRD-related drugs without injectable or intravenous equivalents may be included in the ESRD bundle and separate Medicare payment for these drugs will
no  longer  be  available,  as  is  the  case  today  under  Medicare  Part  D.  While  it  is  too  early  to  project  the  full  impact  that  bundling  may  have  on  sales  of
XPHOZAH, if approved and commercialized, and on our business should XPHOZAH be brought into the bundle in 2025, or at any time, we may be unable
to sell XPHOZAH for the Hyperphosphatemia Indication, if approved, to dialysis providers on a profitable basis if third-party payors reduce their current
levels of payment, or if our costs of production are higher than levels necessary for an appropriate gross margin after payment of all discounts, rebates and
chargebacks.

Outside  the  United  States,  international  operations  are  generally  subject  to  extensive  governmental  price  controls  and  other  market  regulations,  and  we
believe the increasing emphasis on cost-containment initiatives in Europe, Canada, Japan, China and other countries has and will continue to put pressure
on the pricing and usage of IBSRELA and XPHOZAH, even if regulatory approval is received in such countries. In many countries, the prices of medical
products are subject to varying price control mechanisms as part of national health systems. Other countries allow companies to fix their own prices for
medicinal  products,  but  monitor  and  control  company  profits.  Additional  foreign  price  controls  or  other  changes  in  pricing  regulation  could  restrict  the
amount that we are able to charge for our product candidates. Accordingly, in markets outside the United States, the reimbursement for our products may be
reduced compared with the United States and may be insufficient to generate commercially reasonable revenue and profits.

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Moreover,  increasing  efforts  by  governmental  and  third-party  payors  in  the  United  States  and  abroad  to  cap  or  reduce  healthcare  costs  may  cause  such
organizations to limit both coverage and the level of reimbursement for newly approved products and, as a result, these caps may not cover or provide
adequate payment for our product candidates. We expect to experience pricing pressures in connection with the sale of IBSRELA, and if approved and
commercialized,  XPHOZAH,  due  to  the  trend  toward  managed  healthcare,  the  increasing  influence  of  health  maintenance  organizations,  and  additional
legislative changes. The downward pressure on healthcare costs in general, particularly prescription drugs and surgical procedures and other treatments, has
become very intense. As a result, increasingly high barriers are being erected to the entry of new products.

We  rely  completely  on  third  parties  to  manufacture  IBSRELA,  XPHOZAH  and  RDX013.  If  they  are  unable  to  comply  with  applicable  regulatory
requirements, unable to source sufficient raw materials, experience manufacturing or distribution difficulties or are otherwise unable to manufacture
sufficient  quantities  to  meet  demand,  our  commercialization  of  IBSRELA,  and  XPHOZAH,  if  approved  and  commercialized,  and  our  development
efforts for tenapanor and RDX013 may be materially harmed.

We  do  not  currently  have,  nor  do  we  plan  to  acquire,  the  infrastructure  or  capability  internally  to  manufacture  IBSRELA,  or  any  of  other  our  product
candidates on a commercial scale, or to manufacture our drug supplies for use in the conduct of our nonclinical and clinical studies. The facilities used by
our contract manufacturers to manufacture our drug supply are subject to inspection by the FDA. Our ability to control the manufacturing process of our
product  candidates  is  limited  to  the  contractual  requirements  and  obligations  we  impose  on  our  contract  manufacturer.  Although  they  are  contractually
required to so do, we are completely dependent on our contract manufacturing partners for compliance with the regulatory requirements, known as current
Good Manufacturing Practice requirements (“cGMPs”), for manufacture of both active drug substances and finished drug products.
The  manufacture  of  pharmaceutical  products  requires  significant  expertise  and  capital  investment.  Manufacturers  of  pharmaceutical  products  often
encounter  difficulties  in  commercial  production.  These  problems  may  include  difficulties  with  production  costs  and  yields,  quality  control,  including
stability of the product and quality assurance testing, and shortages of qualified personnel, as well as compliance with federal, state and foreign regulations
and the challenges associated with complex supply chain management. Even if our contract manufacturers do not experience problems and commercial
manufacturing  is  achieved,  their  maximum  or  available  manufacturing  capacities  may  be  insufficient  to  meet  commercial  demand.  Finding  alternative
manufacturers or adding additional manufacturers requires a significant amount of time and involves significant expense. New manufacturers would need
to develop and implement the necessary production techniques and processes, which along with their facilities, would need to be inspected and approved by
the regulatory authorities in each applicable territory. In addition, the raw materials necessary to make API for our products are acquired from a limited
number of sources. Any delay or disruption in the availability of these raw materials could result in production disruptions, delays or higher costs with
consequent adverse effects on us.
If our contract manufacturers fail to adhere to applicable GMP or other regulatory requirements, experience delays or disruptions in the availability of raw
materials  or  experience  manufacturing  or  distribution  problems,  we  may  suffer  significant  consequences,  including  the  inability  to  meet  our  product
requirements for our clinical development programs, and if tenapanor is commercialized for any indication, such events could result in product seizures or
recalls, loss of product approval, fines and sanctions, reputational damage, shipment delays, inventory shortages, inventory write-offs and other product-
related charges and increased manufacturing costs. As a result, or if maximum or available manufacturing capacities are insufficient to meet demand, our
development or our commercialization efforts for IBSRELA, and/or XPHOZAH, if approved, may be materially harmed.

Additional Risks Related to Our Business and Industry

Clinical drug development involves a lengthy and expensive process with an uncertain outcome and the results of earlier studies and trials may not be
predictive of future trial results.

Before  obtaining  marketing  approval  from  regulatory  authorities  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  testing  is  expensive  and  can  take  many  years  to  complete,  and  its
outcome is inherently uncertain. Failure can occur at any time during the clinical trial process. The results of preclinical and clinical studies of our product
candidates, including RDX013, may not be predictive of the results of later-stage clinical trials. An unexpected adverse event profile, or the results of drug-
drug interaction studies, may present challenges for the future development and commercialization of a product candidate for a particular condition despite
receipt of positive efficacy data in a clinical study. A number of companies in the pharmaceutical, biopharmaceutical and biotechnology industries have
suffered significant setbacks in advanced clinical trials for similar

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indications that we are pursuing due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier studies, and we cannot be
certain that we will not face similar setbacks.

We could encounter delays in our future development of RDX013 if any clinical trials are suspended or terminated by us, by the IRBs of the institutions in
which the trial is being conducted, or by the FDA or other regulatory authorities. Such authorities may suspend or terminate a clinical trial due to a number
of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial
operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side
effects, failure to demonstrate a benefit from using a drug, changes in governmental regulations or administrative actions or lack of adequate funding to
continue the clinical trial.

In addition, identifying and qualifying patients to participate in our RDX013 clinical trials is critical to the success of the clinical trials. The timing of our
clinical trials depends, in part, on the speed at which we can recruit patients to participate in testing our product candidates. Patients may be unwilling to
participate in our clinical studies because of concerns about adverse events observed with the current standard of care, competitor products and/or other
investigational agents, in each case for the same indications and/or similar patient populations. In addition, patients currently receiving treatment with the
current standard of care or a competitor product may be reluctant to participate in a clinical trial with an investigational drug, or our inclusion and exclusion
criteria  for  our  clinical  trials  may  present  challenges  in  identifying  acceptable  patients.  As  a  result,  the  timeline  for  recruiting  patients  and  conducting
RDX013 clinical trials may be delayed. These delays could result in increased costs, delays in advancing our development of RDX013, or termination of
the clinical studies altogether. Any of these occurrences may significantly harm our business, financial condition and prospects.

We  will  rely  on  third  parties  to  conduct  all  of  our  nonclinical  studies  and  clinical  trials.  If  these  third  parties  do  not  successfully  carry  out  their
contractual duties or meet expected deadlines, we may be unable to obtain regulatory approval for additional products or commercialize our product
candidates.

We do not have the ability to independently conduct nonclinical studies or clinical trials. We rely on medical institutions, clinical investigators, contract
laboratories,  and  other  third  parties,  such  as  CROs,  to  conduct  clinical  trials  on  our  product  candidates.  The  third  parties  with  whom  we  contract  for
execution of the clinical trials play a significant role in the conduct of these trials and the subsequent collection and analysis of data. However, these third
parties are not our employees, and except for contractual duties and obligations, we control only certain aspects of their activities and have limited ability to
control the amount or timing of resources that they devote to our programs. Although we rely, and will continue to rely, on these third parties to conduct our
nonclinical studies and our clinical trials, we remain responsible for ensuring that each of our studies and clinical trials is conducted in accordance with the
applicable protocol, legal, regulatory and scientific standards and our reliance on third parties does not relieve us of our regulatory responsibilities. We, and
these third parties are required to comply with current GLPs for nonclinical studies, and good clinical practices (“GCPs”) for clinical studies. GLPs and
GCPs are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area (“EEA”) and
comparable foreign regulatory authorities for all of our products in nonclinical and clinical development, respectively. Regulatory authorities enforce GCPs
through  periodic  inspections  of  trial  sponsors,  principal  investigators  and  trial  sites.  If  we  or  any  of  our  third-party  contractors  fail  to  comply  with
applicable regulatory requirements, including GCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, the European
Medicines  Agency  (“EMA”),  or  comparable  foreign  regulatory  authorities  may  require  us  to  perform  additional  clinical  trials  before  approving  our
marketing applications. There can be no assurance that upon inspection by a given regulatory authority, such regulatory authority will determine that any of
our clinical trials comply with GCP regulations. In addition, our clinical trials must be conducted with product produced under cGMP regulations. Our
failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process.

We face substantial competition, and our competitors may discover, develop or commercialize products faster or more successfully than us.

The  biotechnology  and  pharmaceutical  industries  are  highly  competitive,  and  we  face  significant  competition  from  companies  in  the  biotechnology,
pharmaceutical  and  other  related  markets  that  are  researching  and  marketing  products  designed  to  address  diseases  that  we  are  currently  developing
products to treat. If approved for marketing by the FDA or other regulatory agencies, tenapanor, as well as our other product candidates, would compete
against existing treatments.

For  example,  numerous  treatments  exist  for  constipation  and  the  constipation  component  of  IBS-C,  many  of  which  are  over-the-counter.  These  include
psyllium  husk  (such  as  Metamucil),  methylcellulose  (such  as  Citrucel),  calcium  polycarbophil  (such  as  FiberCon),  lactulose  (such  as  Cephulac),
polyethylene glycol (such as MiraLax), sennosides (such as Exlax), bisacodyl

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(such as Ducolax), docusate sodium (such as Colace), magnesium hydroxide (such as Milk of Magnesia), saline enemas (such as Fleet), and sorbitol. These
agents are generally inexpensive and work well to temporarily relieve constipation.

We  are  aware  of  four  prescription  products  marketed  for  certain  patients  with  IBS-C,  including  Linzess  (linaclotide),  Amitiza  (lubiprostone),  Trulance
(plecanatide) and Zelnorm (tegaserod maleate).

Additionally, XPHOZAH, if approved for the Hyperphosphatemia Indication will compete with phosphate binders used for the same or similar indication`.
If approved, our label for XPHOZAH may include data comparing the effectiveness of tenapanor to phosphate binders used for the same indication. The
various types of phosphate binders commercialized in the United States include the following:

•

•

•

•

•

•

•

Calcium carbonate (many over-the-counter brands including Tums and Caltrate);

Calcium acetate (several prescription brands including PhosLo and Phoslyra);

Lanthanum carbonate (Fosrenol);

Sevelamer hydrochloride (Renagel);

Sevelamer carbonate (Renvela);

Sucroferric oxyhydroxide (Velphoro); and

Ferric citrate (Auryxia).

All of the phosphate binders listed above are available as generics in the U.S., with the exception of Velphoro and Auryxia. In addition to the currently
available phosphate binders, we are aware of at least two other binders in development, including fermagate (Alpharen), an iron-based binder in Phase 3
being developed by Opko Health, Inc., and PT20, an iron-based binder in Phase 3 being developed by Shield Therapeutics.

It is possible that our competitors' drugs may be less expensive and more effective than our product candidates, or that will render our product candidates
obsolete. It is also possible that our competitors will commercialize competing drugs or treatments before we or our collaboration partners can launch any
products developed from our product candidates. We also anticipate that we will face increased competition in the future as new companies enter into our
target markets.

Many of our competitors have materially greater name recognition and financial, manufacturing, marketing, research and drug development resources than
we do. Additional mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our
competitors. Large pharmaceutical companies in particular have extensive expertise in preclinical and clinical testing and in obtaining regulatory approvals
for  drugs.  In  addition,  academic  institutions,  government  agencies,  and  other  public  and  private  organizations  conducting  research  may  seek  patent
protection with respect to potentially competitive products or technologies. These organizations may also establish exclusive collaboration partnerships or
licensing relationships with our competitors.

We may experience difficulties in managing our current activities and growth given our level of managerial, operational, financial and other resources.

While  we  have  continued  to  work  to  optimize  our  management  composition,  personnel  and  systems  to  support  our  current  activities  for  future  growth,
these resources may not be adequate for this purpose. Our need to effectively execute our business strategy requires that we:

• manage any commercialization activities in which we may engage effectively;

• manage our clinical trials effectively;

• manage our internal development efforts effectively while carrying out our contractual obligations to licensors, contractors, collaborators, government

agencies and other third parties;

•

continue to improve our operational, financial and management controls, reporting systems and procedures; and

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•

retain and motivate our remaining employees and potentially identify, recruit, and integrate additional employees.

If we are unable to maintain or expand our managerial, operational, financial and other resources to the extent required to manage our development and
commercialization activities, our business will be materially adversely affected.

If product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization of IBSRELA,
and/or XPHOZAH, if approved.

We face an inherent risk of product liability as a result of the clinical testing of our product candidates and will face an even greater risk following the
commercial launch of IBSRELA in April 2022. For example, we may be sued if any product we develop allegedly causes injury or is found to be otherwise
unsuitable during product testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing,
defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability, and a breach of warranties. Claims could also be asserted
under state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be
required  to  limit  commercialization  of  our  product  candidates.  Even  successful  defense  would  require  significant  financial  and  management  resources.
Regardless of the merits or eventual outcome, liability claims may result in:

•

•

decreased demand for the product;

injury to our reputation;

• withdrawal of clinical trial participants;

•

•

•

•

•

•

costs to defend the related litigation;

a diversion of management’s time and our resources;

substantial monetary awards to trial participants or patients;

regulatory investigations, product recalls or withdrawals, or labeling, marketing or promotional restrictions;

loss of revenue; and

the inability to commercialize or co-promote our IBSRELA, and/or XPHOZAH, if approved.

Our inability to obtain and maintain sufficient product liability insurance at an acceptable cost and scope of coverage to protect against potential product
liability claims could prevent or inhibit the commercialization of any products we develop. Although we maintain product liability insurance, any claim
that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that
is  in  excess  of  the  limits  of  our  insurance  coverage.  Our  insurance  policies  also  have  various  exclusions  and  deductibles,  and  we  may  be  subject  to  a
product liability claim for which we have no coverage. We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our
coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts. Moreover,
in the future, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses.

If we fail to attract, retain and motivate our executives, senior management and key personnel, our business will suffer.

Recruiting and retaining qualified scientific, clinical, medical, manufacturing, and sales and marketing personnel is critical to our success. We are highly
dependent on our executives, senior management and certain other key employees. The loss of the services of our executives, senior management or other
key employee could impede the achievement of our development and commercial objectives and seriously harm our ability to successfully implement our
business strategy. Furthermore, replacing executives, senior management and other key employees may be difficult and may take an extended period of
time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain marketing
approval of and commercialize products. We may be unable to hire, train or motivate these key personnel on acceptable terms given the intense competition
among numerous biopharmaceutical companies for similar personnel, particularly in our geographic regions. If we are unable to continue to attract and
retain high quality personnel, our ability to grow and pursue our business strategy will be limited.

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Actual or perceived failures to comply with applicable data protection, privacy and security laws, regulations, standards and other requirements could
adversely affect our business, results of operations, and financial condition.

The global data protection landscape is rapidly evolving, and we are or may become subject to numerous state, federal and foreign laws, requirements and
regulations governing the collection, use, disclosure, retention, and security of personal data, such as information that we may collect in connection with
clinical trials in the U.S. and abroad. Implementation standards and enforcement practices are likely to remain uncertain for the foreseeable future, and we
cannot  yet  determine  the  impact  future  laws,  regulations,  standards,  or  perception  of  their  requirements  may  have  on  our  business.  This  evolution  may
create  uncertainty  in  our  business,  affect  our  ability  to  operate  in  certain  jurisdictions  or  to  collect,  store,  transfer  use  and  share  personal  information,
necessitate the acceptance of more onerous obligations in our contracts, result in liability or impose additional costs on us. The cost of compliance with
these laws, regulations and standards is high and is likely to increase in the future. Any failure or perceived failure by us to comply with federal, state or
foreign laws or regulation, our internal policies and procedures or our contracts governing our processing of personal information could result in negative
publicity, government investigations and enforcement actions, claims by third parties and damage to our reputation, any of which could have a material
adverse effect on our operations, financial performance and business.

As our operations and business grow, we may become subject to or affected by new or additional data protection laws and regulations and face increased
scrutiny  or  attention  from  regulatory  authorities.  In  the  U.S.,  HIPAA  imposes,  among  other  things,  certain  standards  relating  to  the  privacy,  security,
transmission and breach reporting of individually identifiable health information. We may obtain health information from third parties (including research
institutions  from  which  we  obtain  clinical  trial  data)  that  are  subject  to  privacy  and  security  requirements  under  HIPAA.  Depending  on  the  facts  and
circumstances, we could be subject to significant penalties if we violate HIPAA.

Certain states have also adopted comparable privacy and security laws and regulations, some of which may be more stringent than HIPAA. Such laws and
regulations will be subject to interpretation by various courts and other governmental authorities, thus creating potentially complex compliance issues for
us and our future customers and strategic partners. For example, the California Consumer Privacy Act ("CCPA") went into effect on January 1, 2020. The
CCPA creates individual privacy rights for California consumers and increases the privacy and security obligations of entities handling certain personal
information. The CCPA provides for civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data
breach  litigation.  Further,  the  California  Privacy  Rights  Act  (CPRA)  recently  passed  in  California.  The  CPRA  will  impose  additional  data  protection
obligations on covered businesses, including additional consumer rights processes, limitations on data uses, new audit requirements for higher risk data,
and opt outs for certain uses of sensitive data. It will also create a new California data protection agency authorized to issue substantive regulations and
could result in increased privacy and information security enforcement. The majority of the provisions will go into effect on January 1, 2023, and additional
compliance  investment  and  potential  business  process  changes  may  be  required.  Similar  laws  have  passed  in  Virginia  and  Colorado,  and  have  been
proposed in other states and at the federal level, reflecting a trend toward more stringent privacy legislation in the United States. The enactment of such
laws could have potentially conflicting requirements that would make compliance challenging. In the event that we are subject to or affected by HIPAA, the
CCPA,  the  CPRA  or  other  domestic  privacy  and  data  protection  laws,  any  liability  from  failure  to  comply  with  the  requirements  of  these  laws  could
adversely affect our financial condition.

Furthermore,  the  Federal  Trade  Commission  (FTC)  and  many  state  Attorneys  General  continue  to  enforce  federal  and  state  consumer  protection  laws
against companies for online collection, use, dissemination and security practices that appear to be unfair or deceptive. For example, according to the FTC,
failing to take appropriate steps to keep consumers’ personal information secure can constitute unfair acts or practices in or affecting commerce in violation
of Section 5(a) of the Federal Trade Commission Act. The FTC expects a company’s data security measures to be reasonable and appropriate in light of the
sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and
reduce vulnerabilities.

We are also or may become subject to rapidly evolving data protection laws, rules and regulations in foreign jurisdictions. For example, in Europe, the
European Union General Data Protection Regulation (GDPR) went into effect in May 2018 and imposes strict requirements for processing the personal
data of individuals within the European Economic Area (EEA). Among other requirements, the GDPR regulates transfers of personal data subject to the
GDPR to third countries that have not been found to provide adequate protection to such personal data, including the United States; in July 2020, the Court
of Justice of the EU (CJEU) limited how organizations could lawfully transfer personal data from the EU/EEA to the United States by invalidating the
Privacy  Shield  for  purposes  of  international  transfers  and  imposing  further  restrictions  on  the  use  of  standard  contractual  clauses.  Companies  that  must
comply with the GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and
potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater. Relatedly,
following the United

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Kingdom’s withdrawal from the European Economic Area and the European Union, and the expiry of the transition period, companies have to comply with
both the GDPR and the GDPR as incorporated into United Kingdom national law, the latter regime having the ability to separately fine up to the greater of
£17.5  million  or  4%  of  global  turnover.  The  relationship  between  the  United  Kingdom  and  the  European  Union  in  relation  to  certain  aspects  of  data
protection  law  remains  unclear,  for  example  around  how  data  can  lawfully  be  transferred  between  each  jurisdiction,  which  may  expose  us  to  further
compliance risk.

Although we work to comply with applicable laws, regulations and standards, our contractual obligations and other legal obligations, these requirements
are evolving and may be modified, interpreted and applied in an inconsistent manner from one jurisdiction to another, and may conflict with one another or
other  legal  obligations  with  which  we  must  comply.  Any  failure  or  perceived  failure  by  us  or  our  employees,  representatives,  contractors,  consultants,
CROs, collaborators, or other third parties to comply with such requirements or adequately address privacy and security concerns, even if unfounded, could
result in additional cost and liability to us, damage our reputation, and adversely affect our business and results of operations.

We and our collaborators, CROs and other contractors and consultants depend on information technology systems, and any failure of these systems
could  harm  our  business.  Security  breaches,  loss  of  data,  and  other  disruptions  could  compromise  sensitive  information  related  to  our  business  or
prevent us from accessing critical information and expose us to liability, which could adversely affect our business, results of operations and financial
condition.

We and our collaborators, CROs, and other contractors and consultants collect and maintain information in digital form that is necessary to conduct our
business, and we are increasingly dependent on information technology systems and infrastructure to operate our business. In the ordinary course of our
business,  we  and  our  collaborators,  CROs  and  other  contractors  and  consultants  collect,  store  and  transmit  large  amounts  of  confidential  information,
including  intellectual  property,  proprietary  business  information  and  personal  information.  It  is  critical  that  we  and  our  collaborators,  CROs  and  other
contractors and consultants do so in a secure manner to maintain the confidentiality and integrity of such confidential information. We have established
physical, electronic and organizational measures designed to safeguard and secure our systems to prevent a data compromise, and rely on commercially
available systems, software, tools, and monitoring to provide security for our information technology systems and the processing, transmission and storage
of digital information. We have also outsourced elements of our information technology infrastructure, and as a result a number of third-party vendors may
or  could  have  access  to  our  confidential  information.  Our  internal  information  technology  systems  and  infrastructure,  and  those  of  our  current  and  any
future collaborators, CROs, contractors and consultants and other third parties on which we rely, are vulnerable to damage from computer viruses, malware,
natural  disasters,  terrorism,  war,  telecommunication  and  electrical  failures,  cyber-attacks  or  cyber-intrusions  over  the  Internet,  attachments  to  emails,
persons inside our organization, or persons with access to systems inside our organization.

The  risk  of  a  security  breach  or  disruption  or  data  loss,  particularly  through  cyber-attacks  or  cyber  intrusion,  including  by  computer  hackers,  foreign
governments and cyber terrorists, has generally increased as the number, intensity and sophistication of attempted attacks and intrusions from around the
world  have  increased.  In  addition,  the  prevalent  use  of  mobile  devices  that  access  confidential  information  increases  the  risk  of  data  security  breaches,
which could lead to the loss of confidential information or other intellectual property. As a result of the COVID-19 pandemic, we may also face increased
cybersecurity risks due to our reliance on internet technology and the number of our employees who are working remotely, which may create additional
opportunities  for  cybercriminals  to  exploit  vulnerabilities.  Furthermore,  because  the  techniques  used  to  obtain  unauthorized  access  to,  or  to  sabotage,
systems  change  frequently  and  often  are  not  recognized  until  launched  against  a  target,  we  may  be  unable  to  anticipate  these  techniques  or  implement
adequate preventative measures. We may also experience security breaches that may remain undetected for an extended period. The costs to us to mitigate
network  security  problems,  bugs,  viruses,  worms,  malicious  software  programs  and  security  vulnerabilities  could  be  significant,  and  while  we  have
implemented  security  measures  to  protect  our  data  security  and  information  technology  systems,  our  efforts  to  address  these  problems  may  not  be
successful, and these problems could result in unexpected interruptions, delays, cessation of service and other harm to our business and our competitive
position. We and certain of our service providers are from time to time subject to cyberattacks and security incidents. While we do not believe that we have
experienced any significant system failure, accident or security breach to date. If such an event were to occur and cause interruptions in our operations, it
could  result  in  a  material  disruption  of  our  product  development  programs,  and/or  of  our  efforts  to  commercialize  tenapanor  for  the  control  of  serum
phosphorus  in  adult  patients  with  CKD  on  dialysis  or  for  another  other  related  indication,  if  approved.  For  example,  the  loss  of  clinical  trial  data  from
completed or 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. In addition, such a breach may require notification to governmental agencies, the media or individuals pursuant to various federal and
state privacy and security laws, if applicable. Moreover, if a computer security breach affects our systems or those of our collaborators, CROs or other
contractors, or results in the unauthorized release of personally identifiable information, our reputation could be materially damaged. We would also

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be  exposed  to  a  risk  of  loss  or  litigation  and  potential  liability,  which  could  materially  adversely  affect  our  business,  results  of  operations  and  financial
condition.

We have previously identified a material weakness in our internal control over financial reporting. If we fail to maintain proper and effective internal
controls,  our  ability  to  produce  accurate  and  timely  financial  statements  could  be  impaired,  which  could  harm  our  operating  results,  our  ability  to
operate our business and investors’ views of us and could have a material adverse effect on the price of our common stock.

In  2019,  management  and  our  independent  registered  public  accounting  firm  identified  a  control  deficiency  that  constituted  a  material  weakness  in  our
internal control over financial reporting. The material weakness was due to a failure in the design and implementation of controls over the evaluation of the
terms  of  our  clinical  trial  contracts  for  inclusion  into  our  clinical  financial  model  which  estimates  clinical  trial  expenses.  Specifically,  we  had  failed  to
properly interpret an expense in our clinical trial contracts which resulted in the over accrual of our clinical trial expenses during 2018 and the first quarter
of 2019.

We developed and implemented a remediation plan for this material weakness which included modifications to the design and implementation of certain
internal controls, and the material weakness was remediated as of December 31, 2019. Although we have remediated this material weakness, as attested by
our independent registered public accounting firm, we can give no assurance that an additional material weakness or significant deficiency in our internal
controls  over  financial  reporting  will  not  be  identified  in  the  future.  Our  failure  to  implement  and  maintain  effective  internal  controls  over  financial
reporting could result in errors in our financial statements that could result in a restatement of our financial statements and cause us to fail to meet our
reporting obligations. If we cannot in the future favorably assess the effectiveness of our internal controls over financial reporting, investor confidence in
the reliability of our financial reports may be adversely affected, which could have a material adverse effect on the trading price of our common stock.

We have formed in the past, and may form in the future, collaboration partnerships, joint ventures and/or licensing arrangements, and we may not
realize the benefits of such collaborations.

We have current collaboration partnerships for the commercialization of tenapanor in certain foreign countries, and we may form additional collaboration
partnerships, create joint ventures or enter into additional licensing arrangements with third parties in the United States and abroad that we believe will
complement or augment our existing business. In particular, we have formed collaboration partnerships with KKC for commercialization of tenapanor for
hyperphosphatemia in Japan; with Fosun Pharma for commercialization of tenapanor for hyperphosphatemia and IBS-C in China and related territories;
and in Canada with Knight for commercialization of tenapanor for IBS-C and hyperphosphatemia. We face significant competition in seeking appropriate
collaboration partners, and the process to identify an appropriate partner and negotiate appropriate terms is time-consuming and complex. Any delays in
identifying  suitable  additional  collaboration  partners  and  entering  into  agreements  to  develop  our  product  candidates  could  also  delay  the
commercialization of our product candidates, which may reduce their competitiveness even if they reach the market. There is no guarantee that our current
collaboration partnerships or any such arrangements we enter into in the future will be successful, or that any collaboration partner will commit sufficient
resources  to  the  development,  regulatory  approval,  and  commercialization  effort  for  such  products,  or  that  such  alliances  will  result  in  us  achieving
revenues that justify such transactions. We have received a CRL from the FDA regarding our NDA for the Hyperphosphatemia Indication. While we are
pursuing  an  appeal  through  the  FDR  process,  there  can  be  no  assurances  that  we  will  be  successful  in  obtaining  approval  for  tenapanor  for  the
Hyperphosphatemia Indication. Even if we are successful in obtaining approval for the NDA, the delay in obtaining such approval may result in delay in
the regulatory process for our partners, which could have a material adverse effect on our business and results of operations.

The ongoing COVID-19 pandemic, or any other outbreak of epidemic diseases, or the perception of their effects, could have a material adverse effect
on our business, financial condition, results of operations or cash flows.

Outbreaks of epidemic, pandemic, or contagious diseases, such as the current novel coronavirus (“COVID-19”) pandemic or, historically, the Ebola virus,
Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome or the H1N1 virus, could disrupt our business. Business disruptions could include
disruptions or restrictions on our ability to conduct our clinical trials, as planned, travel, as well as temporary closures of the facilities of our collaboration
partners,  suppliers  or  contract  manufacturers.  Any  disruption  of  our  clinical  trial  operations,  collaboration  partners,  suppliers  or  contract  manufacturers
could adversely impact our operating results.

Economic and health conditions related to the COVID-19 pandemic in the United States and across most of the globe remain uncertain and continue to
evolve. While at this point, the extent to which the coronavirus outbreak may impact our results is uncertain, it could result in delays in the manufacture of
tenapanor, or in the delivery of key intermediates or raw materials required to manufacture tenapanor or delays in clinical development activities by us, or
our collaboration partners. It

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could  also  materially  and  negatively  impact  our  ability  to  successfully  commercialize  IBSRELA,  and/or  XPHOZAH,  if  approved,  or  the  ability  of  our
collaboration partners to successfully commercialize such products, if approved for marketing and sale by the foreign regulatory authorities, including our
ability, and that of our collaboration partners to educate physicians and patients about the benefits, administration and use of the product.

• Although we have reopened our offices and invited our personnel to return to the office, we continue to permit our personnel to work remotely, which
could negatively impact productivity, or disrupt, delay, or otherwise adversely impact our business. In addition, this could increase our cyber-security
risk, create data accessibility concerns, and make us more susceptible to communication disruptions, any of which could adversely impact our business
operations or delay necessary interactions with local and federal regulators, ethics committees, manufacturing sites, research or clinical trial sites and
important agencies and contractors.

•

The FDA and comparable foreign regulatory agencies may continue to experience operational interruptions or delays, which may impact timelines for
regulatory submission, trial initiation and regulatory approval.

The  full  effects  of  the  COVID-19  remain  unknown.  The  extent  to  which  the  outbreak  may  continue  to  impact  our  business,  including,  our
commercialization and manufacturing will depend on future developments, which are highly uncertain and cannot be predicted with confidence, such as
access to physician offices for our commercial and medical teams, business closures or business disruptions.

We may engage in strategic transactions that could impact our liquidity, increase our expenses and present significant distractions to our management.

We  may  consider  strategic  transactions,  such  as  acquisitions  of  companies,  asset  purchases,  and/or  in-licensing  of  products,  product  candidates  or
technologies. In addition, if we are unable to access capital on a timely basis and on terms that are acceptable to us, we may be forced to further restructure
certain aspects of our business or identify and complete one or more strategic collaborations or other transactions in order to fund the commercialization of
IBSRELA, our continued efforts to seek approval for our NDA for tenapanor for the Hyperphosphatemia Indication and/or the development of RDX013
through  the  use  of  alternative  structures.  Additional  potential  transactions  that  we  may  consider  include  a  variety  of  different  business  arrangements,
including  spin-offs,  spin  outs,  collaboration  partnerships,  joint  ventures,  restructurings,  divestitures,  business  combinations  and  investments.  Any  such
transaction may require us to incur non-recurring or other charges, may increase our near- and long-term expenditures and may pose significant integration
challenges or disrupt our management or business, which could adversely affect our operations and financial results. For example, these transactions may
entail numerous operational and financial risks, including:

•

•

•

•

•

up-front, milestone and royalty payments, equity investments and financial support of new research and development candidates including increase of
personnel, all of which may be substantial;

exposure to unknown liabilities;

disruption  of  our  business  and  diversion  of  our  management’s  time  and  attention  in  order  to  develop  acquired  products,  product  candidates  or
technologies;

incurrence of substantial debt or dilutive issuances of equity securities;

higher-than-expected acquisition and integration costs;

• write-downs of assets or goodwill or impairment charges;

•

•

•

•

increased amortization expenses;

difficulty and cost in combining the operations and personnel of any acquired businesses with our operations and personnel;

impairment of relationships with key suppliers or customers of any acquired businesses due to changes in management and ownership; and

inability to retain key employees of any acquired businesses.

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Accordingly,  although  there  can  be  no  assurance  that  we  will  undertake  or  successfully  complete  any  transactions  of  the  nature  described  above,  any
transactions  that  we  do  complete  may  be  subject  to  the  foregoing  or  other  risks  and  could  have  a  material  adverse  effect  on  our  business,  results  of
operations, financial condition and prospects.

If we seek and obtain approval to commercialize our product candidates outside of the United States, manufacture our product candidates outside of
the  United  States,  or  otherwise  engage  in  business  outside  of  the  United  States,  a  variety  of  risks  associated  with  international  operations  could
materially adversely affect our business.

We or our collaboration partners may decide to seek marketing approval for certain of our product candidates outside the United States or otherwise engage
in  business  outside  the  United  States,  including  entering  into  contractual  agreements  with  third-parties.  We  currently  utilize  contract  manufacturing
organizations  located  outside  of  the  United  States  to  manufacture  our  active  drug  substance  for  tenapanor.  We  are  subject  to  additional  risks  related  to
entering these international business markets and relationships, including:

•

•

•

•

•

•

•

•

•

different regulatory requirements for drug approvals in foreign countries;

differing United States and foreign drug import and export rules;

reduced protection for intellectual property rights in foreign countries;

unexpected changes in tariffs, trade barriers and regulatory requirements;

different reimbursement systems, and different competitive drugs;

economic weakness, including inflation, or political instability in particular foreign economies and markets;

compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

foreign taxes, including withholding of payroll taxes;

foreign  currency  fluctuations,  which  could  result  in  increased  operating  expenses  and  reduced  revenues,  and  other  obligations  incident  to  doing
business in another country;

• workforce uncertainty in countries where labor unrest is more common than in the United States;

•

•

•

production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad;

potential liability resulting from development work conducted by these distributors; and

business interruptions resulting from geopolitical actions, including war and terrorism, or natural disasters.

Our  business  involves  the  use  of  hazardous  materials  and  we  and  third-parties  with  whom  we  contract  must  comply  with  environmental  laws  and
regulations, which can be expensive and restrict how we do business.

Our development activities involve the controlled storage, use and disposal of hazardous materials, including the components of our product candidates and
other  hazardous  compounds.  We  and  manufacturers  and  suppliers  with  whom  we  may  contract  are  subject  to  laws  and  regulations  governing  the  use,
manufacture, storage, handling and disposal of these hazardous materials. In some cases, these hazardous materials and various wastes resulting from their
use are stored at our and our manufacturers’ facilities pending their use and disposal. We cannot eliminate the risk of contamination, which could cause an
interruption  of  our  commercialization  efforts,  and  development  efforts  and  business  operations,  environmental  damage  resulting  in  costly  clean-up  and
liabilities  under  applicable  laws  and  regulations  governing  the  use,  storage,  handling  and  disposal  of  these  materials  and  specified  waste  products.  We
cannot guarantee that the safety procedures utilized by third-party manufacturers and suppliers with whom we may contract will comply with the standards
prescribed by laws and regulations or will eliminate the risk of accidental contamination or injury from these materials. In such an event, we may be held
liable for any resulting damages and such liability could exceed our resources and state or federal or other applicable authorities may curtail our use of
certain  materials  and/or  interrupt  our  business  operations.  Furthermore,  environmental  laws  and  regulations  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. We do not currently carry
biological or hazardous waste insurance coverage.

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We may be adversely affected by earthquakes or other natural disasters and our business continuity and disaster recovery plans may not adequately
protect us from a serious disaster.

We  currently  occupy  a  leased  facility  located  in  the  San  Francisco  Bay  Area,  which  in  the  past  has  experienced  severe  earthquakes.  We  do  not  carry
earthquake  insurance.  Earthquakes  or  other  natural  disasters  could  severely  disrupt  our  operations,  and  have  a  material  adverse  effect  on  our  business,
results of operations, financial condition and prospects.

If a natural disaster, power outage or other event occurred that prevented us from using all or a significant portion of our California facility, that damaged
critical  infrastructure,  such  as  our  enterprise  financial  systems  or  manufacturing  resource  planning  and  enterprise  quality  systems,  or  that  otherwise
disrupted  operations,  it  may  be  difficult  or,  in  certain  cases,  impossible  for  us  to  continue  our  business  for  a  substantial  period  of  time.  The  disaster
recovery and business continuity plans we have in place currently are limited and are unlikely to prove adequate in the event of a serious disaster or similar
event. We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, which, particularly when
taken together with our lack of earthquake insurance, could have a material adverse effect on our business.

Risks Related to Government Regulation

Despite having received regulatory approval for IBSRELA, and even if we receive regulatory approval for XPHOZAH, we will be subject to ongoing
regulatory obligations and continued regulatory review, which may result in significant additional expense. Additionally, IBSRELA, and XPHOZAH, if
approved,  could  be  subject  to  other  restrictions  and  market  withdrawal,  and  we  may  be  subject  to  penalties  if  we  fail  to  comply  with  regulatory
requirements or experience unanticipated problems with our products.

Even if a drug is approved by the FDA or foreign regulatory authorities, the manufacturing processes, labeling, packaging, distribution, pharmacovigilance,
storage, advertising, promotion and recordkeeping for the product will be subject to extensive and ongoing regulatory requirements. These requirements
include  submissions  of  safety  and  other  post-marketing  information  and  reports,  registration,  as  well  as  continued  compliance  with  cGMPs  and  GCP
regulations for any clinical trials that we conduct post-approval. As such, we and our third-party contract manufacturers will be subject to continual review
and  periodic  inspections  to  assess  compliance  with  regulatory  requirements.  Accordingly,  we  and  others  with  whom  we  work  must  continue  to  expend
time, money, and effort in all areas of regulatory compliance, including manufacturing, production, and quality control. Regulatory authorities may also
impose significant restrictions on a product’s indicated uses or marketing or impose ongoing requirements for potentially costly post-marketing studies.
Furthermore, any new legislation addressing drug safety issues could result in delays or increased costs to assure compliance.

We  will  also  be  required  to  report  certain  adverse  reactions  and  production  problems,  if  any,  to  the  FDA,  and  to  comply  with  requirements  concerning
advertising and promotion for our products. Promotional communications with respect to prescription drugs are subject to a variety of legal and regulatory
restrictions and must be consistent with the information in the product’s approved label. As such, we may not promote our products for indications or uses
for which they do not have FDA approval.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with our third-party
manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may result in, among other things:

• warning or untitled letters, fines or holds on clinical trials;

•

•

•

•

•

•

restrictions on the marketing or manufacturing of the product, withdrawal of the product from the market or voluntary or mandatory product recalls;

injunctions or the imposition of civil or criminal penalties;

suspension or revocation of existing regulatory approvals;

suspension of any of our ongoing clinical trials;

refusal to approve pending applications or supplements to approved applications submitted by us;

restrictions on our or our contract manufacturers’ operations; or

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•

product seizure or detention, or refusal to permit the import or export of products.

Any  government  investigation  of  alleged  violations  of  law  could  require  us  to  expend  significant  time  and  resources  in  response  and  could  generate
negative  publicity.  Any  failure  to  comply  with  ongoing  regulatory  requirements  may  significantly  and  adversely  affect  our  ability  to  commercialize
IBSRELA  and  XPHOZAH,  if  approved.  If  regulatory  sanctions  are  applied  or  if  regulatory  approval  is  withdrawn,  the  value  of  our  company  and  our
operating results will be adversely affected.

In addition, the FDA’s policies may change, and additional government regulations may be enacted. If we are slow or unable to adapt to changes in existing
requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval
that we may have obtained, which would adversely affect our business, prospects and ability to achieve or sustain profitability.

We also cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action,
either in the United States or abroad.

Disruptions at the FDA and other government agencies caused by funding shortages or global health concerns could hinder their ability to hire and
retain key leadership and other personnel, or otherwise review and process regulatory submissions in a timely manner, which could negatively impact
our business.

The ability of the FDA to review and process regulatory submissions can be affected by a variety of factors, including government budget and funding
levels, ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory, and policy changes. Average review times at
the agency have fluctuated in recent years as a result.

Disruptions  at  the  FDA  and  other  agencies  may  also  slow  the  time  necessary  for  new  drugs  to  be  reviewed  and/or  approved  by  necessary  government
agencies, which would adversely affect our business. For example, over the last several years, including for 35 days beginning on December 22, 2018, the
U.S. government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical FDA employees and stop
critical  activities.  If  a  prolonged  government  shutdown  occurs,  it  could  significantly  impact  the  ability  of  the  FDA  to  timely  review  and  process  our
regulatory submissions, which could have a material adverse effect on our business.

Separately, in response to the global COVID-19 pandemic, on March 10, 2020, the FDA announced its intention to postpone most foreign inspections of
manufacturing  facilities  and  products  through  April  2020,  and  subsequently,  on  March  18,  2020,  the  FDA  temporarily  postponed  routine  surveillance
inspections of domestic manufacturing facilities. Subsequently, on July 10, 2020, the FDA announced its intention to resume certain on-site inspections of
domestic manufacturing facilities subject to a risk-based prioritization system. The FDA utilized this risk-based assessment system to assist in determining
when and where it was safest to conduct prioritized domestic inspections. Additionally, on April 15, 2021, the FDA issued a guidance document in which
the FDA described its plans to conduct voluntary remote interactive evaluations of certain drug manufacturing facilities and clinical research sites, among
other facilities. According to the guidance, the FDA may request such remote interactive evaluations where the FDA determines that remote evaluation
would be appropriate based on mission needs and travel limitations. In May 2021, the FDA outlined a detailed plan to move toward a more consistent state
of  inspectional  operations,  and  in  July  2021,  the  FDA  resumed  standard  inspectional  operations  of  domestic  facilities.  More  recently,  the  FDA  has
continued to monitor and implement changes to its inspectional activities to ensure the safety of its employees and those of the firms it regulates as it adapts
to the evolving COVID-19 pandemic. Regulatory authorities outside the United States may adopt similar restrictions or other policy measures in response
to the COVID-19 pandemic. If a prolonged government shutdown occurs, or if global health concerns continue to prevent the FDA or other regulatory
authorities from conducting their regular inspections, reviews, or other regulatory activities, it could significantly impact the ability of the FDA or other
regulatory authorities to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

We  and  our  contract  manufacturers  are  subject  to  significant  regulation  with  respect  to  manufacturing  our  IBSRELA  and  XPHOZAH.  The
manufacturing facilities on which we rely may not continue to meet regulatory requirements or may not be able to meet supply demands.

All  entities  involved  in  the  preparation  of  product  for  commercial  sale,  or  product  candidates  for  clinical  trials,  including  our  existing  contract
manufacturers are subject to extensive regulation. Components of a finished therapeutic product approved for commercial sale or used in late-stage clinical
studies must be manufactured in accordance with cGMP regulations. These regulations govern manufacturing processes and procedures (including record
keeping) and the implementation and operation of quality systems to control and assure the quality of investigational products and products approved for
sale. Poor control of production processes can lead to the introduction of contaminants or to inadvertent changes in the properties or stability of our

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product  candidates  that  may  not  be  detectable  in  final  product  testing.  We  or  our  contract  manufacturers  must  supply  all  necessary  documentation  in
support  of  an  NDA  or  comparable  regulatory  filing  on  a  timely  basis  and  must  adhere  to  cGMP  regulations  enforced  by  the  FDA  and  other  regulatory
agencies  through  their  facilities  inspection  programs.  The  facilities  and  quality  systems  of  some  or  all  of  our  third-party  contractors  must  pass  a  pre-
approval  inspection  for  compliance  with  the  applicable  regulations  as  a  condition  of  regulatory  approval  of  our  product  candidates.  In  addition,  the
regulatory authorities may, at any time, audit or inspect a manufacturing facility involved with the manufacture of our product or the associated quality
systems  for  compliance  with  the  regulations  applicable  to  the  activities  being  conducted.  Although  we  oversee  the  contract  manufacturers,  we  cannot
control  the  manufacturing  process  of,  and  are  completely  dependent  on,  our  contract  manufacturing  partners  for  compliance  with  the  regulatory
requirements. If these facilities do not pass a pre-approval plant inspection, regulatory approval of the products may not be granted or may be substantially
delayed  until  any  violations  are  corrected  to  the  satisfaction  of  the  regulatory  authority,  if  ever.  In  addition,  we  have  no  control  over  the  ability  of  our
contract manufacturers to maintain adequate quality control, quality assurance and qualified personnel.

The regulatory authorities also may, at any time following approval of a product for sale, audit the manufacturing facilities of our third-party contractors. If
any such inspection or audit identifies a failure to comply with applicable regulations or if a violation of our product specifications or applicable regulations
occurs independent of such an inspection or audit, we or the relevant regulatory authority may require remedial measures that may be costly and/or time
consuming for us or a third party to implement, and that may include the temporary or permanent suspension of a clinical study or commercial sales or the
temporary or permanent suspension of production or closure of a facility. Any such remedial measures imposed upon us or third parties with whom we
contract could materially harm our business.

If  we  or  any  of  our  third-party  manufacturers  fail  to  maintain  regulatory  compliance,  the  FDA  or  other  applicable  regulatory  authority  can  impose
regulatory  sanctions  including,  among  other  things,  refusal  to  approve  a  pending  application  for  a  new  drug  product,  withdrawal  of  an  approval,  or
suspension of production. As a result, our business, financial condition, and results of operations may be materially harmed.

Additionally,  if  supply  from  one  approved  manufacturer  is  interrupted,  an  alternative  manufacturer  would  need  to  be  qualified  through  an  NDA,  a
supplemental NDA or equivalent foreign regulatory filing, which could result in further delay. The regulatory agencies may also require additional studies
if a new manufacturer is relied upon for commercial production. Switching manufacturers may involve substantial costs and is likely to result in a delay in
our desired clinical and commercial timelines.

These factors could cause us to incur higher costs and could cause the delay or termination of clinical studies, regulatory submissions, required approvals,
or commercialization of our product candidates. Furthermore, if our suppliers fail to meet contractual requirements and we are unable to secure one or more
replacement suppliers capable of production at a substantially equivalent cost, our clinical studies may be delayed, or we could lose potential revenue.

If we fail to comply or are found to have failed to comply with FDA and other regulations related to the promotion of our products for unapproved
uses, we could be subject to criminal penalties, substantial fines or other sanctions and damage awards.

The  regulations  relating  to  the  promotion  of  products  for  unapproved  uses  are  complex  and  subject  to  substantial  interpretation  by  the  FDA  and  other
government  agencies.  With  respect  to  the  commercialization  of  IBSRELA  and/or  XPHOZAH,  if  approved,  we  will  be  restricted  from  marketing  the
product outside of its approved labeling, also referred to as off-label promotion. However, physicians may nevertheless prescribe an approved product to
their patients in a manner that is inconsistent with the approved label, which is an off-label use. In preparation for the commercial launch of IBSRELA, we
have  implemented  compliance  and  training  programs  designed  to  ensure  that  our  sales  and  marketing  practices  comply  with  applicable  regulations
regarding  off-label  promotion.  Notwithstanding  these  programs,  the  FDA  or  other  government  agencies  may  allege  or  find  that  our  practices  constitute
prohibited promotion of our product candidates for unapproved uses. We also cannot be sure that our employees will comply with company policies and
applicable regulations regarding the promotion of products for unapproved uses.

Over the past several years, a significant number of pharmaceutical and biotechnology companies have been the target of inquiries and investigations by
various federal and state regulatory, investigative, prosecutorial and administrative entities in connection with the promotion of products for unapproved
uses and other sales practices, including the Department of Justice and various U.S. Attorneys’ Offices, the Office of Inspector General of the Department
of Health and Human Services, the FDA, the Federal Trade Commission and various state Attorneys General offices. These investigations have alleged
violations of various federal and state laws and regulations, including claims asserting antitrust violations, violations of the FFDCA, the False Claims Act,
the Prescription Drug Marketing Act, anti-kickback laws, and other alleged violations in connection with the

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promotion of products for unapproved uses, pricing and Medicare and/or Medicaid reimbursement. Many of these investigations originate as “qui tam”
actions under the False Claims Act. Under the False Claims Act, any individual can bring a claim on behalf of the government alleging that a person or
entity has presented a false claim, or caused a false claim to be submitted, to the government for payment. The person bringing a qui tam suit is entitled to a
share of any recovery or settlement. Qui tam suits, also commonly referred to as “whistleblower suits,” are often brought by current or former employees.
In a qui tam suit, the government must decide whether to intervene and prosecute the case. If it declines, the individual may pursue the case alone.

If the FDA or any other governmental agency initiates an enforcement action against us or if we are the subject of a qui tam suit and it is determined that
we violated prohibitions relating to the promotion of products for unapproved uses, we could be subject to substantial civil or criminal fines or damage
awards  and  other  sanctions  such  as  consent  decrees  and  corporate  integrity  agreements  pursuant  to  which  our  activities  would  be  subject  to  ongoing
scrutiny and monitoring to ensure compliance with applicable laws and regulations. Any such fines, awards or other sanctions would have an adverse effect
on our revenue, business, financial prospects and reputation.

IBSRELA and/or XPHOZAH, if approved, may cause or contribute to adverse medical events that we are required to report to regulatory agencies and
if we fail to do so we could be subject to sanctions that would materially harm our business.

Some participants in clinical studies of tenapanor have reported adverse effects after being treated with tenapanor, including diarrhea, abdominal distension,
flatulence  and  dizziness.  If  we  are  successful  in  commercializing  any  products,  FDA  and  foreign  regulatory  agency  regulations  require  that  we  report
certain information about adverse medical events if those products may have caused or contributed to those adverse events. The timing of our obligation to
report would be triggered by the date we become aware of the adverse event as well as the nature of the event. We may fail to report adverse events we
become aware of within the prescribed timeframe. We may also fail to appreciate that we have become aware of a reportable adverse event, especially if it
is not reported to us as an adverse event or if it is an adverse event that is unexpected or removed in time from the use of our products. If we fail to comply
with our reporting obligations, the FDA or a foreign regulatory agency could take action, including criminal prosecution, the imposition of civil monetary
penalties, seizure of our products or delay in approval or clearance of future products.

Our employees, independent contractors, principal investigators, CROs, collaboration partners, consultants and vendors may engage in misconduct or
other improper activities, including noncompliance with regulatory standards and requirements.

We are exposed to the risk that our employees, independent contractors, principal investigators, CROs, collaboration partners, consultants and vendors may
engage  in  fraudulent  conduct  or  other  illegal  activity.  Misconduct  by  these  parties  could  include  intentional,  reckless  and/or  negligent  conduct  or
unauthorized activities that violate any of the following: FDA regulations, including those laws that require the reporting of true, complete and accurate
financial and other information to the FDA; manufacturing standards; or federal and state healthcare fraud and abuse laws and regulations. Specifically,
sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks,
self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion,
sales commission, customer incentive programs and other business arrangements. These activities also include the improper use of information obtained in
the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. It is not always possible to identify and deter
misconduct  by  employees  and  other  third  parties,  and  the  precautions  we  take  to  detect  and  prevent  this  activity  may  not  be  effective  in  controlling
unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply
with such laws or regulations. Additionally, we are subject to the risk that a person or government could allege such fraud or other misconduct, even if none
occurred. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a
significant  impact  on  our  business,  including  the  imposition  of  significant  civil,  criminal  and  administrative  penalties,  damages,  monetary  fines,
disgorgements,  possible  exclusion  from  participation  in  Medicare,  Medicaid  and  other  federal  healthcare  programs,  individual  imprisonment,  other
sanctions, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of our operations, any of which could adversely
affect our ability to operate our business and our results of operations.

Failure to obtain regulatory approvals in foreign jurisdictions would prevent us from marketing our products internationally.

In order to market any product in the EEA (which is composed of the 27 Member States of the European Union plus Norway, Iceland and Liechtenstein),
and  many  other  foreign  jurisdictions,  separate  regulatory  approvals  are  required.  In  the  EEA,  medicinal  products  can  only  be  commercialized  after
obtaining a Marketing Authorization (“MA”). Before the MA is

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granted, the EMA or the competent authorities of the Member States of the EEA make an assessment of the risk-benefit balance of the product on the basis
of scientific criteria concerning its quality, safety and efficacy.

The approval procedures vary among countries and can involve additional clinical testing, and the time required to obtain approval may differ from that
required to obtain FDA approval. Clinical trials conducted in one country may not be accepted by regulatory authorities in other countries. Approval by the
FDA  does  not  ensure  approval  by  regulatory  authorities  in  other  countries,  and  approval  by  one  or  more  foreign  regulatory  authorities  does  not  ensure
approval by regulatory authorities in other foreign countries or by the FDA. However, a failure or delay in obtaining regulatory approval in one country
may  have  a  negative  effect  on  the  regulatory  process  in  others.  The  foreign  regulatory  approval  process  may  include  all  of  the  risks  associated  with
obtaining FDA approval. We may not be able to file for regulatory approvals or to do so on a timely basis, and even if we do file, we may not receive
necessary approvals to commercialize our products in any market.

We and our collaboration partners may be subject to healthcare laws, regulation and enforcement; our failure or the failure of any such collaboration
partners to comply with these laws could have a material adverse effect on our results of operations and financial conditions.

Following our commercial introduction of IBSRELA, and the regulatory approval by a foreign government and the commercial introduction of any either
IBSRELA  or  XPHOZAH  by  our  collaboration  partner  in  such  jurisdiction,  we  and  our  collaboration  partners  may  be  subject  to  additional  healthcare
statutory  and  regulatory  requirements  and  enforcement  by  the  federal  government  and  the  states  and  foreign  governments  in  which  we  conduct  our
business. The laws that may affect our ability to operate as a commercial organization include:

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•

•

•

•

•

the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying
remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of,
any good or service for which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs. A person or
entity does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation;

federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for
payment  from  Medicare,  Medicaid,  or  other  third-party  payors  that  are  false  or  fraudulent.  In  addition,  the  government  may  assert  that  a  claim
including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the
false claims statutes;

the federal Civil Monetary Penalties law, which prohibits, among other things, offering or transferring remuneration to a federal healthcare beneficiary
that  a  person  knows  or  should  know  is  likely  to  influence  the  beneficiary’s  decision  to  order  or  receive  items  or  services  reimbursable  by  the
government from a particular provider or supplier;

federal  criminal  laws  that  prohibit  executing  a  scheme  to  defraud  any  healthcare  benefit  program  or  making  false  statements  relating  to  healthcare
matters. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of these statutes or specific intent to
violate them in order to have committed a violation;

the federal physician sunshine requirements under the ACA, which requires manufacturers of drugs, devices, biologics, and medical supplies to report
annually  to  CMS  information  related  to  payments  and  other  transfers  of  value  to  physicians,  (defined  to  include  doctors,  dentists,  optometrists,
podiatrists  and  chiropractors),  certain  non-physician  practitioners  (physician  assistants,  nurse  practitioners,  clinical  nurse  specialists,  certified  nurse
anesthetists,  anesthesiologist  assistants  and  certified  nurse  midwives),  and  teaching  hospitals,  and  ownership  and  investment  interests  held  by
physicians (as defined by the statute) and their immediate family members;

state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed
by any third-party payor, including commercial insurers;

state  laws  that  require  pharmaceutical  companies  to  comply  with  the  pharmaceutical  industry’s  voluntary  compliance  guidelines  and  the  applicable
compliance  guidance  promulgated  by  the  federal  government,  or  otherwise  restrict  payments  that  may  be  made  to  healthcare  providers  and  other
potential referral sources;

state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare
providers or pricing information and marketing expenditures; and

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•

European  and  other  foreign  law  equivalents  of  each  of  the  laws,  including  reporting  requirements  detailing  interactions  with  and  payments  to
healthcare providers.

Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business
activities could be subject to challenge under one or more of such laws. The risk of our being found in violation of these laws is increased by the fact that
many of them have not been fully interpreted by the regulatory authorities or the courts, and their provisions are open to a variety of interpretations. Any
action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our
management’s attention from the operation of our business. If our operations are found to be in violation of any of the laws described above or any other
governmental laws and regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, the curtailment
or  restructuring  of  our  operations,  the  exclusion  from  participation  in  federal  and  state  healthcare  programs  and  imprisonment,  any  of  which  could
adversely affect our ability to market our products and adversely impact our financial results.

Legislative or regulatory healthcare reforms in the United States may make it more difficult and costly for us to obtain regulatory clearance or approval
of our product candidates and to produce, market and distribute our products after clearance or approval is obtained.

From  time  to  time,  legislation  is  drafted  and  introduced  in  Congress  that  could  significantly  change  the  statutory  provisions  governing  the  regulatory
clearance or approval, manufacture, and marketing of regulated products or the reimbursement thereof. In addition, FDA regulations and guidance are often
revised  or  reinterpreted  by  the  FDA  in  ways  that  may  significantly  affect  our  business  and  our  products.  Any  new  regulations  or  revisions  or
reinterpretations of existing regulations may impose additional costs or lengthen review times of our product candidates. We cannot determine what effect
changes in regulations, statutes, legal interpretation or policies, when and if promulgated, enacted or adopted may have on our business in the future. Such
changes could, among other things, require:

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additional clinical trials to be conducted prior to obtaining approval;

changes to manufacturing methods;

recall, replacement, or discontinuance of one or more of our products; and

additional record keeping.

Each of these would likely entail substantial time and cost and could materially harm our business and our financial results. In addition, delays in receipt of
or failure to receive regulatory clearances or approvals for any future products would harm our business, financial condition and results of operations.

In addition, the full impact of recent healthcare reform and other changes in the healthcare industry and in healthcare spending is currently unknown, and
may  adversely  affect  our  business  model.  In  the  United  States,  the  ACA  was  enacted  in  2010  with  a  goal  of  reducing  the  cost  of  healthcare  and
substantially  changing  the  way  healthcare  is  financed  by  both  government  and  private  insurers.  The  ACA,  among  other  things,  increased  the  minimum
Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid
managed care organizations, established annual fees and taxes on manufacturers of certain branded prescription drugs, and created a new Medicare Part D
coverage  gap  discount  program,  in  which  manufacturers  must  now  agree  to  offer  70%  point-of-sale  discounts  off  negotiated  prices  of  applicable  brand
drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA. On June 17, 2021, the U.S. Supreme
Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed
by Congress. Thus, the ACA will remain in effect in its current form. Further, prior to the U.S. Supreme Court ruling, President Biden issued an executive
order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace from February 15, 2021
through August 15, 2021. The executive order instructed certain governmental agencies to review and reconsider their existing policies and rules that limit
access  to  healthcare,  including  among  others,  reexamining  Medicaid  demonstration  projects  and  waiver  programs  that  include  work  requirements,  and
policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

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Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. These new laws, among other things, included
aggregate reductions of Medicare payments of 2% per fiscal year to providers that will remain in effect through 2030, with the exception of a temporary
suspension from May 1, 2020 through March 31, 2022 and a 1% reduction from April 1, 2022 through June 30, 2022, unless additional action is taken by
Congress,  additional  specific  reductions  in  Medicare  payments  to  several  types  of  providers,  including  hospitals,  imaging  centers  and  cancer  treatment
centers, and an increase in the statute of limitations period for the government to recover overpayments to providers from three to five years. More recently,
on  March  11,  2021,  President  Biden  signed  the  American  Rescue  Plan  Act  of  2021  into  law,  which  eliminates  the  statutory  Medicaid  drug  rebate  cap,
currently set at 100% of a drug’s average manufacturer price, beginning January 1, 2024. Recently, there has also been heightened governmental scrutiny
over the manner in which drug manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed
bills  designed  to,  among  other  things,  bring  more  transparency  to  product  pricing,  review  the  relationship  between  pricing  and  manufacturer  patient
programs, and reform government program reimbursement methodologies for drug products. By way of example, the Build Back Better Act, if enacted,
would introduce substantial drug pricing reforms, including the establishment of a drug price negotiation program within the U.S. Department of Health
and  Human  Services  that  would  require  manufacturers  to  charge  a  negotiated  “maximum  fair  price”  for  certain  selected  drugs  or  pay  an  excise  tax  for
noncompliance, and the establishment of rebate payment requirements on manufacturers of certain drugs payable under Medicare Parts B and D. If the
Build Back Better Act is not enacted, similar or other drug pricing proposals could appear in future legislation. Additionally, individual states have become
increasingly  active  in  passing  legislation  and  implementing  regulations  designed  to  control  pharmaceutical  product  pricing,  including  price  or  patient
reimbursement constraints, discounts, restrictions on certain product access, and to encourage importation from other countries and bulk purchasing.

We cannot predict the reform initiatives that may be adopted in the future or whether initiatives that have been adopted will be repealed or modified. The
continuing efforts of the government, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce costs
of healthcare may adversely affect the demand for any drug products for which we may obtain regulatory approval, our ability to set a price that we believe
is fair for our products, our ability to obtain coverage and reimbursement approval for a product, our ability to generate revenues and achieve or maintain
profitability, and the level of taxes that we are required to pay.

Following the commercial launch of IBSRELA, if we fail to comply with our reporting and payment obligations under the Medicaid Drug Rebate
Program or other governmental pricing programs in the United States, we could be subject to additional reimbursement requirements, penalties,
sanctions and fines, which could have a material adverse effect on our business, results of operations and financial condition.

Following the commercial launch of IBSRELA, we intend to participate in the Medicaid Drug Rebate Program ("MDRP") and other federal and
state government pricing programs in the United States, and we may participate in additional government pricing programs in the future. These programs
generally  require  manufacturers  to  pay  rebates  or  otherwise  provide  discounts  to  government  payors  in  connection  with  drugs  that  are  dispensed  to
beneficiaries of these programs. Medicaid drug rebates are based on pricing data that we will be obligated to report on a monthly and quarterly basis to the
U.S. Centers for Medicare & Medicaid Services (“CMS”), the federal agency that administers the MDRP and Medicare programs. For the MDRP, these
data  include  the  average  manufacturer  price  (“AMP”)  and  the  best  price  (“BP”)  for  each  drug.  If  we  become  aware  that  our  MDRP  price  reporting
submission for a prior period was incorrect or has changed as a result of recalculation of the pricing data, we must resubmit the corrected data for up to
three  years  after  those  data  originally  were  due.  In  addition,  there  is  increased  focus  by  the  Office  of  Inspector  General  within  the  U.S.  Department  of
Health  and  Human  Services  on  the  methodologies  used  by  manufacturers  to  calculate  AMP,  and  BP,  to  assess  manufacturer  compliance  with  MDRP
reporting requirements. If we fail to provide information timely or are found to have knowingly submitted false information to the government, we may be
subject to civil monetary penalties and other sanctions, including termination from the MDRP, which would result in payment not being available for our
covered  drugs  under  Medicaid.  Failure  to  make  necessary  disclosures  and/or  to  identify  overpayments  could  result  in  allegations  against  us  under  the
Federal False Claims Act and other laws and regulations.

Federal law requires that a manufacturer that participates in the MDRP also participate in the Public Health Service’s 340B drug pricing program
(the “340B program”) in order for federal funds to be available for the manufacturer’s drugs under Medicaid. We intend to participate in the 340B program,
which is administered by the Health Resources and Services Administration (“HRSA”), and requires us to charge statutorily defined covered entities no
more than the 340B “ceiling price” for the our covered drugs. These 340B covered entities include a variety of community health clinics and other entities
that receive health services grants from the Public Health Service, as well as hospitals that serve a disproportionate share of low-income patients. The 340B
ceiling price is calculated using a statutory formula, which is based on the AMP and rebate amount for the covered drug as calculated under the MDRP. In
general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement. We
will be obligated to report 340B ceiling

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prices to HRSA on a quarterly basis, and HRSA publishes them to 340B covered entities. HRSA has finalized regulations regarding the calculation of the
340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities for 340B-
eligible  drugs.  HRSA  has  also  finalized  an  administrative  dispute  resolution  process  through  which  340B  covered  entities  may  pursue  claims  against
participating manufacturers for overcharges, and through which manufacturers may pursue claims against 340B covered entities for engaging in unlawful
diversion or duplicate discounting of 340B drugs. In addition, legislation may be introduced that, if passed, would further expand the 340B program, such
as adding further covered entities or requiring participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.

In order to be eligible to have drug products paid for with federal funds under Medicaid and purchased by certain federal agencies and grantees, we
also must participate in the U.S. Department of Veterans Affairs (“VA”) Federal Supply Schedule (“FSS”) pricing program. Under the VA/FSS program,
we will become obligated to report the Non-Federal Average Manufacturer Price (“Non-FAMP”) for our covered drugs to the VA and charge certain federal
agencies no more than the Federal Ceiling Price, which is calculated based on Non-FAMP using a statutory formula. These four agencies are the VA, the
U.S. Department of Defense, the U.S. Coast Guard, and the U.S. Public Health Service (including the Indian Health Service). We will also be required to
pay  rebates  on  products  purchased  by  military  personnel  and  dependents  through  the  TRICARE  retail  pharmacy  program.  If  we  fail  to  provide  timely
information or are found to have knowingly submitted false information, we may be subject to civil monetary penalties.

Individual states continue to consider and have enacted legislation to limit the growth of healthcare costs, including the cost of prescription drugs
and combination products. A number of states have either implemented or are considering implementation of drug price transparency legislation that may
prevent or limit our ability to take price increases at certain rates or frequencies. Requirements under such laws include advance notice of planned price
increases,  reporting  price  increase  amounts  and  factors  considered  in  taking  such  increases,  wholesale  acquisition  cost  information  disclosure  to
prescribers, purchasers, and state agencies, and new product notice and reporting. Such legislation could limit the price or payment for IBSRELA, and a
number of states are authorized to impose civil monetary penalties or pursue other enforcement mechanisms against manufacturers who fail to comply with
drug  price  transparency  requirements,  including  the  untimely,  inaccurate,  or  incomplete  reporting  of  drug  pricing  information.  If  we  are  found  to  have
violated state law requirements, we may become subject to penalties or other enforcement mechanisms, which could have a material adverse effect on our
business.

Pricing  and  rebate  calculations  are  complex,  vary  among  products  and  programs,  and  are  often  subject  to  interpretation  by  us,  governmental  or
regulatory  agencies,  and  the  courts.  The  terms,  scope  and  complexity  of  these  government  pricing  programs  change  frequently,  as  do  interpretations  of
applicable  requirements  for  pricing  and  rebate  calculations.  Responding  to  current  and  future  changes  may  increase  our  costs  and  the  complexity  of
compliance  will  be  time  consuming.  Any  required  refunds  to  the  U.S.  government  or  responding  to  a  government  investigation  or  enforcement  action
would  be  expensive  and  time  consuming  and  could  have  a  material  adverse  effect  on  our  business,  results  of  operations  and  financial  condition.  Price
recalculations  under  the  MDRP  also  may  affect  the  ceiling  price  at  which  we  are  required  to  offer  products  under  the  340B  program.  Civil  monetary
penalties can be applied if we are found to have knowingly submitted any false price or product information to the government, if we fail to submit the
required price data on a timely basis, or if we are found to have charged 340B covered entities more than the statutorily mandated ceiling price. In the event
that  CMS  were  to  terminate  our  Medicaid  rebate  agreement,  no  federal  payments  would  be  available  under  Medicaid  or  Medicare  for  IBSRELA.  We
cannot assure you that our submissions will not be found to be incomplete or incorrect.

Risks Related to Intellectual Property

Our success will depend on our ability to obtain, maintain and protect our intellectual property rights

Our success and ability to compete depend in part on our ability to obtain, maintain and enforce issued patents, trademarks and other intellectual property
rights and proprietary technology in the United States and elsewhere. If we cannot adequately obtain, maintain and enforce our intellectual property rights
and proprietary technology, competitors may be able to use our technologies or the goodwill we have acquired in the marketplace and erode or negate any
competitive advantage we may have and our ability to compete, which could harm our business and ability to achieve profitability and/or cause us to incur
significant expenses.

We rely on a combination of contractual provisions, confidentiality procedures and patent, trademark, copyright, trade secret and other intellectual property
laws to protect the proprietary aspects of our products, product candidates, brands, technologies, trade secrets, know-how and data. These legal measures
afford only limited protection, and competitors or others may gain access to or use our intellectual property rights and proprietary information. Our success
will depend, in part, on preserving our trade secrets, maintaining the security of our data and know-how and obtaining, maintaining and enforcing other

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intellectual  property  rights.  We  may  not  be  able  to  obtain,  maintain  and/or  enforce  our  intellectual  property  or  other  proprietary  rights  necessary  to  our
business or in a form that provides us with a competitive advantage.

Failure to obtain, maintain and/or enforce intellectual property rights necessary to our business and failure to protect, monitor and control the use of our
intellectual property rights could negatively impact our ability to compete and cause us to incur significant expenses. The intellectual property laws and
other statutory and contractual arrangements in the United States and other jurisdictions we depend upon may not provide sufficient protection in the future
to  prevent  the  infringement,  use,  violation  or  misappropriation  of  our  patents,  trademarks,  data,  technology  and  other  intellectual  property  rights  and
products  by  others,  and  may  not  provide  an  adequate  remedy  if  our  intellectual  property  rights  are  infringed,  misappropriated  or  otherwise  violated  by
others.
We rely in part on our portfolio of issued and pending patent applications in the United States and other countries to protect our intellectual property and
competitive  position.  However,  it  is  also  possible  that  we  may  fail  to  identify  patentable  aspects  of  inventions  made  in  the  course  of  our  development,
manufacture and commercialization activities before it is too late to obtain patent protection on them. If we fail to timely file for patent protection in any
jurisdiction, we may be precluded from doing so at a later date. Although we enter into non-disclosure and confidentiality agreements with parties who
have access to patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific collaborators,
suppliers, consultants, advisors and other third parties, any of these parties may breach the agreements and disclose such output before a patent application
is filed, thereby jeopardizing our ability to seek patent protection. Furthermore, publications of discoveries in the scientific literature often lag behind the
actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some
cases not at all. Therefore, we cannot be certain that we were the first to make the inventions claimed in any of our patents or pending patent applications,
or  that  we  were  the  first  to  file  for  patent  protection  of  such  inventions.  Moreover,  should  we  become  a  licensee  of  a  third  party’s  patents  or  patent
applications, depending on the terms of any future in-licenses to which we may become a party, we may not have the right to control the preparation, filing
and prosecution of patent applications, or to maintain or enforce the patents, covering technology in-licensed from third parties. Therefore, these patents
and  patent  applications  may  not  be  prosecuted,  maintained  and/or  enforced  in  a  manner  consistent  with  the  best  interests  of  our  business.  Any  of  these
outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.

The  patent  positions  of  companies,  including  our  patent  position,  may  involve  complex  legal  and  factual  questions  that  have  been  the  subject  of  much
litigation in recent years, and, therefore, the scope of any patent claims that we have or may obtain cannot be predicted with certainty. Accordingly, we
cannot provide any assurances about which of our patent applications will issue, the breadth of any resulting patent, whether any of the issued patents will
be found to be infringed, invalid or unenforceable or will be threatened or challenged by third parties, that any of our issued patents have, or that any of our
currently  pending  or  future  patent  applications  that  mature  into  issued  patents  will  include,  claims  with  a  scope  sufficient  to  protect  our  products  and
services. Our pending and future patent applications may not result in the issuance of patents or, if issued, may not issue in a form that will be advantageous
to us. The coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance.
We  cannot  offer  any  assurances  that  the  breadth  of  our  granted  patents  will  be  sufficient  to  stop  a  competitor  from  developing,  manufacturing  and
commercializing  a  product  or  technologies  in  a  non-infringing  manner  that  would  be  competitive  with  one  or  more  of  our  products  or  technologies,  or
otherwise provide us with any competitive advantage. Furthermore, any successful challenge to these patents or any other patents owned by or licensed to
us after patent issuance could deprive us of rights necessary for our commercial success. Further, there can be no assurance that we will have adequate
resources to enforce our patents.

Patents have a limited lifespan. In the United States, the natural expiration of a utility patent is generally 20 years from the earliest effective non-provisional
filing date. Though an issued patent is presumed valid and enforceable, its issuance is not conclusive as to its validity or its enforceability and it may not
provide us with adequate proprietary protection or competitive advantages against competitors with similar products or services. Patents, if issued, may be
challenged, deemed unenforceable, invalidated, narrowed or circumvented. Proceedings challenging our patents or patent applications could result in either
loss of the patent, or denial of the patent application or loss or reduction in the scope of one or more of the claims of the patent or patent application. Any
successful  challenge  to  our  patents  and  patent  applications  could  deprive  us  of  exclusive  rights  necessary  for  our  commercial  success.  In  addition,
defending  such  challenges  in  such  proceedings  may  be  costly.  Thus,  any  patents  that  we  may  own  may  not  provide  the  anticipated  level  of,  or  any,
protection against competitors. Furthermore, an adverse decision may result in a third party receiving a patent right sought by us, which in turn could affect
our ability to develop, manufacture or commercialize our products or technologies.
Some of our patents and patent applications may in the future be co-owned with third parties. If we are unable to obtain an exclusive license to any such
third-party co-owners’ interest in such patents or patent applications, such co-owners may be able to license their rights to other third parties, including our
competitors, and our competitors could market competing products,

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services  and  technology.  In  addition,  we  may  need  the  cooperation  of  any  such  co-owners  of  our  patents  in  order  to  enforce  such  patents  against  third
parties, and such cooperation may not be provided to us.

The degree of future protection for our proprietary rights is uncertain, and we cannot ensure that:

• Any of our patents, or any of our pending patent applications, if issued, will include claims having a scope sufficient to protect our products or product

candidates;

• Any of our pending patent applications will issue as patents;

• We were the first to make the inventions covered by each of our patents and pending patent applications;

• We were the first to file patent applications for these inventions;

• Others will not develop, manufacture and/or commercialize similar or alternative products or technologies that do not infringe our patents;

• Any of our challenged patents will be found to ultimately be valid and enforceable;

• Any patents issued to us will provide a basis for an exclusive market for our commercially viable products or technologies will provide us with any

competitive advantages or will not be challenged by third parties;

• We will develop additional proprietary technologies or products that are separately patentable; or

• Our commercial activities or products will not infringe upon the patents of others.

We may become subject to third party claims alleging infringement, misappropriation or violation of such third parties’ patents or other intellectual
property rights and/or third party claims seeking to invalidate our patents, which would be costly, time consuming and, if successfully asserted against
us, delay or prevent the development, manufacture or commercialization of our products or product candidates.

Our commercial success depends, in part, on our ability to develop, manufacture or commercialize our products and product candidates without infringing,
misappropriating  or  otherwise  violating  the  intellectual  property  rights  of  third  parties.  There  have  been  many  lawsuits  and  other  proceedings  asserting
infringement or misappropriation of patents and other intellectual property rights in the pharmaceutical and biotechnology industries, and companies in the
industry  have  used  intellectual  property  litigation  to  gain  a  competitive  advantage.  While  we  take  steps  to  ensure  that  we  do  not  infringe  upon,
misappropriate or otherwise violate the intellectual property rights of others, there can be no assurances that we will not be subject to claims alleging that
the manufacture, use or sale of IBSRELA or XPHOZAH or of any other product candidates infringes existing or future third-party patents, or that such
claims, if any, will not be successful. Because patent applications can take many years to issue and may be confidential for 18 months or more after filing,
and because pending patent claims can be revised before issuance, there may be applications now pending which may later result in issued patents that may
be infringed by the manufacture, use or sale of IBSRELA or XPHOZAH or other product candidates. Moreover, we may face patent infringement claims
from non-practicing entities that have no relevant product revenue and against whom our own patent portfolio may thus have no deterrent effect. We may
be  unaware  of  one  or  more  issued  patents  that  would  be  infringed  by  the  manufacture,  sale  or  use  of  IBSRELA  or  XPHOZAH  or  our  other  product
candidates.

Third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights. These
proceedings  could  cause  us  to  pay  substantial  damages,  including  treble  damages  and  attorney’s  fees  if  we  are  found  to  be  willfully  infringing  a  third
party’s patents. We may be required to indemnify future collaboration partners against such claims. We are not aware of any threatened or pending claims
related to these matters, but in the future litigation may be necessary to defend against such claims. If a patent infringement suit were brought against us,
we could be forced to stop or delay development, manufacturing or sales of the product or product candidate that is the subject of the suit. As a result of
patent infringement claims, or in order to avoid potential claims, we may choose to seek, or be required to seek, a license from the third party and would
most likely be required to pay license fees or royalties or both. These licenses may not be available on acceptable terms, or at all. Even if we were able to
obtain a license, we may be unable to maintain such licenses and the rights may be nonexclusive, which would give our competitors access to the same
intellectual property. Ultimately, we could be prevented from commercializing a product, or forced to redesign it if, as a result of actual or threatened patent
infringement claims, we are unable to enter into licenses on acceptable terms, or unable to maintain such licenses when granted. Even if we are successful
in defending against such claims, such litigation can be expensive and time consuming to

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litigate and would divert management’s attention from our core business. Any of these events could harm our business significantly.

We also could be ordered to pay substantial damages, including treble damages and attorney’s fees if we are found to be willfully infringing a third party’s
patents or other intellectual property right. Even if we believe such claims are without merit, a court of competent jurisdiction could hold that these third
party  patents  are  valid  and  enforceable,  and  infringed  by  the  use  of  our  products  and/or  technologies,  which  could  have  a  negative  impact  on  the
commercial  success  of  our  current  and  any  future  products  or  technologies.  If  we  were  to  challenge  the  validity  of  any  such  third  party  U.S.  patent  in
federal court, we would need to overcome a presumption of validity. As this burden is a high one requiring us to present clear and convincing evidence as
to the invalidity of any such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S.
patent. We will have similar burdens to overcome in foreign courts in order to successfully challenge a third party claim of patent infringement. Even if we
are successful in defending against such claims, such litigation can be expensive and time consuming to litigate and would divert management’s attention
from our core business. Any of these events could harm our business significantly.

In addition to infringement claims against us, third parties may also raise similar claims before administrative bodies in the United States or abroad. Such
mechanisms  include  reexamination,  post  grant  review,  inter  parties  review,  derivation  or  opposition  proceedings  before  the  United  States  Patent  and
Trademark Office (the “USPTO”) or other jurisdictional body relating to our intellectual property rights or the intellectual property rights of others. If third
parties  prepare  and  file  patent  applications  in  the  United  States  that  also  claim  technology  similar  or  identical  to  ours,  we  may  have  to  participate  in
interference  or  derivation  proceedings  in  the  USPTO  to  determine  which  party  is  entitled  to  a  patent  on  the  disputed  invention.  We  may  also  become
involved in similar opposition proceedings in the European Patent Office or similar offices in other jurisdictions regarding our intellectual property rights
with respect to our products and technology. Since patent applications are confidential for a period of time after filing, we cannot be certain that we were
the first to file any patent application related to our product candidates. Such administrative proceedings could result in revocation of or amendment to our
patents in such a way that they no longer cover our products or product candidates. With respect to the validity question, for example, we cannot be certain
that there is no invalidating prior art, of which we, our patent counsel, and the patent examiner were unaware during prosecution. If a third party were to
prevail  on  a  legal  assertion  of  invalidity  and/or  unenforceability,  we  may  lose  at  least  part,  and  perhaps  all,  of  the  patent  protection  on  our  products  or
technologies.  Such  a  loss  of  patent  protection  would  have  a  material  adverse  impact  on  our  business,  financial  condition,  results  of  operations,  and
prospects.

If  our  intellectual  property  related  to  IBSRELA,  XPHOZAH,  RDX013  or  any  future  product  candidates  is  not  adequate  or  if  we  are  not  able  to
successfully enforce our intellectual property right, the commercial value of IBSRELA, or our product candidates may be adversely affected and we
may not be able to compete effectively in our market.

The  strength  of  patents  in  the  biotechnology  and  pharmaceutical  field  involves  complex  legal  and  scientific  questions  and  can  be  uncertain.  The  patent
applications  that  we  own  or  license  may  fail  to  result  in  issued  patents  in  the  United  States  or  in  foreign  countries.  Additionally,  our  research  and
development efforts may result in product candidates for which patent protection is limited or not available. Even if patents do successfully issue, third
parties may challenge the validity, enforceability or scope thereof, which may result in such patents being narrowed, invalidated or held unenforceable. For
example, U.S. patents can be challenged by any person before the new USPTO Patent Trial and Appeals Board at any time before one year after that person
is served an infringement complaint based on the patents. Patents granted by the European Patent Office may be similarly opposed by any person within
nine  months  from  the  publication  of  the  grant.  Similar  proceedings  are  available  in  other  jurisdictions,  and  in  the  United  States,  Europe  and  other
jurisdictions third parties can raise questions of validity with a patent office even before a patent has granted. Furthermore, even if they are unchallenged,
our patents and patent applications may not adequately protect our intellectual property or prevent others from designing around our claims. For example, a
third party may develop a competitive product that provides therapeutic benefits similar to one or more of our product candidates but has a sufficiently
different  composition  to  fall  outside  the  scope  of  our  patent  protection.  If  the  breadth  or  strength  of  protection  provided  by  the  patents  and  patent
applications  we  hold  or  pursue  with  respect  to  IBSRELA,  XPHOZAH,  RDX013  or  any  future  product  candidates  is  successfully  challenged,  then  our
ability to commercialize such product could be negatively affected, and we may face unexpected competition that could have a material adverse impact on
our business. Further, if we encounter delays in our clinical trials, the period of time during which we or our collaboration partners could market RDX013
or any future product candidates under patent protection would be reduced.

Even where laws provide protection, costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights,
and the outcome of such litigation would be uncertain. If we or one of our collaboration partners were to initiate legal proceedings against a third party to
enforce  a  patent  covering  a  product  or  product  candidate,  the  defendant  could  counterclaim  that  our  patent  is  invalid  and/or  unenforceable.  In  patent
litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace. Grounds for a validity challenge could
be an

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alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement. Grounds for an unenforceability
assertion  could  be  an  allegation  that  someone  connected  with  prosecution  of  the  patent  withheld  relevant  information  from  the  USPTO,  or  made  a
misleading  statement,  during  prosecution.  The  outcome  following  legal  assertions  of  invalidity  and  unenforceability  is  unpredictable.  With  respect  to
validity, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution. If
a  defendant  were  to  prevail  on  a  legal  assertion  of  invalidity  and/or  unenforceability  against  our  intellectual  property  related  to  a  product  or  a  product
candidate, we would lose at least part, and perhaps all, of the patent protection on such product or product candidate. Such a loss of patent protection would
have a material adverse impact on our business. Moreover, our competitors could counterclaim that we infringe their intellectual property, and some of our
competitors have substantially greater intellectual property portfolios than we do.

We also rely on trade secret protection and confidentiality agreements to protect proprietary know-how that may not be patentable, processes for which
patents may be difficult to obtain and/or enforce and any other elements of our drug discovery and development processes that involve proprietary know-
how, information or technology that is not covered by patents. Although we require all of our employees, consultants, advisors and any third parties who
have access to our proprietary know-how, information or technology, to assign their inventions to us, and endeavor to execute confidentiality agreements
with all such parties, we cannot be certain that we have executed such agreements with all parties who may have helped to develop our intellectual property
or who had access to our proprietary information, nor can we be certain that our agreements will not be breached by such consultants, advisors or third
parties, or by our former employees. The breach of such agreements by individuals or entities who were actively involved in the discovery and design of
our products or potential drug candidates, or in the development of our discovery and design platform, including APECCS, could require us to pursue legal
action to protect our trade secrets and confidential information, which would be expensive, and the outcome of which would be unpredictable. If we are not
successful in prohibiting the continued breach of such agreements, our business could be negatively impacted. We cannot guarantee that our trade secrets
and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently
develop substantially equivalent information and techniques.

Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a
result, we may encounter significant problems in protecting and defending our intellectual property both in the United States and abroad. If we are unable
to  prevent  material  disclosure  of  the  intellectual  property  related  to  our  technologies  to  third  parties,  we  will  not  be  able  to  establish  or  maintain  a
competitive advantage in our market, which could materially adversely affect our business, results of operations and financial condition.

If we do not obtain patent term extension in the United States under the Hatch-Waxman Act and in foreign countries under similar legislation, thereby
potentially extending the term of marketing exclusivity for IBSRELA or our product candidates, our business may be materially harmed.

Following the approval by the FDA for our NDA to market tenapanor for IBS-C, we became eligible to seek and sought patent term restoration under the
Hatch-Waxman Act for one of the U.S. patents covering our approved product or the use thereof. The Hatch-Waxman Act allows a maximum of one patent
to be extended per FDA approved product. Patent term extension also may be available in certain foreign countries upon regulatory approval of our product
candidates. Despite seeking patent term extension for tenapanor or other product candidates, we may not be granted patent term extension either in the
United States or in any foreign country because of, for example, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant
patents or otherwise failing to satisfy applicable requirements. Moreover, the term of extension, as well as the scope of patent protection during any such
extension, afforded by the governmental authority could be less than we request.

If we are unable to obtain patent term extension or restoration, or the term of any such extension is less than we request, the period during which we will
have the right to exclusively market our product will be shortened and our competitors may obtain approval of competing products following our patent
expiration, and our revenue could be reduced, possibly materially.

Obtaining  and  maintaining  our  patent  protection  depends  on  compliance  with  various  procedural,  document  submission,  fee  payment  and  other
requirements  imposed  by  governmental  patent  agencies,  and  our  patent  protection  could  be  reduced  or  eliminated  for  non-compliance  with  these
requirements.

The  USPTO  and  various  foreign  patent  agencies  require  compliance  with  a  number  of  procedural,  documentary,  fee  payment  and  other  provisions  to
maintain  patent  applications  and  issued  patents.  Noncompliance  with  these  requirements  can  result  in  abandonment  or  lapse  of  a  patent  or  patent
application, resulting in partial or complete loss of patent rights in the

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relevant jurisdiction. In such an event, competitors might be able to enter the market earlier than would otherwise have been the case.

We may not be able to enforce our intellectual property rights throughout the world.

The laws of some foreign countries do not protect intellectual property rights to the same extent as the laws of the United States. Many companies have
encountered  significant  problems  in  protecting  and  defending  intellectual  property  rights  in  certain  foreign  jurisdictions.  The  legal  systems  of  some
countries, particularly developing countries, do not favor the enforcement of patents and other intellectual property protection, especially those relating to
life sciences. This could make it difficult for us to stop the infringement of our patents or the misappropriation of our other intellectual property rights. For
example, many foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties.

Proceedings  to  enforce  our  patent  rights  in  foreign  jurisdictions,  whether  or  not  successful,  could  result  in  substantial  costs  and  divert  our  efforts  and
attention from other aspects of our business. Furthermore, while we intend to protect our intellectual property rights in our expected significant markets, we
cannot ensure that we will be able to initiate or maintain similar efforts in all jurisdictions in which we may wish to market our products. Accordingly, our
efforts to protect our intellectual property rights in such countries may be inadequate. In addition, changes in the law and legal decisions by courts in the
United States and foreign countries may affect our ability to obtain and enforce adequate intellectual property protection for our technology.

We may be subject to claims that we or our employees have misappropriated the intellectual property, including know-how or trade secrets, of a third
party, or claiming ownership of what we regard as our own intellectual property.

Many  of  our  employees,  consultants  and  contractors  were  previously  employed  at  or  engaged  by  other  biotechnology  or  pharmaceutical  companies,
including our competitors or potential competitors. Some of these employees, consultants and contractors, executed proprietary rights, non-disclosure and
non-competition agreements in connection with such previous employment. Although we try to ensure that our employees, consultants and contractors do
not use the intellectual property and other proprietary information or know-how or trade secrets of others in their work for us, and do not perform work for
us that is in conflict with their obligations to another employer or any other entity, we may be subject to claims that we or these employees, consultants and
contractors have used or disclosed such intellectual property, including know-how, trade secrets or other proprietary information. In addition, an employee,
advisor or consultant who performs work for us may have obligations to a third party that are in conflict with their obligations to us, and as a result such
third party may claim an ownership interest in the intellectual property arising out of work performed for us. We are not aware of any threatened or pending
claims  related  to  these  matters,  but  in  the  future  litigation  may  be  necessary  to  defend  against  such  claims.  If  we  fail  in  defending  any  such  claims,  in
addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, or access to consultants and contractors. Even if we
are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

In  addition,  while  we  typically  require  our  employees,  consultants  and  contractors  who  may  be  involved  in  the  development  of  intellectual  property  to
execute  agreements  assigning  such  intellectual  property  to  us,  we  may  be  unsuccessful  in  executing  such  an  agreement  with  each  party  who  in  fact
develops intellectual property that we regard as our own, which may result in claims by or against us related to the ownership of such intellectual property.
If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights. Even if
we are successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to our management and
scientific personnel.

Risks Related to Our Common Stock

Our stock price may be volatile and our stockholders may not be able to resell shares of our common stock at or above the price they paid.

The trading price of our common stock is highly volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond
our control. These factors include those discussed in this “Risk Factors” section and others such as:

•

•

the success or lack of success with regards to our commercial launch of IBSRELA in April 2022;

announcements of regulatory decisions regarding our NDA seeking marketing approval for tenapanor for the Hyperphosphatemia Indication;

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•

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•

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•

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•

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•

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•

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•

•

announcements regarding any potential receipt from Nasdaq of notice regarding a de-listing of our common stock;

results  of  regulatory  inspections  of  our  facilities  or  those  of  our  contract  manufacturing  organizations,  or  specific  label  restrictions  or  patient
populations for XPHOZAH’s use, if approved, or changes or delays in the regulatory review process;

announcements  regarding  whether  XPHOZAH,  if  approved,  alone  or  with  other  oral  only  medications,  will  be  included  in  the  bundled  prospective
payment system for the treatment of ESRD patients, and the time and manner in which such transition is achieved;

announcements regarding results from our RDX013 Phase 2 clinical trial;

announcements relating to our current or future collaboration partnerships;

announcements of therapeutic innovations or new products by us or our competitors;

adverse actions taken by regulatory agencies with respect to our product label, our clinical trials, manufacturing supply chain or sales and marketing
activities;

changes or developments in laws or regulations applicable to our approved products or our product candidates;

the success of our testing and clinical trials;

failure  to  meet  any  of  our  projected  timelines  or  goals  with  regard  to  the  commercial  launch  of  IBSRELA,  or  the  clinical  development  and
commercialization of any of our product candidates;

the success of our efforts to acquire or license or discover additional product candidates;

any intellectual property infringement actions in which we may become involved;

the success of our efforts to obtain adequate intellectual property protection for our product candidates;

announcements concerning our competitors or the pharmaceutical industry in general;

achievement of expected product sales and profitability;

• manufacture, supply or distribution shortages;

•

•

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•

•

•

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actual or anticipated fluctuations in our operating results;

FDA or other U.S. or foreign regulatory actions affecting us or our industry or other healthcare reform measures in the United States;

changes in financial estimates or recommendations by securities analysts;

trading volume of our common stock;

sales of our common stock by us, our executive officers and directors or our stockholders in the future;

sales of debt securities and sales or licensing of assets;

general economic and market conditions and overall fluctuations in the United States equity markets; and

the loss of any of our key scientific or management personnel.

In addition, the stock markets in general, and the markets for pharmaceutical, biopharmaceutical and biotechnology stocks in particular, have experienced
extreme  volatility  that  may  have  been  unrelated  to  the  operating  performance  of  the  issuer.  These  broad  market  fluctuations  may  adversely  affect  the
trading  price  or  liquidity  of  our  common  stock.  In  the  past,  when  the  market  price  of  a  stock  has  been  volatile,  holders  of  that  stock  have  sometimes
instituted securities class action litigation against the issuer. If any of our stockholders were to bring such a lawsuit against us, we could incur substantial
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lawsuit and the attention of our management would be diverted from the operation of our business, which could seriously harm our financial position. Any
adverse determination in litigation could also subject us to significant liabilities.

Our principal stockholders own a significant percentage of our stock and, together with our management, will be able to exert significant control over
matters subject to stockholder approval.

Based on the number of shares outstanding as of December 31, 2021, our officers, directors and stockholders who hold at least 5% of our stock together
beneficially own approximately 17.6% of our outstanding common stock. If these officers, directors, and principal stockholders or a group of our principal
stockholders  act  together,  they  will  be  able  to  exert  a  significant  degree  of  influence  over  our  management  and  affairs  and  control  matters  requiring
stockholder approval, including the election of directors, amendments to our organizational documents, and approval of any merger, sale of assets or other
business  combination  transactions.  The  interests  of  this  concentration  of  ownership  may  not  always  coincide  with  our  interests  or  the  interests  of  other
stockholders. For instance, officers, directors and principal stockholders, acting together, could cause us to enter into transactions or agreements that we
would not otherwise consider. Similarly, this concentration of ownership may have the effect of delaying or preventing a change in control of our company
otherwise favored by our other stockholders.

Sales of a substantial number of shares of our common stock in the public market could cause our stock price to fall.

If our existing stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market, the trading price of our
common  stock  could  decline.  As  of  December  31,  2021,  we  had  approximately  130.2  million  shares  of  common  stock  outstanding.  Of  those  shares,
approximately 18.7 million were held by current directors, executive officers and stockholders owning 5% or more of our outstanding common stock.

As of December 31, 2021, 3.5 million shares of common stock issuable upon vesting of outstanding restricted stock units and approximately 10.4 million
shares of common stock issuable upon exercise of outstanding options were eligible for sale in the public market to the extent permitted by the provisions
of the applicable vesting schedules, and Rule 144 and Rule 701 under the Securities Act. If these additional shares of common stock are issued and sold, or
if it is perceived that they will be sold, in the public market, the trading price of our common stock could decline.

If  we  sell  shares  of  our  common  stock  in  future  financings,  stockholders  may  experience  immediate  dilution  and,  as  a  result,  our  stock  price  may
decline.

We may from time to time issue additional shares of common stock at a discount from the current trading price of our common stock. As a result, our
stockholders would experience immediate dilution upon the purchase of any shares of our common stock sold at such discount. In addition, as opportunities
present themselves, we may enter into financing or similar arrangements in the future, including the issuance of debt securities, preferred stock or common
stock. If we issue common stock or securities convertible into common stock, our common stockholders would experience additional dilution and, as a
result, our stock price may decline.

General Risk Factors

We incur significant costs as a result of operating as a public company, and our management will devote substantial time to new compliance initiatives.
We may fail to comply with the rules that apply to public companies, including Section 404 of the Sarbanes-Oxley Act of 2002, which could result in
sanctions or other penalties that would harm our business.

We incur significant legal, accounting and other expenses as a public company, including costs resulting from public company reporting obligations under
the Securities Exchange Act of 1934, as amended (the “Exchange Act”) and regulations regarding corporate governance practices. The listing requirements
of The Nasdaq Global Market require that we satisfy certain corporate governance requirements relating to director independence, distributing annual and
interim  reports,  stockholder  meetings,  approvals  and  voting,  soliciting  proxies,  conflicts  of  interest  and  a  code  of  conduct.  Our  management  and  other
personnel will need to devote a substantial amount of time to ensure that we comply with all of these requirements. Moreover, the reporting requirements,
rules and regulations will increase our legal and financial compliance costs and will make some activities more time consuming and costly. Any changes
we make to comply with these obligations may not be sufficient to allow us to satisfy our obligations as a public company on a timely basis, or at all. These
reporting requirements, rules and regulations, coupled with the increase in potential litigation exposure associated with being a public company, could also
make it more difficult for us to attract and retain qualified persons to serve on our board of directors or board committees or to serve as executive officers,
or to obtain certain types of insurance, including directors’ and officers’ insurance, on acceptable terms.

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We  are  subject  to  Section  404  of  The  Sarbanes-Oxley  Act  of  2002  (“Section  404”)  and  the  related  rules  of  the  Securities  and  Exchange  Commission
(“SEC”)  which  require,  among  other  things,  our  management  and  independent  registered  public  accounting  firm  to  report  on  the  effectiveness  of  our
internal control over financial reporting. Our compliance with Section 404 requires that we incur substantial expense and expend significant management
efforts.

During the course of our review and testing of our internal controls, we may identify deficiencies and be unable to remediate them before we must provide
the required reports. Furthermore, if we have a material weakness in our internal controls over financial reporting, we may not detect errors on a timely
basis and our financial statements may be materially misstated. We or our independent registered public accounting firm may not be able to conclude on an
ongoing basis that we have effective internal control over financial reporting, which could harm our operating results, cause investors to lose confidence in
our reported financial information and cause the trading price of our stock to fall. In addition, as a public company we are required to file accurate and
timely quarterly and annual reports with the SEC under the Exchange Act. Any failure to report our financial results on an accurate and timely basis could
result  in  sanctions,  lawsuits,  delisting  of  our  shares  from  The  Nasdaq  Global  Market  or  other  adverse  consequences  that  would  materially  harm  our
business.

We may be adversely affected by the global economic environment.

Our ability to attract and retain collaboration partners or customers, invest in and grow our business and meet our financial obligations depends on our
operating and financial performance, which, in turn, is subject to numerous factors, including the prevailing economic conditions and financial, business
and other factors beyond our control, such as the rate of unemployment, the number of uninsured persons in the United States, presidential elections, other
political influences and inflationary pressures. Our results of operations could be adversely affected by general conditions in the global economy and in the
global financial markets. The 2008 global financial crisis caused extreme volatility and disruptions in the capital and credit markets. We cannot anticipate
all the ways in which the global economic climate and global financial market conditions could adversely impact our business in the future.

We  are  exposed  to  risks  associated  with  reduced  profitability  and  the  potential  financial  instability  of  our  collaboration  partners  or  customers,  many  of
which may be adversely affected by volatile conditions in the financial markets. For example, unemployment and underemployment, and the resultant loss
of insurance, may decrease the demand for healthcare services and pharmaceuticals. If fewer patients are seeking medical care because they do not have
insurance coverage, our collaboration partners or customers may experience reductions in revenues, profitability and/or cash flow that could lead them to
reduce their support of our programs or financing activities. If collaboration partners or customers are not successful in generating sufficient revenue or are
precluded from securing financing, they may not be able to pay, or may delay payment of, accounts receivable that are owed to us. In addition, volatility in
the financial markets could cause significant fluctuations in the interest rate and currency markets. We currently do not hedge for these risks. The foregoing
events, in turn, could adversely affect our financial condition and liquidity. In addition, if economic challenges in the United States result in widespread and
prolonged unemployment, either regionally or on a national basis, or if certain provisions of the Patient Protection and ACA, as amended by the Health
Care  and  Education  Reconciliation  Act,  collectively  known  as  the  ACA,  are  repealed,  a  substantial  number  of  people  may  become  uninsured  or
underinsured. To the extent economic challenges result in fewer individuals pursuing or being able to afford our product candidates once commercialized,
our business, results of operations, financial condition and cash flows could be adversely affected.

Provisions in our charter documents and under Delaware law could discourage a takeover that stockholders may consider favorable and may lead to
entrenchment of management.

Our amended and restated certificate of incorporation and amended and restated bylaws contain provisions that could significantly reduce the value of our
shares  to  a  potential  acquirer  or  delay  or  prevent  changes  in  control  or  changes  in  our  management  without  the  consent  of  our  board  of  directors.  The
provisions in our charter documents include the following:

•

•

•

a classified board of directors with three-year staggered terms, which may delay the ability of stockholders to change the membership of a majority of
our board of directors;

no cumulative voting in the election of directors, which limits the ability of minority stockholders to elect director candidates;

the exclusive right of our board of directors to elect a director to fill a vacancy created by the expansion of the board of directors or the resignation,
death or removal of a director, which prevents stockholders from being able to fill vacancies on our board of directors;

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•

•

•

•

•

•

•

the required approval of at least two-thirds of the shares entitled to vote to remove a director for cause, and the prohibition on removal of directors
without cause;

the ability of our board of directors to authorize the issuance of shares of preferred stock and to determine the price and other terms of those shares,
including preferences and voting rights, without stockholder approval, which could be used to significantly dilute the ownership of a hostile acquirer;

the ability of our board of directors to alter our bylaws without obtaining stockholder approval;

the required approval of at least two-thirds of the shares entitled to vote at an election of directors to adopt, amend or repeal our bylaws or repeal the
provisions of our amended and restated certificate of incorporation regarding the election and removal of directors;

a prohibition on stockholder action by written consent, which forces stockholder action to be taken at an annual or special meeting of our stockholders;

the requirement that a special meeting of stockholders may be called only by the chairman of the board of directors, the chief executive officer, the
president or the board of directors, which may delay the ability of our stockholders to force consideration of a proposal or to take action, including the
removal of directors; and

advance notice procedures that stockholders must comply with in order to nominate candidates to our board of directors or to propose matters to be
acted  upon  at  a  stockholders’  meeting,  which  may  discourage  or  deter  a  potential  acquirer  from  conducting  a  solicitation  of  proxies  to  elect  the
acquirer’s own slate of directors or otherwise attempting to obtain control of us.

In addition, these provisions would apply even if we were to receive an offer that some stockholders may consider beneficial.

We are also subject to the anti-takeover provisions contained in Section 203 of the Delaware General Corporation Law. Under Section 203, a corporation
may not, in general, engage in a business combination with any holder of 15% or more of its capital stock unless the holder has held the stock for three
years or, among other exceptions, the board of directors has approved the transaction.

Claims for indemnification by our directors and officers may reduce our available funds to satisfy successful third-party claims against us and may
reduce the amount of money available to us.

Our amended and restated certificate of incorporation and amended and restated bylaws provide that we will indemnify our directors and officers, in each
case to the fullest extent permitted by Delaware law.

In addition, as permitted by Section 145 of the Delaware General Corporation Law, our amended and restated bylaws and our indemnification agreements
that we have entered into with our directors and officers provide that:

• We will indemnify our directors and officers for serving us in those capacities or for serving other business enterprises at our request, to the fullest
extent permitted by Delaware law. Delaware law provides that a corporation may indemnify such person if such person acted in good faith and in a
manner such person reasonably believed to be in or not opposed to the best interests of the registrant and, with respect to any criminal proceeding, had
no reasonable cause to believe such person’s conduct was unlawful.

• We may, in our discretion, indemnify employees and agents in those circumstances where indemnification is permitted by applicable law.

• We are required to advance expenses, as incurred, to our directors and officers in connection with defending a proceeding, except that such directors or

officers shall undertake to repay such advances if it is ultimately determined that such person is not entitled to indemnification.

• We  will  not  be  obligated  pursuant  to  our  amended  and  restated  bylaws  to  indemnify  a  person  with  respect  to  proceedings  initiated  by  that  person
against  us  or  our  other  indemnities,  except  with  respect  to  proceedings  authorized  by  our  board  of  directors  or  brought  to  enforce  a  right  to
indemnification.

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•

The rights conferred in our amended and restated bylaws are not exclusive, and we are authorized to enter into indemnification agreements with our
directors, officers, employees and agents and to obtain insurance to indemnify such persons.

• We may not retroactively amend our amended and restated bylaw provisions to reduce our indemnification obligations to directors, officers, employees

and agents.

We do not currently intend to pay dividends on our common stock, and, consequently, our stockholders’ ability to achieve a return on their investment
will depend on appreciation in the price of our common stock.

We do not currently intend to pay any cash dividends on our common stock for the foreseeable future. We currently intend to invest our future earnings, if
any, to fund our growth. Additionally, the terms of our loan and security agreements could restrict our ability to pay dividends. Therefore, our stockholders
are not likely to receive any dividends on our common stock for the foreseeable future. Since we do not intend to pay dividends, our stockholders’ ability to
receive  a  return  on  their  investment  will  depend  on  any  future  appreciation  in  the  market  value  of  our  common  stock.  There  is  no  guarantee  that  our
common stock will appreciate or even maintain the price at which our holders have purchased it.

The  United  Kingdom’s  withdrawal  from  the  European  Union  may  have  a  negative  effect  on  global  economic  conditions,  financial  markets  and  our
business.

Following a national referendum and enactment of legislation by the government of the United Kingdom, the United Kingdom formally withdrew from the
European Union and ratified a trade and cooperation agreement governing its future relationship with the European Union. The agreement, which is being
applied  provisionally  from  January  1,  2021,  until  it  is  ratified  by  the  European  Parliament  and  the  Council  of  the  European  Union,  addresses  trade,
economic  arrangements,  law  enforcement,  judicial  cooperation  and  a  governance  framework  including  procedures  for  dispute  resolution,  among  other
things.  Because  the  agreement  merely  sets  forth  a  framework  in  many  respects  and  will  require  complex  additional  bilateral  negotiations  between  the
United Kingdom and the European Union as both parties continue to work on the rules for implementation, significant political and economic uncertainty
remains about how the precise terms of the relationship between the parties will differ from the terms before withdrawal.

These developments, or the perception that any related developments could occur, have had and may continue to have a material adverse effect on global
economic conditions and financial markets, and may significantly reduce global market liquidity, restrict the ability of key market participants to operate in
certain financial markets or restrict our access to capital. Any of these factors could have a material adverse effect on our business, financial condition and
results of operations and reduce the price of our common stock.

ITEM 1B.    UNRESOLVED STAFF COMMENTS

None.

ITEM 2.    PROPERTIES

Our  headquarters  is  currently  located  in  Waltham,  Massachusetts  consisting  of  12,864  square  feet  of  leased  office  space  under  a  lease  agreement  that
expires in June 2026. In addition, we lease 72,500 square feet of office and laboratory space in Fremont, California under a lease agreement that expires in
March 2025 and 4,768 square feet of office space in Milwaukee, Wisconsin under a lease agreement that expires in February 2026. Prior to October 2021,
our headquarters were co-located in Fremont, California and Waltham, Massachusetts.

ITEM 3.    LEGAL PROCEEDINGS

On July 30, 2021, a putative securities class action lawsuit was commenced in the U.S. District Court for the Northern District of California naming as
defendants Ardelyx and two current officers. The complaint alleges that the defendants violated Sections 10(b) and 20(a) of the Securities Exchange Act of
1934, as amended, and Rule 10b-5 thereunder, by making false and misleading statements and omissions of material fact related to tenapanor. The plaintiff
seeks  to  represent  all  persons  who  purchased  or  otherwise  acquired  Ardelyx  securities  between  August  6,  2020,  and  July  19,  2021.  The  plaintiff  seeks
damages and interest, and an award of costs, including attorneys’ fees. We believe the plaintiff’s claims are without merit and we have not recorded any
accrual for a contingent liability associated with these legal proceedings.

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From time to time, we may be involved in legal proceedings arising in the ordinary course of business. We believe that as of December 31, 2021, there is
no  litigation  pending  that  would  reasonably  be  expected  to  have  a  material  adverse  effect  on  our  results  of  operations  and  financial  condition,  and  no
contingent liabilities were accrued as of December 31, 2021.

ITEM 4.    MINE SAFETY DISCLOSURES

Not applicable.

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ITEM 5.    MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF

PART II

EQUITY SECURITIES

Common Stock

On June 19, 2014, our common stock commenced trading on The Nasdaq Global Market under the symbol “ARDX”. Prior to that date, there was no public
trading market for our common stock. As of December 31, 2021, there were 30 holders of record of our common stock.

Dividends

We  have  never  declared  or  paid  cash  dividends  on  our  capital  stock.  We  currently  intend  to  retain  any  future  earnings  to  finance  the  growth  and
development of our business.

Securities Authorized for Issuance under Equity Compensation Plans

The information required by this item regarding executive compensation will be incorporated by reference to the information set forth in the sections titled
“Executive Compensation” in our Proxy Statement.

Recent Sales of Unregistered Securities

None.

Use of Proceeds

Not applicable.

Issuer Purchases of Equity Securities

Not applicable.

ITEM 6.

Reserved

ITEM 7.    MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS

You should read the following discussion and analysis of our financial condition and results of operations in conjunction with our financial statements and
related  notes  included  elsewhere  in  this  report.  This  discussion  and  other  parts  of  this  report  contain  forward-looking  statements  that  involve  risk  and
uncertainties, such as statements of our plans, objectives, expectations and intentions. Our actual results could differ materially from those discussed in
these forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in the section of
this report entitled “Risk Factors. ” These forward-looking statements speak only as of the date hereof. Except as required by law, we assume no obligation
to update or revise these forward-looking statements for any reason. Unless the context requires otherwise, the terms “Ardelyx”, “Company”, “we”, “us”,
and “our” refer to Ardelyx, Inc.

OVERVIEW

We  are  a  biopharmaceutical  company  founded  with  a  mission  to  discover,  develop  and  commercialize  innovative  first-in-class  medicines  that  meet
significant unmet medical needs. This includes adult patients with irritable bowel syndrome with constipation (“IBS-C”), adult patients with chronic kidney
disease  (“CKD”)  on  dialysis  suffering  from  elevated  serum  phosphorus,  or  hyperphosphatemia;  and  adult  patients  with  CKD  and/or  heart  failure  with
elevated serum potassium, or hyperkalemia.

Since  commencing  operations  in  October  2007,  substantially  all  our  efforts  have  been  dedicated  to  our  research  and  development  (“R&D”)  activities,
including developing tenapanor and developing our proprietary drug discovery and design

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platform. We have not generated any revenues from product sales. As of December 31, 2021, we had an accumulated deficit of $712.9 million.

We expect to continue to incur substantial operating losses for the foreseeable future as we prepare for commercialization of IBSRELA  (tenapanor)  in
April of this year, seek to gain approval for XPHOZAH (tenapanor) for the control of serum phosphorus in adult patients with CKD on dialysis; prepare
for the potential commercialization of XPHOZAH, if approved; incur manufacturing and development cost for, tenapanor; and incur development costs for
RDX013.  To  date,  we  have  funded  our  operations  from  the  sale  and  issuance  of  common  stock  and  convertible  preferred  stock,  funds  from  our
collaboration partnerships, which includes license fees, milestones and product supply revenue, as well as funds from our loan agreements with our lenders.

® 

®

On  February  28,  2022,  we  received  a  letter  from  Nasdaq  indicating  that  we  have  failed  to  comply  with  the  minimum  bid  price  requirement  of  Nasdaq
Listing Rule 5550(a)(2). Nasdaq Listing Rule 5550(a)(2) requires that companies listed on the Nasdaq Capital Market maintain a minimum closing bid
price of at least $1.00 per share. Under Nasdaq Listing Rule 5810(c)(3)(A), we have a 180 calendar day grace period to regain compliance by meeting the
continued  listing  standard.  To  regain  compliance,  the  closing  bid  price  of  the  Company’s  common  stock  must  meet  or  exceed  $1.00  per  share  for  a
minimum  of  ten  consecutive  business  days  during  this  grace  period.  We  are  monitoring  the  bid  price  of  our  common  stock  and  will  consider  options
available  to  us  to  achieve  compliance.  There  can  be  no  assurances  that  we  will  be  successful  in  restoring  our  compliance  with  the  Nasdaq  listing
requirements.

OUR PRODUCT PIPELINE

IBSRELA for IBS-C

Our  unique  discovery  platform  and  deep  understanding  of  the  primary  mechanism  of  sodium  transport  in  the  intestine  resulted  in  our  discovery  and
development  of  IBSRELA,  a  first-in-class,  FDA  approved,  sodium  hydrogen  exchanger  3  ("NHE3")  inhibitor  for  the  treatment  of  IBS-C  in  adults.
IBSRELA  acts  locally  in  the  gut  and  is  minimally  absorbed.  By  inhibiting  NHE3,  IBSRELA  exerts  a  triple  action  mechanism.  First,  it  blocks  dietary
sodium absorption, leading to increased intestinal transit time and softer stool to address constipation. Second, it decreases intestinal permeability to reduce
abdominal pain, and, third, it decreases visceral hypersensitivity to reduce abdominal pain. The triple action mechanism of IBSRELA is differentiated from
existing therapies and has been shown to provide significant improvement in abdominal pain, bloating, and constipation – with a quick onset of action and
sustained efficacy. Treatment with IBSRELA has been demonstrated to result in improved quality of life versus placebo and patient treatment satisfaction.

We plan to launch IBSRELA in the U.S. in April 2022.

IBS-C is a gastrointestinal disorder characterized by both abdominal pain and altered bowel movements, estimated to affect 11 million people in the U.S.
IBS-C is associated with significantly impaired quality of life, reduced productivity, and substantial economic burden. The introduction of new agents over
the last decade has led to an established prescription ("RX") treated market with 9,000 writers accounting for 50% of the RXs. Despite the active use of
GCC agonist therapies, 83% of Health Care Providers ("HCPs") report a significant unmet need for new therapies, and report that approximately 35% of
the patients currently under their care do not adequately respond to the available treatments. When presented with the IBSRELA product profile, 75% of
HCPs respond favorably, with the efficacy profile and novel method of action rated as the most compelling aspects of the product profile.

In  preparation  for  our  commercial  launch  of  IBSRELA,  we  have  built  a  commercial  organization  highly  experienced  in  launching  novel  therapies  into
specialty  areas.  The  established  nature  of  the  market,  limited  number  of  players,  concentration  of  prescribers,  recognized  unmet  need,  and  favorable
response to the novel mechanism IBSRELA product profile enable a targeted promotional effort centered on the 9,000 health care providers that account
for 50% of IBS-C prescriptions. Central to the go to market strategy is a highly experienced specialty sales force, many with existing relationships across
their GI target base, full company engagement, and innovative peer-to-peer and digital initiatives leveraging the rapidly evolving market dynamics in how
HCPs receive information and interact with industry.

With a concentrated promotional focus on patients currently being managed for IBS-C by high writing HCPs - in contrast to the DTC centered, market
building approach taken by the existing GCC agonists - competition for IBSRELA will come largely from the four prescription products indicated for IBS-
C: Linzess (linaclotide); Amitiza (lubiprostone); Trulance (plecanatide) and Zelnorm (tegaserod). Additionally, over the counter products are commonly
used to treat the constipation component of IBS-C, both alone, and in combination with the IBS-C indicated RX therapies.

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We have established commercial agreements with Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. (“Fosun Pharma”) in China and Knight
Therapuetics, Inc. (“Knight”) in Canada for IBSRELA for IBS-C. Knight is currently marketing IBSRELA in Canada.

Development Candidate XPHOZAH: A New Approach for The Control of Serum Phosphorus in Adult Patients with CKD on Dialysis

XPHOZAH  is  a  first-in-class  medicine  being  developed  for  the  control  of  serum  phosphorus  in  adult  patients  with  CKD  on  dialysis.  XPHOZAH  has  a
unique mechanism of action and acts locally in the gut to inhibit NHE3. This results in the tightening of the epithelial cell junctions, thereby significantly
reducing paracellular uptake of phosphate, the primary pathway of phosphate absorption. If approved, XPHOZAH would be the first therapy for phosphate
management that blocks phosphorus absorption at the primary site of uptake. It is not a phosphate binder.

In  June  2020,  we  submitted  a  new  drug  application  ("NDA")  to  the  U.S.  Food  and  Drug  Administration  (“FDA”)  for  tenapanor  the  control  of  serum
phosphorus in adult patients with CKD on dialysis. The NDA was supported by three Phase 3 trials involving over 1,000 adult patients that evaluated the
use of tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis, with two trials evaluating tenapanor as monotherapy and one
trial  evaluating  tenapanor  as  part  of  a  dual  mechanism  approach  with  phosphate  binders.  All  three  Phase  3  trials  met  their  primary  and  key  secondary
endpoints.

On July 28, 2021, we received a Complete Response Letter ("CRL") from the FDA regarding our NDA for tenapanor for the control of serum phosphorus
in adult patients with CKD on dialysis. According to the CRL, while the FDA agrees “that the submitted data provide substantial evidence that tenapanor is
effective in reducing serum phosphorus in adult patients with CKD on dialysis,” the FDA characterizes the magnitude of the treatment effect as “small and
of unclear clinical significance.” Following an End-of-Review Type A meeting (“End of Review Meeting”) in October 2021, with the FDA’s Division of
Cardiology and Nephrology (the “Division”), we submitted a Formal Dispute Resolution Request (“FDRR”) in December 2021. The FDRR was focused
on demonstrating that the data submitted in the NDA supported the clinical significance of the treatment effect of tenapanor.

On February 4, 2022, we received an Appeal Denied Letter (“ADL”) from the FDA’s Office of Cardiology, Hematology, Endocrinology and Nephrology
(“OCHEN”). On February 18, 2022, we submitted an appeal of the ADL to the FDA’s Center for Drug Evaluation and Research, Office of New Drugs
(“OND”). If accepted, we expect a decision on the appeal to the OND in April 2022. While the CRL noted that in order for the NDA to be approved, we
need to conduct an additional adequate and well-controlled trial demonstrating a clinically relevant treatment effect on serum phosphorus or an effect on
the  clinical  outcome  thought  to  be  caused  by  hyperphosphatemia  in  adult  patients  with  CKD  on  dialysis,  the  ADL  provided  a  potential  additional  path
forward involving the resubmission of the NDA (without conducting an additional trial) with a number of new analyses of each of our Phase 3 clinical
trials; an assessment of tenapanor’s benefits and risks; and a proposal of how to label tenapanor for prescribers. There can be no assurances that the Formal
Dispute  Resolution  (“FDR”)  process  will  result  in  approval  of  our  NDA,  or  in  a  clear  path  to  resubmission  of  our  NDA  that  is  achievable  in  terms  of
clinical endpoints, time and cost.

RDX013 Program: Small Molecule for Treating Hyperkalemia

We  are  also  advancing  a  small  molecule  potassium  secretagogue  program,  RDX013,  for  the  potential  treatment  of  hyperkalemia.  Hyperkalemia  is  a
common  problem  in  patients  with  heart  and  kidney  disease,  particularly  in  patients  taking  customary  blood  pressure  medications  known  as  renin-
angiotensin-aldosterone  system  (“RAAS”)  inhibitors.  RDX013  is  a  novel  mechanism  agent  designed  to  target  the  underlying  biological  mechanisms  of
potassium secretion to lower elevated potassium. While currently available therapies are all ion exchange agents, RDX013 is a first in class secretagogue
with  demonstrated  proof  of  concept  in  a  Phase  2  dose  ranging  study  evaluating  the  safety  and  pharmacodynamics  of  RDX013  in  adult  patients  with
hyperkalemia.  The  next  steps  for  RDX013  will  be  determined  based  on  final  analyses  of  the  Phase  2  results,  continued  formulation  development,  and
sufficient financial resources.

RDX020 Program: Small molecule for Treating Metabolic Acidosis

We  have  an  ongoing  discovery  program  targeting  the  inhibition  of  bicarbonate  exchange  inhibitor  for  the  treatment  of  metabolic  acidosis,  a  highly
prevalent comorbidity in CKD patients that is strongly correlated with disease progression and adverse outcomes. We have identified lead compounds that
are potent, selective and proprietary inhibitors of bicarbonate secretion. Our research organization was eliminated as part of our October 2021 restructuring,
and therefore, we currently expect to continue to advance this discovery program utilizing third-party resources managed by internal non-clinical expertise.

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FINANCIAL OPERATIONS OVERVIEW

Revenue

Our revenue to date has been generated primarily through license, research and development collaborative agreements with various collaboration partners.
We have not generated any revenue from commercial product sales. We currently expect to commence commercialization of IBSRELA in April 2022. In
the future, we may generate revenue from a combination of our own product sales and payments in connection with our current or future collaborative
partnerships,  including  license  fees,  other  upfront  payments,  milestone  payments,  royalties  and  payments  for  drug  product  and/or  drug  substance.  We
expect that any revenue we generate will fluctuate in future periods as a result of, among other factors: the extent to which we are successful in our efforts
to commercialize IBSRELA; whether we receive regulatory approval for tenapanor for the control of serum phosphorous in adult patients with CKD on
dialysis (the “Hyperphosphatemia Indication”), and if such approval is received, the timing of such approval and the extent to which we are successful in
our  efforts  to  commercialize  XPHOZAH  for  such  indication;  the  timing  and  progress  of  goods  and  services  provided  pursuant  to  our  current  or  future
collaborative partnerships; our or our collaborators’ achievement of preclinical, clinical, regulatory or commercialization milestones, to the extent achieved;
the timing and amount of any payments to us relating to the aforementioned milestones; and the extent to which any of our product candidates are approved
and successfully commercialized by a collaboration partner. If we are not able to obtain market acceptance for IBSRELA; if we are not successful in our
efforts to obtain and sustain an adequate level of coverage and reimbursement for IBSRELA by third-party payors; if we fail to obtain regulatory approval
for tenapanor for the Hyperphosphatemia indication and/or our current collaboration partners or any future collaboration partners fail to obtain regulatory
approval for tenapanor in their respective territories, our ability to generate future revenue from our product sales or from our collaborative arrangements,
and our results of operations and financial position, would be materially and adversely affected. Our past revenue performance is not necessarily indicative
of results to be expected in future periods. See Note 2, Summary of Significant Accounting Policies, in the notes to our financial statements, included in
Part II, Item 8, of this Annual Report on Form 10-K, for further details.

Cost of Revenue

Cost of revenue represents payments due to AstraZeneca AB (“AstraZeneca”), which under the terms of a termination agreement entered into in 2015 (the
“AZ Termination Agreement”) is entitled to (i) future royalties at a rate of 10% of net sales of tenapanor or other NHE3 products by us or our licensees,
and (ii) 20% of non-royalty revenue received from our collaboration partners as a result of the development and commercialization of tenapanor or certain
other NHE3 inhibitors. We have agreed to pay AstraZeneca up to a maximum of $75.0 million in the aggregate for (i) and (ii). We recognize these expenses
as cost of revenue when we recognize the corresponding revenue that gives rise to payments due to AstraZeneca. To date, we recognized an aggregate of
$11.6 million as cost of revenue under the AZ Termination Agreement since 2017. See details in Note 5, Collaboration and Licensing Agreements, under
AstraZeneca, in the notes to our financial statements, included in Part II, Item 8, of this Annual Report on Form 10-K.

Research and Development

Pursuant to the October 2021 restructuring plan, we have eliminated our internal research organization and expect to continue our discovery efforts with
respect to RDX020 through the use of third-parties managed internally by non-clinical expertise. We recognized all research and development expenses as
they  were  incurred  to  support  the  discovery,  research,  development  and  manufacturing  of  our  product  candidates.  Research  and  development  expenses
include, but are not limited to, the following:

•

•

•

•

•

external  research  and  development  expenses  incurred  under  agreements  with  consultants,  third-party  contract  research  organizations  (“CROs”)
and investigative sites where a substantial portion of our clinical studies are conducted, and with contract manufacturing organizations where our
clinical supplies are produced;

expenses associated with supplies and materials consumed in connection with our research operations;

expenses associated with producing tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis prior to FDA approval;

other costs associated with research, clinical development and regulatory activities;

employee-related expenses, which include salaries, bonuses, benefits, travel and stock-based compensation; and

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•

facilities  and  other  allocated  expenses,  which  include  direct  and  allocated  expenses  for  rent  and  maintenance  of  facilities,  depreciation  and
amortization expense, information technology expense and other supplies.

General and Administrative

General and administrative expenses consist primarily of salaries and related benefits, including stock-based compensation, for certain of our executives,
our board members, and our finance, legal, business development, market development, commercial and support staff. Other general and administrative
expenses  include  facility  related  costs  and  professional  fees  for  legal,  accounting  and  audit,  investor  relations,  other  consulting  services  and  allocated
facility related costs not otherwise included in research and development expenses.

Interest Expense

Interest expense represents the interest paid on our loan payable.

Other Income, net

Other income, net consists of interest income earned on our cash and cash equivalents and held-to-maturity investments, the periodic revaluation of the exit
fee related to our loan and currency exchange gains and losses.

Provision for Income Taxes

Our provision for income taxes includes current and deferred tax, including foreign withholding taxes paid on payments received from certain collaboration
partners. Deferred income taxes reflect the tax effects of temporary differences between the carrying amounts of assets and liabilities for financial reporting
purposes and the amounts used for income tax purposes. Our deferred tax assets continue to be fully offset by a valuation allowance, including deferred tax
assets related to our net operating loss carryforwards, which may be subject to annual limitations as a result of ownership changes that may have occurred
or could occur in the future.

CRITICAL ACCOUNTING POLICES AND ESTIMATES

A  detailed  discussion  of  our  significant  accounting  policies  can  be  found  in  Note  2,  Summary  of  Significant  Accounting  Policies,  in  the  notes  to  our
financial  statements,  included  in  Part  II,  Item  8,  of  this  Annual  Report  on  Form  10-K.  Critical  accounting  policies  are  those  that  require  significant
judgment and/or estimates by management at the time that financial statements are prepared such that materially different results might have been reported
if other assumptions had been made. These estimates form the basis for making judgments about the carrying values of assets and liabilities. We base our
estimates and judgments on historical experience and on various other assumptions that we believe to be reasonable under the circumstances. Actual results
could differ materially from these estimates.

We consider certain accounting policies related to revenue recognition, accrued research and development expenses and stock-based compensation to be
critical policies to understanding the judgments and estimates applied in our reported financial results.

Revenue Recognition

We generate revenue primarily from research and collaboration and license agreements with customers. Goods and services in the agreements may include
the  grant  of  licenses  for  the  use  of  our  technology,  the  provision  of  services  associated  with  the  research  and  development  of  product  candidates,
manufacturing services, and participation in joint steering committees. The terms of these arrangements typically include payment to us of one or more of
the following: non-refundable, up-front license fees; research, development, regulatory and commercial milestone payments; reimbursement of research
and development services; option payments; reimbursement of certain costs; payments for manufacturing supply services; and future royalties on net sales
of licensed products.

When two or more contracts are entered into with the same customer at or near the same time, we evaluate the contracts to determine whether the contracts
should be accounted for as a single arrangement. Contracts are combined and accounted for as a single arrangement if one or more of the following criteria
are met: (i) the contracts are negotiated as a package with a single commercial objective; (ii) the amount of consideration to be paid in one contract depends
on the price or performance of the other contract; or (iii) the goods or services promised in the contracts (or some goods or services promised in each of the
contracts) are a single performance obligation.

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In determining the appropriate amount of revenue to be recognized as we fulfill our obligations under each of our agreements, management performs the
following  steps:  (i)  identification  of  the  promised  goods  or  services  in  the  contract;  (ii)  determination  of  whether  the  promised  goods  or  services  are
performance  obligations  including  whether  they  are  distinct  in  the  context  of  the  contract;  (iii)  measurement  of  the  transaction  price,  including  any
constraints on variable consideration; (iv) allocation of the transaction price to the performance obligations; and (v) recognition of revenue when (or as) we
satisfy each performance obligation. As part of the accounting for contracts with customers, we develop assumptions that require judgment to determine
whether promised goods and services represent distinct performance obligations and the standalone selling price for each performance obligation identified
in  the  contract.  This  evaluation  is  subjective  and  requires  us  to  make  judgments  about  the  promised  goods  and  services  and  whether  those  goods  and
services are separable from other aspects of the contract. Further, determining the standalone selling price for performance obligations requires significant
judgment, and when an observable price of a promised good or service is not readily available, we consider relevant assumptions to estimate the standalone
selling price, including, as applicable, market conditions, development timelines, probabilities of technical and regulatory success, reimbursement rates for
personnel costs, forecasted revenues, potential limitations to the selling price of the product and discount rates.

We apply judgment in determining whether a combined performance obligation is satisfied at a point in time or over time, and, if over time, concluding
upon the appropriate method of measuring progress to be applied for purposes of recognizing revenue. We evaluate the measure of progress each reporting
period and, as estimates related to the measure of progress change, related revenue recognition is adjusted accordingly. Changes in our estimated measure
of  progress  are  accounted  for  prospectively  as  a  change  in  accounting  estimate.  We  recognize  collaboration  revenue  by  measuring  the  progress  toward
complete satisfaction of the performance obligation using an input measure. In order to recognize revenue over the research and development period, we
measure actual costs incurred to date compared to the overall total expected costs to satisfy the performance obligation. Revenues are recognized as the
program  costs  are  incurred.  We  will  re-evaluate  the  estimate  of  expected  costs  to  satisfy  the  performance  obligation  each  reporting  period  and  make
adjustments  for  any  significant  changes.  Amounts  received  prior  to  satisfying  the  revenue  recognition  criteria  are  recorded  as  contract  liabilities  in  our
balance sheets. If the related performance obligation is expected to be satisfied within the next twelve months, this will be classified in current liabilities.
Amounts recognized as revenue prior to receipt are recorded as contract assets in our balance sheets. If we expect to have an unconditional right to receive
the consideration in the next twelve months, this will be classified in current assets. A net contract asset or liability is presented for each contract with a
customer.

Milestone  Payments:  At  the  inception  of  each  arrangement  that  includes  research  and  development  milestone  payments,  we  evaluate  whether  the
milestones are considered probable of being reached and estimate the amount to be included in the transaction price using the most likely amount method.
Amounts  of  variable  consideration  are  included  in  the  transaction  price  to  the  extent  that  it  is  probable  that  a  significant  reversal  in  the  amount  of
cumulative  revenue  recognized  will  not  occur  and  when  the  uncertainty  associated  with  the  variable  consideration  is  subsequently  resolved.  Milestone
payments  that  are  not  within  the  control  of  us  or  the  licensee,  such  as  regulatory  approvals,  are  not  considered  probable  of  being  achieved  until  those
approvals are received. The transaction price is then allocated to each performance obligation on a relative standalone selling price basis, for which we
recognize revenue as or when the performance obligations under the contract are satisfied. At the end of each subsequent reporting period, we re-evaluate
the probability of achievement of such development milestones and any related constraints, and if necessary, adjust our estimate of the overall transaction
price. Any such adjustments are recorded on a cumulative catch-up basis, which would affect earnings in the period of adjustment.

Manufacturing  supply  services:  Arrangements  that  include  a  promise  for  the  future  supply  of  drug  substance  or  drug  product  for  either  clinical
development or commercial supply at the customer’s discretion are generally considered as options. We assess if these options provide a material right to
the licensee and if so, they are accounted for as separate performance obligations. If we are entitled to additional payments when the customer exercises
these options, any payments are recorded in product supply revenues when the customer obtains control of the goods, which is upon delivery.

Royalties: For arrangements that include sales-based royalties, including milestone payments based on the level of sales, and where the license is deemed to
be the predominant item to which the royalties relate, we recognize revenue at the later of (i) when the related sales occur, or (ii) when the performance
obligation to which some or all of the royalty has been allocated has been satisfied (or partially satisfied). To date, we have not recognized any royalty
revenue resulting from any of our licensing arrangements.

Licenses of intellectual property: If a license granted to a customer to use our intellectual property is determined to be distinct from the other performance
obligations identified in the arrangement, we recognize revenue from consideration allocated to the license when the license is transferred to the licensee
and the licensee is able to use and benefit from the license. For licenses that are bundled with other promises, we apply judgment to assess the nature of the
combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time and, if over

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time,  to  conclude  upon  the  appropriate  method  of  measuring  progress  for  purposes  of  recognizing  revenue  related  to  consideration  allocated  to  the
performance obligation.

Options: Customer options, such as options granted to allow a licensee to choose to research, develop and commercialize licensed compounds are evaluated
at contract inception in order to determine whether those options provide a material right (i. e., an optional good or service offered for free or at a discount)
to the customer. If the customer options represent a material right, the material right is treated as a separate performance obligation at the outset of the
arrangement. We allocate the transaction price to material rights based on the standalone selling price, and revenue is recognized when or as the future
goods  or  services  are  transferred  or  when  the  option  expires.  Customer  options  that  are  not  material  rights  do  not  give  rise  to  a  separate  performance
obligation, and as such, the additional consideration that would result from a customer exercising an option in the future is not included in the transaction
price for the current contract. Instead, the option is deemed a marketing offer, and additional option fee payments are recognized or being recognized as
revenue  when  the  licensee  exercises  the  option.  The  exercise  of  an  option  that  does  not  represent  a  material  right  is  treated  as  a  separate  contract  for
accounting purposes.

Contract modifications:  Contract  modifications,  defined  as  changes  in  the  scope  or  price  (or  both)  of  a  contract  that  are  approved  by  the  parties  to  the
contract, such as a contract amendment, exist when the parties to a contract approve a modification that either creates new or changes existing enforceable
rights and obligations of the parties to the contract. Depending on facts and circumstances, we account for a contract modification as one of the following:
(i) a separate contract; (ii) a termination of the existing contract and a creation of a new contract; or (iii) a combination of the preceding treatments. A
contract modification is accounted for as a separate contract if the scope of the contract increases because of the addition of promised goods or services that
are distinct and the price of the contract increases by an amount of consideration that reflects our standalone selling prices of the additional promised goods
or services. When a contract modification is not considered a separate contract and the remaining goods or services are distinct from the goods or services
transferred  on  or  before  the  date  of  the  contract  modification,  we  account  for  the  contract  modification  as  a  termination  of  the  existing  contract  and  a
creation of a new contract. When a contract modification is not considered a separate contract and the remaining goods or services are not distinct, we
account for the contract modification as an add-on to the existing contract and as an adjustment to revenue on a cumulative catch-up basis.

We receive payments from our licensees as established in each contract. Upfront payments and fees are recorded as deferred revenue upon receipt or when
due  and  may  require  deferral  of  revenue  recognition  to  a  future  period  until  we  perform  our  obligations  under  these  arrangements.  Where  applicable,
amounts  are  recorded  as  unbilled  revenue  when  our  right  to  consideration  is  unconditional.  We  do  not  assess  whether  a  contract  with  a  customer  has  a
significant financing component if the expectation at contract inception is such that the period between payment by the licensees and the transfer of the
promised goods or services to the licensees will be one year or less.

Accrued Research and Development Expenses

As  part  of  the  process  of  preparing  our  financial  statements,  we  are  required  to  estimate  our  accrued  expenses.  This  process  involves  reviewing  open
contracts and purchase orders, communicating with our personnel to identify services that have been performed on our behalf and estimating the level of
service performed and the associated cost incurred for the service when we have not yet been invoiced or otherwise notified of the actual cost. The majority
of our service providers invoice us monthly in arrears for services performed or when contractual milestones are met. We make estimates of our accrued
expenses as of each balance sheet date in our financial statements based on facts and circumstances known to us at that time. We periodically confirm the
accuracy of our estimates with the service providers and make adjustments if necessary. Examples of estimated accrued research and development expenses
include fees paid to:

•

•

•

•

•

CROs in connection with clinical studies;

investigative sites in connection with clinical studies;

vendors related to contract manufacturing, development and distribution of clinical supplies;

collaborator entities in connection with our collaboration agreements; and

vendors in connection with preclinical development activities.

We  record  expenses  related  to  clinical  studies  and  manufacturing  development  activities  based  on  our  estimates  of  the  services  received  and  efforts
expended pursuant to contracts with our CROs and manufacturing vendors that conduct and manage these activities on our behalf. The financial terms of
these agreements are subject to negotiation, vary from contract to

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contract,  and  may  result  in  uneven  payment  flows.  There  may  be  instances  in  which  payments  made  to  our  vendors  will  exceed  the  level  of  services
provided  and  result  in  a  prepayment  of  the  expense.  Payments  under  some  of  these  contracts  depend  on  factors  such  as  the  successful  enrollment  of
subjects and the completion of clinical trial milestones. In accruing service fees, we estimate the time period over which each component of a service will
be performed, and estimate, with vendor input if appropriate, the resulting level of completion of each component of the service, with such estimates often
involving  drivers  that  provide  a  surrogate  measurement  of  completion  such  as  number  of  enrolled  subjects  and/or  number  of  sites  activated  in  the
calculation of clinical trial fee accruals. If the actual timing of the performance of services or the level of effort varies from our estimate, we adjust the
accrued or prepaid expense balance accordingly. Although we do not expect our estimates to be materially different from amounts actually incurred, if our
estimates of the status and timing of services performed differ from the actual status and timing of services performed, we may report amounts that are too
high or too low in any particular period.

Stock-Based Compensation

We estimate the fair value of stock options and Employee Stock Purchase Plan (“the ESPP”) shares using the Black-Scholes valuation model. The Black-
Scholes model requires the input of highly subjective assumptions which determine the fair value of stock-based awards. These assumptions include:

Expected Term—We  have  limited  historical  information  to  develop  reasonable  expectations  about  future  exercise  patterns  and  post-vesting  employment
termination behavior for our stock-option grants. As such, the expected term is estimated using the simplified method whereby the expected term equals the
arithmetic average of the vesting term and the original contractual term of the option. Beginning in 2021, we estimate the expected term of our options
based upon historical exercises and post-vesting termination behavior, which has not resulted in a material difference as compared to using the simplified
method.

Expected Volatility— We use the historic volatility of our own stock over the retrospective period corresponding to the expected remaining term of the
options, or the period since our shares were first quoted on The Nasdaq Global Market, if that is shorter, to compute our expected stock price volatility.

Risk-Free Interest Rate—The risk-free interest rate assumption is based on zero-coupon U.S. Treasury instruments on the date of grant with a maturity date
consistent with the expected term of our stock option grants.

Expected Dividend— To date, we have not declared or paid any cash dividends and do not have any plans to do so in the future. Therefore, we use an
expected dividend yield of zero.

As  required,  we  review  our  valuation  assumptions  at  each  grant  date  and,  as  a  result,  we  are  likely  to  change  our  valuation  assumptions  used  to  value
employee  stock-based  awards  granted  in  future  periods.  Employee  and  director  stock-based  compensation  costs  are  to  be  recognized  over  the  vesting
period of the award, and we have elected to use the straight-line attribution method. Forfeitures are estimated at the time of grant and revised, if necessary,
in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience.

Restricted stock units ("RSUs") are measured at the fair value of our common stock on the date of grant and expensed over the period of vesting using the
straight-line attribution approach.

Performance-based  RSUs  ("PRSUs")  are  valued  at  grant-date  fair  market  value.  The  vesting  of  the  PRSUs  is  based  on  performance  conditions.
Performance conditions include: (i) a specific performance criteria and (ii) the employee’s continuous employment by the company for a stated period of
time in order to earn the right to the related PRSUs to vest. The Company recognizes compensation cost with respect to the vesting of the PRSUs on a
ratable basis over the requisite service period, upon the performance conditions being deemed probable of achievement.

Restructuring

We recognize restructuring charges related to reorganization plans that have been committed to by management and when liabilities have been incurred. In
connection  with  these  activities,  we  record  restructuring  charges  at  fair  value  for,  (a)  contractual  employee  termination  benefits  when  obligations  are
associated to services already rendered, rights to such benefits have vested, and payment of benefits is probable and can be reasonably estimated, (b) one-
time  employee  termination  benefits  when  management  has  committed  to  a  plan  of  termination,  the  plan  identifies  the  employees  and  their  expected
termination  dates,  the  details  of  termination  benefits  are  complete,  it  is  unlikely  changes  to  the  plan  will  be  made  or  the  plan  will  be  withdrawn  and
communication to such employees has occurred, and (c) contract termination costs when a contract is terminated before the end of its term.

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One-time employee termination benefits are recognized in their entirety when communication has occurred and future services are not required. If future
services  are  required,  the  costs  are  recorded  ratably  over  the  remaining  period  of  service.  Contract  termination  costs  to  be  incurred  over  the  remaining
contract term without economic benefit are recorded in their entirety when the contract is canceled.

RESULTS OF OPERATIONS

Comparison of the Years Ended December 31, 2021, 2020 and 2019

Revenue

Below is a summary of our total revenue (dollars in thousands):

Collaborative development revenue
Product supply revenue
Licensing revenue

Total revenues

Year Ended December 31,

2021

2020

2019

$

$

4,177  $
907 
5,013 
10,097  $

5,364  $
1,501 
706 
7,571  $

459  $
322 
4,500 
5,281  $

Change 
2021 vs. 2020

Change 
2020 vs. 2019

$

(1,187)
(594)
4,307 
2,526 

%

(22.1)% $
(39.6)%
610.1 %
33.4 % $

$

4,905 
1,179 
(3,794)
2,290 

%

1,068.6 %
366.1 %
(84.3)%

43.4 %

Fiscal 2021  compared  to  2020: The  increase  to  total  revenues  is  primarily  attributable  to  a  $5.0  million  development  milestone  which  we  earned  and
recognized  as  licensing  revenue  during  the  current  year  upon  the  initiation  by  KKC  of  phase  3  clinical  studies  in  Japan  to  evaluate  tenapanor  for
hyperphosphatemia.  The  increase  was  partially  offset  by  lower  collaborative  development  revenue  and  product  supply  revenue  from  KKC  during  the
current year.

Fiscal 2020 compared to 2019: The increase in our revenue was primarily attributable to $4.9 million higher collaborative development revenue recognized
in  connection  with  the  KKC  Agreement,  which  was  entered  into  in  November  2019,  a  $0.7  million  licensing  revenue  recognized  upon  Knight’s
achievement of a development milestone pursuant to the Knight Agreement and a $1.4 million increase in manufacturing supply of tenapanor and other
materials  sold  to  KKC  in  accordance  with  the  2017  KKC  Agreement,  partially  offset  by  $3.0  million  revenue  related  to  achievement  of  a  milestone
pursuant to the Fosun agreement during the year ended December 31, 2019.

Operating Expenses

Below is a summary of our operating expenses (dollars in thousands):

Year Ended December 31,

2021

2020

2019

$

$

1,000  $

91,140 
72,303 
164,443  $

145  $

65,053 
33,153 
98,351  $

600  $

71,677 
24,267 
96,544  $

Change 
2021 vs. 2020

Change 
2020 vs. 2019

$

855 
26,087 
39,150 
66,092 

%
589.7 % $
40.1 %
118.1 %
67.2 % $

$

(455)
(6,624)
8,886 
1,807 

%
(75.8)%
(9.2)%
36.6 %

1.9 %

Cost of revenue
Research and development
General and administrative

Total operating expenses

Cost of Revenue

Fiscal 2021 compared to 2020: The increase in cost of revenue was for payment due to AstraZeneca under the AZ Termination Agreement related to the
development milestone we earned upon the initiation by KKC of phase 3 clinical studies in Japan to evaluate tenapanor for hyperphosphatemia.

Fiscal 2020 compared to 2019: Cost of revenue was $0.1 million for the year ended December 31, 2020, a decrease of $0.5 million, or 75.8%, compared to
$0.6 million for the year ended December 31, 2019. Cost of revenue in both periods is the portion of tenapanor-related upfront and milestone payment from
our collaboration partners that we are required to make to AstraZeneca under the AstraZeneca Termination Agreement.

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Research and Development

Below is a summary of our research and development expenses (dollars in thousands):

External R&D expenses
Employee-related expenses
Facilities, equipment and depreciation
expenses
Other

Total research and development expenses

$

$

Year Ended December 31,

2021

2020

2019

56,747  $
27,268 

37,624  $
20,911 

45,989  $
19,466 

5,803 
1,322 
91,140  $

5,738 
780 
65,053  $

5,934 
288 
71,677  $

Change 
2021 vs. 2020

Change 
2020 vs. 2019

$
19,123 
6,357 

65 
542 
26,087 

%

50.8 % $
30.4 %

1.1 %
69.5 %
40.1 % $

$
(8,365)
1,445 

(196)
492 
(6,624)

%
(18.2)%
7.4 %

(3.3)%
170.8 %

(9.2)%

Fiscal 2021 compared to 2020: The increase in our external R&D expenses is the result of tenapanor manufacturing costs as well as clinical study costs
from  the  advancement  of  our  OPTIMIZE  study  which  were  partially  offset  by  lower  costs  for  the  PHREEDOM  clinical  study.  The  increase  in  our
employee-related expenses is related to compensation and benefits expenses for our research and development workforce. Employee-related expenses for
twelve  months  ended  December  31,  2021  include  $2.7  million  severance  payments  and  other  employee-related  costs  as  discussed  in  Note  11  -
Restructuring to the financial statements included elsewhere in this Annual Report.

Fiscal 2020  compared  to  2019: The  decrease  in  our  external  R&D  expenses  for  the  year  ended  December  31,  2020  primarily  includes  a  $9.7  million
decrease in our tenapanor-related expenses, partially offset by $3.0 million of higher expenses attributable to KKC Research Agreement-related research
and general R&D expenses. Of the overall tenapanor-related decrease, approximately $11.0 million relates to lower clinical study costs due to the winding
down of expenses associated with our Phase 3 clinical program for tenapanor for the control of hyperphosphatemia, offset by an out-of-period adjustment
recorded during 2019 that reduced clinical trial expenses by $3.6 million related to our tenapanor clinical trials for the nine months ended September 30,
2019;  and  approximately  $2.9  million  related  to  lower  manufacturing  expenses  due  to  reduced  validation  related  expenses  for  tenapanor  in  2020  as
compared to 2019; offset by an increase of $3.1 million related to regulatory expenses that includes $2.9 million paid to the FDA for the filing of a NDA
for tenapanor for the control of serum phosphorus in adult patients with CKD on dialysis in June 2020.

General and Administrative

Fiscal 2021 compared to 2020: The  increase  in  general  and  administrative  expenses  was  primarily  due  to  increased  costs  associated  with  building  and
staffing our commercial infrastructure and teams as we prepared for a potential U.S. launch of tenapanor. The increase consisted of headcount and related
personnel costs and an increase in external spending for disease awareness initiatives, commercial infrastructure and strategy. General and administrative
expenses for the twelve months ended December 31, 2021 include $3.5 million severance payments and other employee-related costs as discussed in Note
11 - Restructuring to the financial statements included elsewhere in this Annual Report.

Fiscal  2020  compared  to  2019:  The  increase  in  general  and  administrative  expenses  for  the  year  ended  December  31,  2020  was  primarily  due  to  an
increase in costs associated with building and staffing our commercial infrastructure and teams as we prepare for the anticipated U.S. launch of tenapanor
for the control of serum phosphorus in adult patients with CKD on dialysis. The increase consisted of headcount and related personnel costs and an increase
in external spending for disease awareness initiatives, commercial infrastructure and strategy.

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Other Income, net

Below is a summary of our other income (expense), net (dollars in thousands):

Interest expense
Other income, net

Total other income, net

Year Ended December 31,

Change 
2021 vs. 2020

Change 
2020 vs. 2019

2021

2020

2019

$

$

$

(4,502) $
687 
(3,815) $

(5,099) $
1,568 
(3,531) $

(5,726) $
2,352 
(3,374) $

597 
(881)
(284)

%
(11.7)% $
(56.2)%

8.0 % $

$

627 
(784)
(157)

%
(11.0)%
(33.3)%

4.7 %

Fiscal 2021 compared to 2020: The decrease in interest expense was primarily due to lower interest rates on our variable-rate term loan. The changes in
other income, net were primarily due to lower income earned on our investments, which was largely offset by the revaluation of our derivative liability
related to our term loan agreement following receipt of the FDA CRL on July 28, 2021.

Fiscal 2020 compared to 2019: The decrease in interest expense for the year ended December 31, 2020 was primarily due to lower interest rates on our
variable-rate term loan. The decrease in other income, net for the year ended December 31, 2020 was primarily due to a decrease in investment income, a
lower exit fee revaluation adjustment related to our loan agreement and a decrease in currency exchange losses.

LIQUIDITY AND CAPITAL RESOURCES

Below is a summary of our cash, cash equivalents and marketable securities (in thousands):

Cash and cash equivalents
Short-term investments
Long-term investments

Total liquid funds

Year Ended December 31,

2021

2020

$

$

72,428  $
44,261 
— 
116,689  $

91,032  $
95,452 
2,114 
188,598  $

Change 
2021 vs. 2020

$
(18,604)
(51,191)
(2,114)
(71,909)

%

(20.4)%
(53.6)%
(100.0)%

(38.1)%

As  of  December  31,  2021,  we  had  cash  and  investments  of  approximately  $116.7  million.  We  have  incurred  operating  losses  since  inception  and  our
accumulated deficit as of December 31, 2021 is $712.9 million. Our current level of cash and investments alone is not sufficient to meet our plans for the
next twelve months following the filing of these financial statements on February 28, 2022. These factors raise substantial doubt regarding our ability to
continue  as  a  going  concern  for  a  period  of  one  year  from  the  issuance  of  these  financial  statements.  We  plan  to  address  our  operating  cash  flow
requirements with our current cash and investments, cash generated from the product launch of IBSRELA, our potential receipt of anticipated milestone
payments from our collaboration partners, our ability to access the capital markets, as well as through the implementation of cash preservation activities to
reduce or defer discretionary spending.

There are no assurances that our efforts to meet our operating cash flow requirements will be successful. If our current cash and investments as well as our
plans to meet our operating cash flow requirements are not sufficient to fund necessary expenditures and meet our obligations for at least the next twelve
months  following  the  issuance  of  these  financial  statements,  our  liquidity,  financial  condition  and  business  prospects  will  be  materially  affected.  These
financial  statements  have  been  prepared  on  a  going  concern  basis  and  do  not  include  any  adjustments  to  the  amounts  and  classification  of  assets  and
liabilities that may be necessary in the event that we can no longer continue as a going concern.

In July 2020, we filed a Form S-3 registration statement, which became effective in August 2020, containing (i) a base prospectus for the offering, issuance
and sale by us of up to a maximum aggregate offering price of $250.0 million of our common stock, preferred stock, debt securities, warrants and/or units,
from  time  to  time  in  one  or  more  offerings;  and  (ii)  a  prospectus  supplement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a  maximum  aggregate
offering price of $100.0 million of its common stock that may be issued and sold, from time to time, under an Open Market Sales Agreement with Jefferies
LLC,  as  sales  agent,  deemed  to  be  “at  the  market  offerings”  (the  "2020  Open  Market  Sales  Agreement").  Pursuant  to  the  2020  Open  Market  Sales
Agreement, Jefferies, as sales agent, received a commission of up to 3.0% of the gross sales price for shares

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of common stock sold under the 2020 Open Market Sales Agreement. We sold a cumulative total of 23.3 million shares and received gross proceeds of
$100.0 million at a weighted average sales price of approximately $4.30 per share under the 2020 Open Market Sales Agreement.

In  August  2021,  we  filed  an  additional  prospectus  supplement  under  the  Registration  Statement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a
maximum  aggregate  offering  price  of  $150.0  million  of  our  common  stock  that  may  be  issued  and  sold,  from  time  to  time,  under  an  additional  sales
agreement  we  entered  into  with  Jefferies  (the  "2021  Open  Market  Sales  Agreement"),  pursuant  to  which  we  may,  from  time  to  time,  sell  up  to  $150.0
million in shares of our common stock through Jefferies. We are not required to sell shares under the 2021 Open Market Sales Agreement. Pursuant to the
2021 Open Market Sales Agreement, Jefferies, as our sales agent, receives a commission of up to 3.0% of the gross sales price for shares of common stock
sold  under  the  2021  Open  Market  Sales  Agreement.  As  of  December  31,  2021  we  have  sold  15.7  million  shares  and  received  gross  proceeds  of  $25.0
million at a weighted average sales price of approximately $1.60 per share under the 2021 Open Market Sales Agreement.

On May 16, 2018, we entered into a loan and security agreement (the "2018 Loan Agreement") with Solar Capital Ltd. and Western Alliance Bank (“the
Lenders”). The 2018 Loan Agreement provides for a $50.0 million term loan facility with a maturity date of November 1, 2022 (”the 2018 Term Loan”).
The  full  amount  of  the  2018  Term  Loan  was  funded  on  May  16,  2018.  We  received  net  proceeds  from  the  loan  of  approximately  $49.3  million,  after
deducting  the  closing  fee,  legal  expenses  and  issuance  costs.  On  October  9,  2020,  we  and  the  Lenders  entered  into  an  amendment  to  the  2018  Loan
Agreement (“the 2020 Amendment”), as defined and discussed in Note 6, Borrowing, to extend the date through which we were permitted to make interest-
only  payments  on  the  2018  Term  Loan  by  twelve  months  to  December  1,  2021.  In  May  and  July  2021,  we  and  the  Lenders  entered  into  additional
amendments to the 2018 Loan Agreement (“the 2021 Amendments”) which together extended the period of time that we were permitted to make interest-
only payments on the loan to December 1, 2021; provided that if we had not received FDA approval for our NDA for tenapanor for the control of serum
phosphorus in adult patients with CDK on dialysis on or before October 25, 2021, the interest-only period would expire and principal repayments would be
required to begin on November 1, 2021. If principal repayments were required to begin prior to December 1, 2021 under the 2021 Amendments, then the
first such repayment was required to include all payments that would have been due if monthly principal repayment had begun on June 1, 2021. During
November  2021,  in  compliance  with  the  terms  of  our  2018  Loan  Agreement,  we  paid  the  first  principal  repayment  on  the  loan  in  the  amount  of  $16.7
million. See Note 6, Borrowings, in the notes to our financial statements, included in Part II, Item 8, for details on our 2018 Loan Agreement.

As discussed in Note 18 - Subsequent Events, on February 23, 2022 (the “Closing Date”), we entered into a loan and security agreement (the “2022 Loan
Agreement”)  with  SLR  Investment  Corp.  as  collateral  agent  (the  “Agent”),  and  the  lenders  listed  in  the  2022  Loan  Agreement  (collectively  the  “2022
Lenders”). The 2022 Loan Agreement provides for a senior secured term loan facility, with $27.5 million (the “Term A Loan”) funded on the Closing Date
and an additional $22.5 million that we may borrow on or prior to July 25, 2023; provided that (i) we have received approval by the FDA for our NDA for
tenapanor  for  the  control  of  serum  phosphorus  in  chronic  kidney  disease  patients  on  dialysis  by  December  31,  2022,  and  (ii)  we  have  achieved  certain
product revenue milestone targets described in the 2022 Loan Agreement (the “Term B Loan”, and collectively, the Term A Loan and the Term B Loan, the
“2022 Term Loan”). The Term A Loan funds are being used to repay the 2018 Term Loan with the Lenders as discussed in Note 6 - Borrowings and to fund
our ongoing operations. We had $25.0 million principal from the 2018 Term Loan outstanding as of the Closing Date.

Our  primary  sources  of  cash  have  been  from  the  sale  and  issuance  of  common  stock  (in  both  public  offerings  and  private  placements)  and  private
placements of convertible preferred stock, funds from our collaboration partnerships and funds from our 2018 Loan Agreement. Our primary uses of cash
have  been  to  fund  operating  expenses,  primarily  research  and  development  expenditures  and  pre-commercial  expenses.  Cash  used  to  fund  operating
expenses is impacted by the timing of when we pay these expenses, as reflected in the change in our outstanding accounts payable and accrued expenses.

Our future funding requirements are difficult to forecast and will depend on many factors, including:

•

the extent to which we are able to generate product revenue from sales of IBSRELA;

• whether  we  are  successful  in  our  efforts  under  the  FDR  process  to  secure  approval  for  our  NDA  for  tenapanor  for  the  Hyperphosphatemia
Indication, or to reach resolution with the FDA regarding a path to address the deficiencies in the NDA noted in the CRL, and the time and cost
associated with such path;

•

•

the sales price and the availability of adequate third-party reimbursement for IBSRELA and XPHOZAH, if approved;

the manufacturing costs of IBSRELA and XPHOZAH;

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•

•

•

•

•

•

•

•

the selling and marketing costs associated with IBSRELA and XPHOZAH, if approved;

our ability to maintain our existing collaboration partnerships and to establish additional collaboration partnerships, in-license/out-license, joint
ventures or other similar arrangements and the financial terms of such agreements;

the timing, receipt, and amount of sales of, or royalties on, tenapanor, if any;

the cash requirements of any future acquisitions or discovery of product candidates;

any clinical trials we are required to or decide to pursue for tenapanor or RDX013;

the time and cost necessary to respond to technological and market developments;

the costs of filing, prosecuting, maintaining, defending and enforcing any patent claims and other intellectual property rights, including litigation
costs  and  the  outcome  of  such  litigation,  including  costs  of  defending  any  claims  of  infringement  brought  by  others  in  connection  with  the
development, manufacture or commercialization of tenapanor or any of our product candidates; and

the payment of interest and principal related to our loan and security agreement entered into with SLR Investment Corp. in February 2022.

CASH FLOW ACTIVITIES

The following table summarizes our cash flows for the periods indicated (in thousands):

Year Ended December 31,
2020
(81,435) $

2021
(152,551) $

$

Change 
2021 vs. 2020

Change 
2020 vs. 2019

2019
(76,484) $

$

(71,116)

%

87.3 % $

$
(4,951)

50,948 
82,999 

(31,442)
22,776 

23,373 
155,476 

82,390 
60,223 

(262.0)%
264.4 %

(54,815)
(132,700)

%

6.5 %

(234.5)%
(85.4)%

$

(18,604) $

(90,101) $

102,365  $

71,497 

(79.4)% $

(192,466)

(188.0)%

Net cash used in operating activities
Net cash provided by (used in) investing
activities
Net cash provided by financing activities
Net (decrease) increase in cash and cash
equivalents

Cash Flows from Operating Activities

Fiscal 2021 compared to 2020: Net cash used in operating activities during the year ended December 31, 2021 increased by $71.1 million as a result of our
increased net loss for the period. The increased net loss was primarily driven by costs associated with building and staffing our commercial infrastructure
and  teams  as  we  prepared  for  the  anticipated  U.S.  launch  of  tenapanor  for  the  control  of  serum  phosphorus  in  adult  patients  with  CKD  on  dialysis.  In
addition to the increased net loss, cash flows related to our operating assets and liabilities increased in the amount of $8.7 million.

Fiscal 2020 compared to 2019: Net cash used in operating activities during the year ended December 31, 2020 increased $5.0 million as compared to the
prior year. The most significant factors that contributed to the increase was primarily a $6.2 million decrease to changes in operating assets and liabilities,
primarily driven by cash received in 2019 and reported as deferred revenue for the KKC Research Agreement that was recognized as revenue in 2020,
offset by a $0.6 million increase in non-cash charges and $0.6 million decrease to the net loss.

Cash Flows from Investing Activities

Fiscal 2021 compared to 2020: Net cash provided by investing activities increased by $82.4 million as our investment maturities increased to exceed the
cost to purchase investments.

Fiscal  2020  compared  to  2019:  Net  cash  provided  by  investing  activities  decreased  by  $54.8  million  during  the  year  ended  December  31,  2020,  as
compared to the year ended December 31, 2019. This decrease was attributable to a $48.2 million

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increase  in  purchases  of  available-for-sale  investments  and  a  decrease  in  proceeds  from  maturities  and  redemptions  of  short-term  investments  of  $6.6
million.

Cash Flows from Financing Activities

Fiscal 2021 compared to 2020: Net cash provided by financing activities increased by $60.2 million due to net proceeds from issuance of our common
stock pursuant to our at-the-market offerings, which were partially offset by principal repayments for our loan payable.

Fiscal 2020  compared  to  2019:  Net  cash  provided  by  financing  activities  decreased  by  $132.7  million  during  the  year  ended  December  31,  2020,  as
compared to the year ended December 31, 2019. This decrease was predominantly attributable to $134.9 million in net proceeds received in connection
with  underwritten  public  offering  initiatives  that  was  received  in  2019  but  did  not  recur  in  2020.  This  decrease  was  partially  offset  by  $2.4  million  net
additional proceeds received in 2020 as compared to 2019 from sales of our common stock pursuant to our at-the-market sales agreement with Jefferies
LLC, employee stock plan purchases and option exercises, and the 2019 sale of common stock in the Private Placement with KKC.

SMALLER REPORTING COMPANY AND NON-ACCELERATED FILER STATUS

On  June  28,  2018,  the  SEC  adopted  amendments  that  raise  the  thresholds  in  the  smaller  reporting  company  ("SRC")  definition,  whereby  we  were
determined to qualify as an SRC. We elected to reflect that determination and avail ourselves with most of the SRC scaled disclosure accommodations in
our filings subsequent to the adoption. On March 12, 2020, the SEC amended its rules to allow SRCs that have less than $100.0 million in annual revenue
and a public float of less than $700.0 million to qualify as a non-accelerated filer. As a non-accelerated filer, we were not required to obtain an opinion of
our independent auditors with respect to our internal controls over financial reporting for the periods through December 31, 2020.

On June 30, 2021, our public float exceeded $700.0 million and therefore, as of December 31, 2021, we no longer qualify as an SRC and are considered a
large accelerated filer. The disclosures contained within this Annual Report on Form 10-K have been expanded accordingly.

ITEM 7A.    QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK

Interest Rate Risk

We are subject to market risks, including interest rate fluctuation exposure through our investments, in the ordinary course of our business. However, the
goals  of  our  investment  policy  are  the  preservation  of  capital,  fulfillment  of  liquidity  needs  and  fiduciary  control  of  cash.  To  achieve  our  goal  of
maximizing income without assuming significant market risk, we maintain our excess cash and cash equivalents in money market funds and short-term
debt securities. Because of the short-term maturities of our cash equivalents, we do not believe that a decrease in interest rates would have any material
negative impact on the fair value of our cash equivalents.

As of December 31, 2021, we had cash, cash equivalents and marketable securities of $116.7 million, which consist of bank deposits and money market
funds, as well as high quality fixed income instruments including corporate bonds, commercial paper, and asset-backed securities collateralized by non-
mortgage  consumer  receivables.  The  credit  rating  of  our  short-term  investments  must  be  rated  A-1/P-1,  or  better  by  Standard  and  Poor’s  and  Moody’s
Investors  Service.  Asset-backed  securities  must  be  rated  AAA/Aaa.  Money  Market  funds  must  be  rated  AAAm/Aaa.  Such  interest-earning  instruments
carry a degree of interest rate risk. However, because our investments are high quality and short-term in duration, we believe that our exposure to interest
rate risk is not significant and that a 10% movement in market interest rates would not have a significant impact on the total value of our portfolio, as noted
above. We do not enter into investments for trading or speculative purposes.

We are subject to interest rate fluctuation exposure through our borrowings under the 2018 Loan Agreement and our investment in money market accounts
which bear a variable interest rate. Borrowings under the 2018 Loan Agreement bear interest at a rate equal to one-month London Interbank Offered Rate,
or LIBOR, plus 7.45% per annum. A hypothetical increase in one-month LIBOR of 100 basis points above the current one-month LIBOR rates would have
increased  our  interest  expense  by  approximately  $0.5  million  for  the  year  ended  December  31,  2021.  As  of  December  31,  2021  we  had  an  aggregate
principal amount of $32.3 million outstanding pursuant to our 2018 Loan Agreement.

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Foreign Currency Exchange Risk

The majority of our transactions are denominated in U.S. dollars. However, we do have certain transactions that are denominated in currencies other than
the U.S. dollar, primarily Swiss francs and the euro, and we therefore are subject to foreign exchange risk. The fluctuation in the value of the U.S. dollar
against other currencies affects the reported amounts of expenses, assets and liabilities associated with a limited number of manufacturing activities.

We do not use derivative financial instruments for speculative trading purposes, nor do we hedge foreign currency exchange rate exposure in a manner that
entirely offsets the earnings effects of changes in foreign currency exchange rates. The counterparties to our forward foreign currency exchange contracts
are creditworthy commercial banks, which minimizes the risk of counterparty nonperformance.

As of December 31, 2021, we had no open forward foreign currency exchange contracts.

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ITEM 8.    FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA

ARDELYX, INC.
INDEX TO FINANCIAL STATEMENTS

Report of Independent Registered Public Accounting Firm (PCAOB ID: 42)

Balance Sheets

Statements of Operations and Comprehensive Loss

Statements of Stockholders’ Equity

Statements of Cash Flows

Notes to Financial Statements

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70

72

73

74

75

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Report of Independent Registered Public Accounting Firm

To the Stockholders and the Board of Directors of Ardelyx, Inc.

Opinion on the Financial Statements

We  have  audited  the  accompanying  balance  sheets  of  Ardelyx,  Inc.  (the  “Company”)  as  of  December  31,  2021  and  2020,  the  related  statements  of
operations and comprehensive loss, stockholders’ equity, and cash flows for each of the three years in the period ended December 31, 2021, and the related
notes (collectively referred to as the “financial statements”). In our opinion, the financial statements present fairly, in all material respects, the financial
position of the Company as of December 31, 2021 and 2020, and the results of its operations and its cash flows for each of the three years in the period
ended December 31, 2021, in conformity with U.S. generally accepted accounting principles.

We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (“PCAOB”), the Company's
internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control—Integrated Framework issued by the
Committee of Sponsoring Organizations of the Treadway Commission (2013 Framework) and our report dated February 28, 2022 expressed an unqualified
opinion thereon.

The Company’s Ability to Continue as a Going Concern

The accompanying financial statements have been prepared assuming that the Company will continue as a going concern. As discussed in Note 2 to the
financial statements, the Company has suffered recurring losses from operations and has stated that substantial doubt exists about the Company’s ability to
continue as a going concern. Management's evaluation of the events and conditions and management’s plans regarding these matters are also described in
Note 2. The financial statements do not include any adjustments that might result from the outcome of this uncertainty.

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  accounting  firm  registered  with  the  PCAOB  and  are  required  to  be  independent  with  respect  to  the
Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities 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 evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the
financial statements. We believe that our audits provide a reasonable basis for our opinion.

Critical Audit Matter

The  critical  audit  matter  communicated  below  is  a  matter  arising  from  the  current  period  audit  of  the  financial  statements  that  was  communicated  or
required to be communicated to the audit committee and that: (1) relates to accounts or disclosures that are material to the financial statements and (2)
involved our especially challenging, subjective or complex judgments. The communication of the critical audit matter does not alter in any way our opinion
on the financial statements, taken as a whole, and we are not, by communicating the critical audit matter below, providing a separate opinion on the critical
audit matter or on the accounts or disclosures to which it relates.

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Description of the Matter

Accounting for Restructuring activities

During  2021,  the  Company  incurred  $6.2  million  of  restructuring  charges  in  connection  with  two
restructuring  plans  that  were  implemented  in  August  2021  and  October  2021,  following  the  receipt  of  a
Complete Response Letter from the FDA and the conclusion of an End of Review Type A meeting with the
FDA, respectively. Of these charges, $2.7 million was recorded in research and development expenses, and
$3.5 million was recorded in general and administrative expenses. Further, in November 2021, in connection
with  its  announced  plans  to  launch  IBSRELA  in  2022,  the  Company  retained  certain  employees  whose
positions were originally eliminated as part of the October 2021 restructuring plan. As described in Note 11
to the financial statements, the restructuring activities consisted primarily of workforce reduction through the
elimination of the Company’s research organization and its commercial sales and marketing organizations.
These  actions  resulted  in  restructuring  charges  that  included  one-time  employee  termination  benefits  and
severance  payments,  as  well  as  other  employee-related  costs.  The  Company’s  liability  for  accrued
restructuring charges was $0.5 million as of December 31, 2021.

Auditing the Company’s restructuring charges was especially challenging due to the multiple restructuring
plans implemented during the year, various one-time termination benefit arrangements approved for different
ranks  and  groups  of  the  impacted  employees  and  various  retention  plans  approved  for  the  remaining
employees, as well as the impact of the Company’s later decision to retain certain employees whose positions
were  originally  eliminated  as  part  of  the  October  2021  restructuring  plan.  This  required  the  Company  to
maintain complete record-keeping of the multiple restructuring plans implemented, assess and evaluate the
differences  between  the  various  severance  agreements  and  retention  plans  executed,  as  well  as  to  apply
applicable  technical  accounting  guidance  in  determining  the  timing  of  recognition,  classification,  and
disclosure of restructuring charges in the financial statements. In addition, the Company needed to analyze
and  ensure  completeness  of  any  contract  termination  costs  to  be  recorded  as  a  result  of  the  restructuring
activities and changing needs of its business.

How We Addressed the Matter in Our Audit To test the restructuring charges and year-end liability for accrued restructuring charges, our audit procedures
included,  among  others,  gaining  an  understanding  of  the  approved  restructuring  plans  and  evaluating  the
accounting treatment, timing of recognition, and classification of restructuring charges incurred. In addition,
we tested the accuracy and completeness of underlying data used in management’s analysis and computation
of restructuring charges and year-end liability for accrued restructuring charges by agreeing related details to
supporting  documentation.  We  reviewed  management’s  analysis  of  contract  termination  costs  to  determine
whether any amount needed to be recorded or accrued as restructuring charges during the year. We also met
with  internal  finance  and  legal  personnel  to  understand  the  nature  and  the  comprehensive  scope  of  the
approved restructuring plans, as well as inspected and evaluated the accounting treatment of the terms and
conditions  for  a  sample  of  severance  agreements  and  retention  plans  executed.  Additionally,  we  tested
subsequent  cash  payments  made  related  to  the  restructuring  activities.  Further,  we  tested  the  classification
and disclosure of the restructuring expenses in the financial statements.

/s/ Ernst & Young LLP

We have served as the Company’s auditor since 2009.

Redwood City, California
February 28, 2022

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Assets

Current assets:

Cash and cash equivalents

Short-term investments

Accounts receivable

Prepaid expenses and other current assets

Total current assets

Property and equipment, net

Long-term investments

Right-of-use assets

Other assets

Total assets

Liabilities and stockholders’ equity

Current liabilities:

Accounts payable

Accrued compensation and benefits

Current portion of operating lease liability

Loan payable, current portion

Deferred revenue

Accrued expenses and other current liabilities

Total current liabilities

Operating lease liability, net of current portion

Loan payable, net of current portion

Deferred revenue, non-current

Total liabilities

Commitments and contingencies (Note 17)

Stockholders’ equity:

ARDELYX, INC.
BALANCE SHEETS
(in thousands, except share and per share amounts)

December 31,

2021

2020

$

72,428  $

44,261 

502 

16,458 

133,649 

2,362 

— 

12,752 

1,150 

91,032 

95,452 

— 

8,202 

194,686 

1,936 

2,114 

2,274 

552 

149,913  $

201,562 

$

$

4,277  $

5,422 

3,492 

32,264 

— 

7,366 

52,821 

9,748 

— 

4,727 

67,296 

5,626 

5,672 

2,117 

4,167 

4,177 

6,657 

28,416 

413 

46,621 

— 

75,450 

— 

9 

680,872 

(554,765)

(4)

126,112 

201,562 

Preferred stock, $0.0001 par value; 5,000,000 shares authorized; no shares issued and outstanding as of
December 31, 2021 and December 31, 2020, respectively.

Common stock, $0.0001 par value; 300,000,000 shares authorized; 130,182,535 and 93,599,975 shares issued and
outstanding as of December 31, 2021 and December 31, 2020, respectively.

Additional paid-in capital

Accumulated deficit

Accumulated other comprehensive income (loss)

Total stockholders’ equity

Total liabilities and stockholders’ equity

— 

13 

795,540 

(712,930)

(6)

82,617 

$

149,913  $

The accompanying notes are an integral part of these financial statements.

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ARDELYX, INC.
STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(in thousands, except share and per share amounts)

Revenues:

Collaborative development revenue
Product supply revenue
Licensing revenue
Total revenues
Operating expenses:
Cost of revenue
Research and development
General and administrative
Total operating expenses

Loss from operations
Interest expense
Other income, net

Loss before provision for income taxes
Provision for income taxes

Net loss

Net loss per common share, basic and diluted

Shares used in computing net loss per share - basic and diluted
Comprehensive loss:
Net loss
Unrealized (losses) gains on available-for-sale securities

Comprehensive loss

2021

Year Ended December 31,
2020

2019

$

$

$

$

$

4,177  $
907 
5,013 
10,097 

5,364  $
1,501 
706 
7,571 

1,000 
91,140 
72,303 
164,443 
(154,346)
(4,502)
687 
(158,161)
4 

145 
65,053 
33,153 
98,351 
(90,780)
(5,099)
1,568 
(94,311)
2 

(158,165) $

(94,313) $

(1.52) $

(1.05) $

459 
322 
4,500 
5,281 

600 
71,677 
24,267 
96,544 
(91,263)
(5,726)
2,352 
(94,637)
303 
(94,940)

(1.47)

104,205,645 

89,582,138 

64,478,066 

(158,165) $

(2)

(158,167) $

(94,313) $
(24)
(94,337) $

(94,940)
58 
(94,882)

The accompanying notes are an integral part of these financial statements.

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ARDELYX, INC.
STATEMENTS OF STOCKHOLDERS’ EQUITY
(in thousands, except share amounts)

Balance as of December 31, 2018

62,516,627 

$

6 

$

481,357 

$

(365,512)

$

(38)

$

115,813 

Common Stock

Shares

Amount

Additional
Paid-In
Capital

Accumulated
Deficit

Accumulated
Other
Comprehensive
(Loss) Income

Total
Stockholders'
Equity

Issuance of common stock under employee
stock purchase plan
Issuance of common stock for services
Issuance of common stock upon exercise of
options
Issuance of common stock upon vesting of
restricted stock units
Stock-based compensation
Unrealized gains on available-for-sale
securities
Issuance of common stock upon
underwritten public offering, net of issuance
costs
Issuance of common stock upon private
placement, net of issuance costs
Net loss

Balance as of December 31, 2019

Issuance of common stock under employee
stock purchase plan
Issuance of common stock for services
Issuance of common stock upon exercise of
options
Issuance of common stock upon vesting of
restricted stock units
Stock-based compensation
Unrealized gains on available-for-sale
securities
Issuance of common stock in At-the-market
offering
Net loss

Balance as of December 31, 2020

Issuance of common stock under employee
stock purchase plan
Issuance of common stock for services
Issuance of common stock upon exercise of
options
Issuance of common stock upon vesting of
restricted stock units
Taxes paid for net share settlement of equity
awards
Stock-based compensation
Unrealized gains on available-for-sale
securities
Issuance of common stock in At-the-market
offering
Net loss

Balance as of December 31, 2021

160,744 
113,136 

68,062 

85,609 
— 

— 

23,000,000 

2,873,563 
— 
88,817,741 

$

169,931 
42,403 

445,942 

866,528 
— 

— 

3,257,430 
— 
93,599,975 

$

386,664 
25,989 

331,310 

167,158 

— 
— 

— 

35,671,439 
— 
130,182,535 

$

— 
— 

— 

— 
— 

— 

3 

— 
— 
9 

— 
— 

— 

— 
— 

— 

— 
— 
9 

— 
— 

— 

— 

— 
— 

— 

4 
— 
13 

$

$

$

396 
312 

178 

— 
9,936 

— 

134,924 

19,975 
— 
647,078 

$

834 
310 

1,020 

— 
10,583 

— 

— 
— 

— 

— 
— 

— 

— 

— 
(94,940)
(460,452)

$

— 
— 

— 

— 
— 

— 

21,047 
— 
680,872 

$

— 
(94,313)
(554,765)

$

819 
190 

584 

— 

(106)
12,039 

— 

—  0
— 

— 

— 

— 
— 

— 

101,142 
— 
795,540 

$

— 
(158,165)
(712,930)

$

— 
— 

— 

— 
— 

58 

— 

— 
— 
20 

— 
— 

— 

— 
— 

(24)

— 
— 
(4)

— 
— 

— 

— 

— 
— 

(2)

— 
— 
(6)

$

$

$

396 
312 

178 

— 
9,936 

58 

134,927 

19,975 
(94,940)
186,655 

834 
310 

1,020 

— 
10,583 

(24)

21,047 
(94,313)
126,112 

819 
190 

584 

— 

(106)
12,039 

(2)

101,146 
(158,165)
82,617 

The accompanying notes are an integral part of these financial statements.

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ARDELYX, INC.
STATEMENTS OF CASH FLOWS
(in thousands)

Operating activities

Net loss
Adjustments to reconcile net loss to net cash used in operating activities:

Depreciation expense
Amortization of deferred financing costs
Amortization of deferred compensation for services
Amortization of (discount) premium on investment securities
Non-cash lease expense
Stock-based compensation
Change in derivative liabilities
Non-cash interest associated with debt discount accretion
Changes in operating assets and liabilities:

Unbilled revenue
Accounts receivable
Prepaid expenses and other assets
Accounts payable
Accrued compensation and benefits
Operating Lease liabilities
Accrued and other liabilities
Deferred revenue
Net cash used in operating activities
Investing activities

Proceeds from maturities and redemptions of investments
Purchases of investments
Purchases of property and equipment

Net cash provided by (used in) investing activities
Financing activities

Proceeds from underwritten public offering, net of issuance costs
Proceeds from issuance of common stock upon private placement, net of issuance costs
Proceeds from issuance of common stock in At-the-market offering, net of issuance costs
Proceeds from issuance of common stock under equity incentive and stock purchase plans
Principal repayments for loan payable
Payments for loan payable, net of issuance costs
Payments for taxes related to net share settlement of equity awards

Net cash provided by financing activities
Net (decrease) increase in cash and cash equivalents
Cash and cash equivalents at beginning of period

Cash and cash equivalents at end of period
Supplementary disclosure of cash flow information:

Cash paid for interest
Cash paid for income taxes

Supplementary disclosure of non-cash activities:

Right-of-use assets obtained in exchange for lease obligations
Issuance of common stock for services

2021

2020

2019

$

(158,165)

$

(94,313)

$

(94,940)

1,441 
638 
240 
488 
3,085 
12,039 
(678)
283 

— 
(502)
(8,904)
(1,349)
(250)
(2,853)
1,386 
550 
(152,551)

125,550 
(72,735)
(1,867)
50,948 

— 
— 
101,146 
1,403 
(19,444)
— 
(106)
82,999 
(18,604)
91,032 
72,428 

3,469 
4 

1,604 
190 

$

$
$

$
$

1,824 
496 
313 
(92)
2,147 
10,583 
407 
413 

750 
— 
(4,653)
3,439 
1,219 
(2,604)
(1,000)
(364)
(81,435)

119,734 
(150,852)
(324)
(31,442)

— 
— 
21,047 
1,854 
— 
(125)
— 
22,776 
(90,101)
181,133 
91,032 

4,200 
1 

450 
310 

$

$
$

$
$

2,501 
670 
309 
(698)
1,839 
9,936 
436 
478 

4,250 
85 
93 
39 
1,730 
(1,892)
(5,861)
4,541 
(76,484)

126,369 
(102,671)
(325)
23,373 

134,927 
19,975 
— 
574 
— 
— 
— 
155,476 
102,365 
78,768 
181,133 

4,920 
2 

5,810 
312 

$

$
$

$
$

The accompanying notes are an integral part of these financial statements.

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ARDELYX, INC.
NOTES TO FINANCIAL STATEMENTS

1. ORGANIZATION AND BASIS OF PRESENTATION
Ardelyx,  Inc.  (the  “Company,”  “we,”  “us”  or  “our”)  is  a  biopharmaceutical  company  founded  with  a  mission  to  discover,  develop  and  commercialize
innovative first-in-class medicines that meet significant unmet medical needs. This includes adult patients with irritable bowel syndrome with constipation
(“IBS-C”), adult patients with chronic kidney disease (“CKD”) on dialysis suffering from elevated serum phosphorus, or hyperphosphatemia; and adult
CKD patients and/or heart failure patients with elevated serum potassium, or hyperkalemia.

We operate in one business segment, which is the development and planned commercialization of biopharmaceutical products.

2.    SUMMARY OF SIGNIFICANT ACCOUNTING POLICIES

Basis of Presentation

The accompanying financial statements have been prepared in accordance with accounting principles generally accepted in the United States of America
(“U.S. GAAP”).

Prior Period Errors

In connection with our review of our financial statements as of and for the six months ended June 30, 2019, we corrected errors related to the accounting
for  clinical  trial  accruals  that  had  resulted  in  an  overstatement  of  research  and  development  expenses  during  the  year  ended  December  31,  2018.
Specifically, management concluded that our research and development expenses recorded during the year ended December 31, 2018 had been overstated
by $3.6 million and that our accrued expenses and other current liabilities as of December 31, 2018 had been overstated by the same amount. We analyzed
the  potential  impact  of  these  errors  in  accordance  with  the  U.S.  Securities  and  Exchange  Commission’s  (“SEC”)  Staff  Accounting  Bulletin  No.  108,
Considering the Effects of Prior Year Misstatements when Quantifying Misstatements in Current Year Financial Statements, and concluded that while the
errors were significant to our financial statements as of and for the six months ended June 30, 2019, a correction of the errors would not have been material
to the full year results for 2019 and 2018 nor affect the trend of financial results. Accordingly, we reduced accrued and other liabilities by $3.6 million and
recorded a cumulative adjustment of $3.6 million in the statement of operations and comprehensive loss to reduce research and development expenses in
2019.

Use of Estimates

The  preparation  of  financial  statements  in  conformity  with  U.S.  GAAP  requires  management  to  make  estimates  and  judgments  that  affect  the  amounts
reported  in  the  financial  statements  and  accompanying  notes.  On  an  ongoing  basis,  management  evaluates  its  estimates,  including  those  related  to
recognition  of  revenue,  clinical  trial  accruals,  contract  manufacturing  accruals,  fair  value  of  assets  and  liabilities,  income  taxes  and  stock-based
compensation. Management bases its estimates on historical experience and on various other market-specific and relevant assumptions that management
believes to be reasonable under the circumstances. Actual results could materially differ from those estimates.

Liquidity

As  of  December  31,  2021,  we  had  cash  and  investments  of  approximately  $116.7  million.  We  have  incurred  operating  losses  since  inception  and  our
accumulated deficit as of December 31, 2021 is $712.9 million. Our current level of cash and investments alone is not sufficient to meet our plans for the
next twelve months following the issuance of these financial statements. These factors raise substantial doubt regarding our ability to continue as a going
concern for a period of one year from the issuance of these financial statements. We plan to address our operating cash flow requirements with our current
cash and investments, cash generated from the product launch of IBSRELA, our potential receipt of anticipated milestones from our collaboration partners,
our ability to access the capital markets, as well as through the implementation of cash preservation activities to reduce or defer discretionary spending.

There are no assurances that our efforts to meet our operating cash flow requirements will be successful. If our current cash and investments as well as our
plans to meet our operating cash flow requirements are not sufficient to fund necessary expenditures and meet our obligations for at least the next twelve
months following the issuance of these financial statements,

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our liquidity, financial condition and business prospects will be materially affected. These financial statements have been prepared on a going concern basis
and  do  not  include  any  adjustments  to  the  amounts  and  classification  of  assets  and  liabilities  that  may  be  necessary  in  the  event  that  we  can  no  longer
continue as a going concern.

Cash and Cash Equivalents

We consider all highly liquid investments purchased with an original maturity date of 90 days or less on the date of purchase to be cash equivalents.

Short-Term Investments

Short-term investments consist of debt securities classified as available-for-sale and have maturities greater than 90 days, but less than one year, from the
date  of  acquisition.  Short-term  investments  are  carried  at  fair  value  based  upon  quoted  market  prices.  Unrealized  gains  and  losses  on  available-for-sale
securities are included in earnings and are reported as an allowance for credit losses on our Balance Sheets. The cost of available-for-sale securities sold is
based on the specific-identification method.

Concentration of Credit Risk

Financial  instruments  that  potentially  subject  us  to  significant  concentrations  of  credit  risk  consist  primarily  of  cash,  cash  equivalents,  short-term
investments and accounts receivable. We are exposed to credit risks in the event of default by the counterparties to the extent of the amount recorded in its
balance sheet. Cash, cash equivalents and short-term investments are invested through banks and other financial institutions in the U.S.

Foreign Currency

We manage our foreign currency exposures with the use of foreign currency purchases. We primarily conduct business in U.S. dollars; however, a portion
of our expense and capital activities are transacted in foreign currencies which are subject to exchange rate fluctuations that can affect cash or earnings. We
have  been  in  a  loss  position  and  therefore  our  primary  objective  is  to  conserve  and  manage  cash.  There  are  generally  two  methods  by  which  we  may
manage the cash flow risk of foreign exchange fluctuations when a contract is signed (i) we can purchase the foreign funds, in full or in part, upon the
execution of the contract, or (ii) we can obtain the right to purchase such funds, in full or in part, at the execution of the contract, i.e., obtain a forward
contract from an appropriate bank, that can be exercised to obtain the currency of interest at a particular point in time. The derivative instruments that we
may use to hedge the exposure shall generally not be designated as cash flow hedges, and as a result, changes in their fair value would be recorded in other
income (expense), net, in our statements of operations and comprehensive loss. The fair values of forward foreign currency exchange contracts would be
estimated using current exchange rates and interest rates and the current creditworthiness of the counterparties is taken into consideration.

Property and Equipment

Property and equipment are stated at cost, less accumulated depreciation and amortization. Depreciation is computed using the straight-line method over
the estimated useful lives of the respective assets, with ranges generally from three to five years. Leasehold improvements are amortized over the lesser of
the estimated useful lives or the related remaining lease term.

Impairment of Long-Lived Assets

The  carrying  value  of  long-lived  assets,  including  property  and  equipment,  are  reviewed  for  impairment  whenever  events  or  changes  in  circumstances
indicate that the asset may not be recoverable. An impairment loss is recognized when the total of estimated future undiscounted cash flows, expected to
result  from  the  use  of  the  asset  and  its  eventual  disposition,  are  less  than  the  asset’s  carrying  amount.  Impairment,  if  any,  would  be  assessed  using
discounted  cash  flows  or  other  appropriate  measures  of  fair  value.  For  the  years  ending  December  31,  2021,  2020  and  2019  we  have  recognized  no
impairment losses.

Income Taxes

We use the asset and liability method of accounting for income taxes. Under this method, deferred tax assets and liabilities are determined based on the
differences between the financial reporting and the tax bases of assets and liabilities and are measured using the enacted tax rates and laws that will be in
effect when the differences are expected to reverse. A valuation allowance is provided when it is more likely than not that some portion or all of a deferred
tax asset will not be realized.

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Revenue Recognition

On January 1, 2018 we adopted the Financial Accounting Standards Board’s (“FASB”) Accounting Standards Update (“ASU”) No. 2014-9, Revenue from
Contracts with Customers (Topic 606) and related amendments  (“ASC  606”),  on  a  modified  retrospective  basis,  which  resulted  in  an  adjustment  to  the
opening accumulated deficit balance on the adoption date. As a result of the adoption of the new standard, on January 1, 2018, we recorded the following:
(i) unbilled revenue under current assets of $5.0 million representing a future receivable related to the first milestone under our license agreement with
Kyowa Kirin Co., Ltd. (formerly known as Kyowa Hakko Kirin Co., Ltd ("KHK") (“KKC”), which was subsequently achieved by KKC and collected in
February 2019, thereby reducing the unbilled revenue balance to zero, (ii) uncharged license fees under current liabilities of $1.0 million representing the
corresponding future payable related to AstraZeneca AB ("AstraZeneca") in accordance with our termination agreement with AstraZeneca, which, upon
KKC achieving the milestone, was reclassified to accounts payable and subsequently paid to AstraZeneca during the second quarter of 2019, and (iii) a
related decrease in accumulated deficit of approximately $4.0 million as the new standard permitted revenue from milestones that possess certain criteria to
be recognized earlier and also contained different recognition criteria related to milestones than under the previous accounting standard.

We generate revenue primarily from research and collaboration and license agreements with customers. Goods and services in the agreements may include
the  grant  of  licenses  for  the  use  of  our  technology,  the  provision  of  services  associated  with  the  research  and  development  of  product  candidates,
manufacturing services, and participation in joint steering committees. The terms of these arrangements typically include payment to us of one or more of
the following: non-refundable, up-front license fees; research, development, regulatory and commercial milestone payments; reimbursement of research
and development services; option payments; reimbursement of certain costs; payments for manufacturing supply services; and future royalties on net sales
of licensed products.

When two or more contracts are entered into with the same customer at or near the same time, we evaluate the contracts to determine whether the contracts
should be accounted for as a single arrangement. Contracts are combined and accounted for as a single arrangement if one or more of the following criteria
are met: (i) the contracts are negotiated as a package with a single commercial objective; (ii) the amount of consideration to be paid in one contract depends
on the price or performance of the other contract; or (iii) the goods or services promised in the contracts (or some goods or services promised in each of the
contracts) are a single performance obligation.

In determining the appropriate amount of revenue to be recognized as we fulfill our obligations under each of its agreements, management performs the
following  steps:  (i)  identification  of  the  promised  goods  or  services  in  the  contract;  (ii)  determination  of  whether  the  promised  goods  or  services  are
performance  obligations  including  whether  they  are  distinct  in  the  context  of  the  contract;  (iii)  measurement  of  the  transaction  price,  including  the
constraints on variable consideration; (iv) allocation of the transaction price to the performance obligations; and (v) recognition of revenue when (or as) we
satisfy each performance obligation. As part of the accounting for contracts with customers, we develop assumptions that require judgment to determine
whether promised goods and services represent distinct performance obligations and the standalone selling price for each performance obligation identified
in  the  contract.  This  evaluation  is  subjective  and  requires  us  to  make  judgments  about  the  promised  goods  and  services  and  whether  those  goods  and
services are separable from other aspects of the contract. Further, determining the standalone selling price for performance obligations requires significant
judgment, and when an observable price of a promised good or service is not readily available, we consider relevant assumptions to estimate the standalone
selling price, including, as applicable, market conditions, development timelines, probabilities of technical and regulatory success, reimbursement rates for
personnel costs, forecasted revenues, potential limitations to the selling price of the product and discount rates.

We apply judgment in determining whether a combined performance obligation is satisfied at a point in time or over time, and, if over time, concluding
upon the appropriate method of measuring progress to be applied for purposes of recognizing revenue. We evaluate the measure of progress each reporting
period and, as estimates related to the measure of progress change, related revenue recognition is adjusted accordingly. Changes in our estimated measure
of  progress  are  accounted  for  prospectively  as  a  change  in  accounting  estimate.  We  recognize  collaboration  revenue  by  measuring  the  progress  toward
complete satisfaction of the performance obligation using an input measure. In order to recognize revenue over the research and development period, we
measure actual costs incurred to date compared to the overall total expected costs to satisfy the performance obligation. Revenues are recognized as the
program  costs  are  incurred.  We  will  re-evaluate  the  estimate  of  expected  costs  to  satisfy  the  performance  obligation  each  reporting  period  and  make
adjustments for any significant changes.

Amounts received prior to satisfying the revenue recognition criteria are recorded as contract liabilities in our Balance Sheets. If the related performance
obligation is expected to be satisfied within the next twelve months it will be classified in current liabilities. Amounts recognized as revenue prior to receipt
are recorded as contract assets in our Balance Sheets. If we

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expect to have an unconditional right to receive the consideration in the next twelve months, it will be classified in current assets. A net contract asset or
liability is presented for each contract with a customer.

Milestone  Payments:  At  the  inception  of  each  arrangement  that  includes  development  milestone  payments,  we  evaluate  whether  the  milestones  are
considered probable of being reached and estimates the amount to be included in the transaction price using the most likely amount method. Amounts of
variable consideration are included in the transaction price to the extent that it is probable that a significant reversal in the amount of cumulative revenue
recognized will not occur and when the uncertainty associated with the variable consideration is subsequently resolved. Milestone payments that are not
within  our  control  or  the  control  of  the  licensee,  such  as  regulatory  approvals,  are  not  considered  probable  of  being  achieved  until  those  approvals  are
received. The transaction price is then allocated to each performance obligation on a relative standalone selling price basis, for which we recognize revenue
as or when the performance obligations under the contract are satisfied. At the end of each subsequent reporting period, we re-evaluate the probability of
achievement of such development milestones and any related constraints, and if necessary, adjusts its estimate of the overall transaction price. Any such
adjustments are recorded on a cumulative catch-up basis, which would affect earnings in the period of adjustment.

Manufacturing supply services: Arrangements that include a promise for future supply of drug substance or drug product for either clinical development or
commercial supply at the customer’s discretion are generally considered as options. We assess if these options provide a material right to the licensee and if
so, they are accounted for as separate performance obligations. If we are entitled to additional payments when the customer exercises these options, any
payments are recorded in product supply revenue when the customer obtains control of the goods, which is upon delivery.

Royalties: For arrangements that include sales-based royalties, including milestone payments based on the level of sales, and where the license is deemed to
be the predominant item to which the royalties relate, we recognize revenue at the later of (i) when the related sales occur, or (ii) when the performance
obligation to which some or all of the royalty has been allocated has been satisfied (or partially satisfied). To date, we have not recognized any royalty
revenue resulting from any of its licensing arrangements.

Licenses of intellectual property: If a license granted to a customer to use our intellectual property is determined to be distinct from the other performance
obligations identified in the arrangement, we recognize revenue from consideration allocated to the license when the license is transferred to the licensee
and the licensee is able to use and benefit from the license. For licenses that are bundled with other promises, we apply judgment to assess the nature of the
combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time and, if over time, to
conclude upon the appropriate method of measuring progress for purposes of recognizing revenue related to consideration allocated to the performance
obligation.

Options:  Customer  options,  such  as  options  granted  to  allow  a  licensee  to  choose  to  research,  develop  and  commercialize  licensed  compounds  are
evaluated at contract inception in order to determine whether those options provide a material right (i.e., an optional good or service offered for free or at a
discount) to the customer. If the customer options represent a material right, the material right is treated as a separate performance obligation at the outset
of the arrangement. The Company allocates the transaction price to material rights based on the standalone selling price, and revenue is recognized when or
as  the  future  goods  or  services  are  transferred  or  when  the  option  expires.  Customer  options  that  are  not  material  rights  do  not  give  rise  to  a  separate
performance obligation, and as such, the additional consideration that would result from a customer exercising an option in the future is not included in the
transaction  price  for  the  current  contract.  Instead,  the  option  is  deemed  a  marketing  offer,  and  additional  option  fee  payments  are  recognized  or  being
recognized as revenue when the licensee exercises the option. The exercise of an option that does not represent a material right is treated as a separate
contract for accounting purposes.

Contract modifications:  Contract  modifications,  defined  as  changes  in  the  scope  or  price  (or  both)  of  a  contract  that  are  approved  by  the  parties  to  the
contract, such as a contract amendment, exist when the parties to a contract approve a modification that either creates new or changes existing enforceable
rights and obligations of the parties to the contract. Depending on facts and circumstances, we account for a contract modification as one of the following:
(i) a separate contract; (ii) a termination of the existing contract and a creation of a new contract; or (iii) a combination of the preceding treatments. A
contract modification is accounted for as a separate contract if the scope of the contract increases because of the addition of promised goods or services that
are distinct and the price of the contract increases by an amount of consideration that reflects our standalone selling prices of the additional promised goods
or services. When a contract modification is not considered a separate contract and the remaining goods or services are distinct from the goods or services
transferred  on  or  before  the  date  of  the  contract  modification,  we  account  for  the  contract  modification  as  a  termination  of  the  existing  contract  and  a
creation of a new contract. When a contract modification is not considered a separate contract and the remaining goods or services are not distinct, we
account for the contract modification as an add-on to the existing contract and as an adjustment to revenue on a cumulative catch-up basis.

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We receive payments from its licensees as established in each contract. Upfront payments and fees are recorded as deferred revenue upon receipt or when
due  and  may  require  deferral  of  revenue  recognition  to  a  future  period  until  we  perform  our  obligations  under  these  arrangements.  Where  applicable,
amounts are recorded as accounts receivable or unbilled revenue when our right to consideration is unconditional. We do not assess whether a contract with
a customer has a significant financing component if the expectation at contract inception is such that the period between payment by the licensees and the
transfer of the promised goods or services to the licensees will be one year or less.

Research and Development Costs

Research and development costs are charged to expense as incurred and consisted of costs incurred to further our research and development activities and
include salaries and related employee benefits, costs associated with clinical trials, costs related to pre-commercialization manufacturing activities such as
manufacturing  process  validation  activities  and  the  manufacturing  of  clinical  drug  supply,  nonclinical  research  and  development  activities,  regulatory
activities,  research-related  overhead  expenses  and  fees  paid  to  external  service  providers  and  contract  research  and  manufacturing  organizations  that
conduct certain research and development activities on our behalf.

Accrued Research and Development Expenses

We are required to estimate our accrued expenses at the end of each reporting period. This process involves reviewing open contracts and purchase orders,
communicating  with  our  personnel  to  identify  services  that  have  been  performed  on  our  behalf  and  estimating  the  level  of  service  performed  and  the
associated cost incurred for the service when we have not yet been invoiced or otherwise notified of the actual costs. The majority of our service providers
submit invoices in arrears for services performed or when contractual milestones are met. We make estimates of our accrued expenses as of each balance
sheet date in the financial statements based on facts and circumstances known to us at that time. We periodically confirm the accuracy of our estimates with
our service providers and make adjustments if necessary. Examples of estimated accrued research and development expenses include fees paid to:

•

•

•

•

contract research organizations ("CROs") in connection with clinical studies;

investigative sites in connection with clinical studies;

vendors related to product manufacturing, development and distribution of clinical supplies; and

vendors in connection with preclinical development activities.

We  record  expenses  related  to  clinical  studies  and  manufacturing  development  activities  based  on  our  estimates  of  the  services  received  and  efforts
expended pursuant to contracts with multiple CROs and manufacturing vendors that conduct and manage these activities on our behalf. The financial terms
of these agreements are subject to negotiation, vary from contract to contract, and may result in uneven payment flows. There may be instances in which
payments  made  to  our  vendors  will  exceed  the  level  of  services  provided  and  result  in  a  prepayment  of  the  expense.  Payments  under  some  of  these
contracts  depend  on  factors  such  as  the  successful  enrollment  of  subjects  and  the  completion  of  clinical  trial  milestones.  In  accruing  service  fees,  we
estimate the time period over which services will be performed, enrollment of subjects, number of sites activated and the level of effort to be expended in
each period. If the actual timing of the performance of services or the level of effort varies from our estimate, we will adjust the accrued or prepaid expense
balance accordingly.

Inventory

We  consider  regulatory  approval  of  product  candidates  to  be  uncertain,  and  product  manufactured  prior  to  regulatory  approval  may  not  be  sold  unless
regulatory approval is obtained. We expense manufacturing costs for product candidates incurred prior to regulatory approval as research and development
expenses as manufacturing processes are performed. If and when regulatory approval of a product is obtained and we have plans to commercially launch
the  approved  product,  we  begin  capitalizing  manufacturing  costs  related  to  the  approved  product  into  inventory.  Although  we  received  approval  of
IBSRELA (tenapanor) for the treatment of IBS-C in adults from the Food and Drug Administration (“FDA”) in September 2019, we did not plan to launch
IBSRELA commercially at that time and, therefore, continued to expense manufacturing costs of tenapanor, which is also under development for another
indication that has not received FDA approval. On November 30, 2021, we made the decision and announced our plans to commercially launch IBSRELA
and as a result, in December 2021 we began to capitalize the costs of manufacturing processes associated with IBSRELA as those processes are completed.
No manufacturing processes related to IBSRELA were completed in December, resulting in no inventory balance at December 31, 2021.

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Stock-Based Compensation

We recognize compensation expense for all stock-based payment awards made to employees, nonemployees and directors based on estimated fair values.
For  employee  and  nonemployee  stock  options,  we  determine  the  grant  date  fair  value  of  the  awards  using  the  Black-Scholes  option-pricing  model  and
generally  recognizes  the  fair  value  as  stock-based  compensation  expense  on  a  straight-line  basis  over  the  vesting  period  of  the  respective  awards.  For
restricted stock and performance-based restricted stock, to the extent they are probable, the compensation cost for these awards is based on the closing price
of our common stock on the date of grant and recognized as compensation expense on a straight-line basis over the requisite service period. Stock-based
compensation expense is based on the value of the portion of stock-based payment awards that is ultimately expected to vest. As such, our stock-based
compensation is reduced for the estimated forfeitures at the date of grant and revised, if necessary, in subsequent periods if actual forfeitures differ from
those estimates.

Derivatives and Hedging Activities

We account for our derivative instruments as either assets or liabilities on the balance sheet and measure them at fair value. Derivatives are adjusted to fair
value through other income (expense), net in the statements of operations and comprehensive loss.

Leases

We  determine  if  an  arrangement  is  a  lease  at  the  inception  of  the  arrangement.  Operating  leases  are  included  in  right-of-use  assets,  current  portion  of
operating  lease  liability,  and  operating  lease  liability,  net  of  current  portion  in  our  balance  sheets.  Right-of-use  assets  represent  our  right  to  use  an
underlying asset for the lease term and lease liabilities represent our obligation to make lease payments arising from the lease. Operating lease right-of-use
assets and liabilities are recognized at the lease commencement date based on the present value of lease payments over the lease term. In determining the
present value of lease payments, we use our incremental borrowing rate based on the information available at the lease commencement date. The operating
lease right-of-use assets also include any lease payments made and exclude lease incentives. Our lease terms may include options to extend or terminate the
lease when it is reasonably certain that we will exercise any such options. Lease expense is recognized on a straight-line basis over the expected lease term.
We have elected not to separate lease and non-lease components, such as common area maintenance charges, and instead it accounts for these as a single
lease component.

Restructuring

We  recognize  restructuring  charges  related  to  reorganization  plans  that  have  been  committed  to  by  management  when  liabilities  have  been  incurred.  In
connection  with  these  activities,  we  record  restructuring  charges  at  fair  value  for,  (a)  contractual  employee  termination  benefits  when  obligations  are
associated to services already rendered, rights to such benefits have vested, and payment of benefits is probable and can be reasonably estimated, (b) one-
time  employee  termination  benefits  when  management  has  committed  to  a  plan  of  termination,  the  plan  identifies  the  employees  and  their  expected
termination  dates,  the  details  of  termination  benefits  are  complete,  it  is  unlikely  changes  to  the  plan  will  be  made  or  the  plan  will  be  withdrawn  and
communication to such employees has occurred, and (c) contract termination costs when a contract is terminated before the end of its term.

One-time employee termination benefits are recognized in their entirety when communication has occurred and future services are not required. If future
services  are  required,  the  costs  are  recorded  ratably  over  the  remaining  period  of  service.  Contract  termination  costs  to  be  incurred  over  the  remaining
contract term without economic benefit are recorded in their entirety when the contract is canceled.

Net Loss per Share

Basic net loss per common share is calculated by dividing the net loss by the weighted-average number of common shares outstanding during the period,
without consideration of potential common shares. Diluted net loss per common share in the periods presented is the same as basic net loss per common
share, since the effects of potentially dilutive securities are antidilutive due to the net loss for all periods presented.

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Recent Accounting Pronouncements

New Accounting Pronouncements - Recently Adopted

In December 2019, as part of its initiative to reduce complexity in the accounting standards, the Financial Accounting Standards Board (“FASB”) issued
Accounting  Standards  Update  (“ASU”)  2019-12,  Income  Taxes  (Topic  740):  Simplifying  the  Accounting  for  Income  Taxes  (“ASU  2019-12”),  which
eliminates certain exceptions related to the approach for intra-period tax allocation, the methodology for calculating income taxes in an interim period and
the recognition of deferred tax liabilities for outside basis differences. ASU 2019-12 also clarifies and simplifies other aspects of the accounting for income
taxes.  The  standard  is  effective  for  fiscal  years,  and  interim  periods  within  those  fiscal  years,  beginning  after  December  15,  2020,  with  early  adoption
permitted. We early adopted ASU 2019-12 on April 1, 2020 and this adoption had no material impact on our financial position or results of operations.

We adopted Accounting Standards Update 2016-13, Financial Instruments - Credit Losses: Measurement of Credit Losses on Financial Instruments ("ASU
2016-13"), as of December 1, 2021 under the modified retrospective approach. ASU 2016-13 requires an entity to measure and recognize expected credit
losses for certain financial instruments, including trade receivables, as an allowance that reflects the entity's current estimate of credit losses expected to be
incurred. For available-for-sale debt securities with unrealized credit losses, the standard requires allowances to be recorded through net income instead of
directly reducing the amortized cost of the investment under the previous other-than-temporary impairment model. The adoption of this standard did not
have a material impact on our financial statements or a significant impact on our internal controls.

Recent Accounting Pronouncements Not Yet Adopted

There  were  various  accounting  standards  and  interpretations  issued  recently,  none  of  which  are  expected  to  a  have  a  material  impact  on  our  financial
position, operations or cash flows.

3.     CASH AND INVESTMENTS

Securities classified as cash and investments as of December 31, 2021 and 2020 are summarized below (in thousands). Estimated fair value is based on
quoted market prices for these investments.

December 31, 2021
Gross Unrealized

Amortized Cost

Gains

Losses

Fair Value

Cash and cash equivalents:
Money market funds
Cash

Total cash and cash equivalents
Short-term investments:
Commercial paper
Corporate bonds
Asset-backed securities
U.S. treasury notes

Total short-term investments

Total cash equivalents and investments

71,175  $
1,253 
72,428 

31,936  $
7,025 
5,306 
— 
44,267 
116,695  $

—  $
— 
— 

1  $

— 
— 
— 
1 
1  $

—  $
— 
— 

(2) $
(3)
(2)
— 
(7)
(7) $

71,175 
1,253 
72,428 

31,935 
7,022 
5,304 
— 
44,261 
116,689 

$

$

$

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Cash and cash equivalents:
Money market funds
Commercial paper
Cash

Total cash and cash equivalents
Short-term investments
Commercial paper
Corporate bonds
U.S. government-sponsored agency bonds
U.S. treasury notes

Total short-term investments
Long-term investments:
Corporate bonds

Total cash equivalents and investments

December 31, 2020
Gross Unrealized

Amortized Cost

Gains

Losses

Fair Value

$

$

$
$

88,151  $
2,100 
781 
91,032 

60,631  $
24,547 
9,277 
1,000 
95,455 

2,115  $
188,602  $

—  $
— 
— 
— 

2  $
3 
2 
— 
7 

—  $
7  $

—  $
— 
— 
— 

(4) $
(6)
— 
— 
(10)

(1) $
(11) $

88,151 
2,100 
781 
91,032 

60,629 
24,544 
9,279 
1,000 
95,452 

2,114 
188,598 

Cash equivalents consist of money market funds and other debt securities with original maturities of three months or less at the time of purchase, and the
carrying amount is a reasonable approximation of fair value. We invest our cash in high quality securities of financial and commercial institutions. These
securities are carried at fair value, which is based on readily available market information, with unrealized gains and losses included in accumulated other
comprehensive  income  (loss)  within  stockholders’  equity  on  ours  balance  sheets.  We  use  the  specific  identification  method  to  determine  the  amount  of
realized gains or losses on sales of marketable securities. Realized gains or losses have been insignificant and are included in other income (expense), net,
in the statement of operations.

All  short-term  available-for-sale  securities  held  as  of  December  31,  2021  and  2020,  had  contractual  maturities  of  less  than  one  year.  The  long-term
securities  held  as  of  December  31,  2020  had  contractual  maturities  greater  than  one  year.  Our  available-for-sale  securities  are  subject  to  a  periodic
impairment review. We consider a debt security to be impaired when its fair value is less than its carrying cost, in which case we would further review the
investment to determine whether it is other-than-temporarily impaired. When we evaluate an investment for other-than-temporary impairment, we review
factors such as the length of time and extent to which fair value has been below cost basis, the financial condition of the issuer and any changes thereto,
intent to sell, and whether it is more likely than not we will be required to sell the investment before the recovery of its cost basis. If an investment is other-
than-temporarily  impaired,  we  write  it  down  through  the  statement  of  operations  to  its  fair  value  and  establishes  that  value  as  a  new  cost  basis  for  the
investment.  We  did  not  identify  any  of  its  available-for-sale  securities  as  other-than-temporarily  impaired  in  any  of  the  periods  presented.  As  of
December 31, 2021 and 2020, no investment was in a continuous unrealized loss position for more than one year and we believe that it is more likely than
not that the investments will be held until maturity or a forecasted recovery of fair value.

As  of  December  31,  2021,  the  amortized  cost  and  estimated  fair  value  of  available-for-sale  debt  securities  by  contractual  maturity  were  as  follows  (in
thousands):

Due in one year or less

4.     FAIR VALUE MEASUREMENTS

Amortized Cost
$

44,267  $

Fair Value

44,261 

Fair  value  is  defined  as  the  exchange  price  that  would  be  received  for  an  asset  or  paid  to  transfer  a  liability  (an  exit  price)  in  the  principal  or  most
advantageous market for the asset or liability in an orderly transaction between market participants on the measurement date. Valuation techniques used to
measure fair value must maximize the use of observable inputs and minimize the use of unobservable inputs.

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The three-level hierarchy for the inputs to valuation techniques is briefly summarized as follows:

Level 1   – Valuations are based on quoted prices in active markets for identical assets or liabilities and readily accessible by the Company at the
reporting date. Examples of assets and liabilities utilizing Level 1 inputs are certain money market funds, U.S. treasuries and trading securities
with quoted prices on active markets.

Level 2   –  Valuations based on inputs other than Level 1 that are observable, either directly or indirectly, such as quoted prices for similar assets
or liabilities; quoted prices in markets that are not active; or other inputs that are observable or can be corroborated by observable market data for
substantially the full term of the assets or liabilities. Examples of assets and liabilities utilizing Level 2 inputs are corporate bonds, commercial
paper, certificates of deposit and over-the-counter derivatives.

Level 3  –  Valuations based on unobservable inputs in which there is little or no market data, which require the Company to develop its own
assumptions.

The following table sets forth the fair value of our financial assets and liabilities measured on a recurring basis by level within the fair value hierarchy (in
thousands):

Assets:

Money market funds
Commercial paper
Corporate bonds
Asset-backed securities

Total

Liabilities:

Derivative liability for exit fee

Total

Assets:

Money market funds
Commercial paper
Corporate bonds
U.S. government-sponsored agency bonds
U.S. treasury notes

Total

Liabilities:

Derivative liability for exit fee

Total

Total Fair Value

Level 1

Level 2

Level 3

December 31, 2021

71,175  $
31,935 
7,022 
5,304 
115,436  $

71,175  $
— 
— 
— 
71,175  $

—  $

31,935 
7,022 
5,304 
44,261  $

698  $
698  $

—  $
—  $

—  $
—  $

Total
Fair Value

Level 1

Level 2

Level 3

December 31, 2020

88,151  $
62,729 
26,658 
9,279 
1,000 
187,817  $

88,151  $
— 
— 
— 
— 
88,151  $

—  $

62,729 
26,658 
9,279 
1,000 
99,666  $

— 
— 
— 
— 
— 

698 
698 

— 
— 
— 
— 
— 
— 

1,376  $
1,376  $

—  $
—  $

—  $
—  $

1,376 
1,376 

$

$

$
$

$

$

$
$

Where quoted prices are available in an active market, securities are classified as Level 1. We classify money market funds, U.S. treasury securities and
U.S. treasury notes as Level 1. When quoted market prices are not available for the specific security, we estimate fair value by using benchmark yields,
reported  trades,  broker/dealer  quotes  and  issuer  spreads.  We  classify  corporate  bonds,  commercial  paper,  asset-backed  securities  and  foreign  currency
derivative  contracts  as  Level  2.  In  certain  cases,  where  there  is  limited  activity  or  less  transparency  around  inputs  to  valuation,  securities  or  derivative
liabilities such as the 2018 Exit Fee, as defined and discussed in Note 7 - Derivative Liability, are classified as Level 3.

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The carrying amounts reflected in the balance sheets for cash equivalents, short-term investments, accounts receivable, prepaid expenses and other current
assets, accounts payable and accrued expenses approximate their fair values at both December 31, 2021 and December 31, 2020, due to their short-term
nature.

Based  on  our  procedures  under  the  expected  credit  loss  model,  including  an  assessment  of  unrealized  losses  in  our  portfolio,  we  concluded  that  any
unrealized losses on our marketable securities were not attributable to credit and, therefore, we have not recorded an allowance for credit losses for these
securities as of December 31, 2021 and 2020.

Fair Value of Debt

The interest rate of our term loan facility approximates the rate at which we could obtain alternative financing. Therefore, the carrying amount of the term
loan facility approximated its fair value at December 31, 2021 and 2020.

5.     COLLABORATION AND LICENSING AGREEMENTS

Kyowa Kirin Co., Ltd. (2019 KKC Agreement)

In November 2019, we entered into a research collaboration and option agreement with KKC (the "2019 KKC Agreement”), to undergo research to identify
two preclinical study-ready compounds for designation as development compounds, with one compound inhibiting the first undisclosed target (“Program
1”)  and  a  second  inhibiting  the  second  undisclosed  target  (“Program  2”).  Pursuant  to  the  2019  KKC  Agreement,  upon  completion  of  the  research  and
designation  by  the  research  steering  committee  of  one  or  more  development  candidates  (“DCs”),  KKC  has  the  right  to  execute  one  or  more  separate
collaborative agreements relating to the development and commercialization of one or both DCs in certain specified territories.

Under the terms of the 2019 KKC Agreement, KKC agreed to pay us a non-refundable, non-creditable upfront fee of $10.0 million, which was payable as
follows: the first installment of $5.0 million within 30 days of the Effective Date, and the second installment of $5.0 million on the first anniversary of the
effective  date,  unless  the  2019  KKC  Agreement  was  earlier  terminated  by  KKC  due  to  material  breach  by  us.  The  term  of  the  2019  KKC  Agreement
commenced on November 11, 2019 (“the Effective Date”) and ends on the earliest of: (a) two years following the Effective Date, or (b) the nomination of a
program DC for both programs, (c) or the nomination of one program DC and the decision by the parties to cease research for the other program, (d) or the
decision by the parties to cease research for both programs. We assessed the 2019 KKC Agreement in accordance with ASC 606 and concluded that the
contract’s counterparty, KKC, is a customer. Management also considered the modification guidance prescribed in ASC 606 and concluded that the 2019
KKC Agreement should be accounted for as a separate contract from the 2017 KKC Agreement, as defined and discussed below.

We  identified  various  promises  in  the  2019  KKC  Agreement,  including  the  grant  of  an  initial  research  license,  the  Program  1  research,  the  Program  2
research, the right to obtain certain development and commercialization rights with Program 1 in certain territories and the right to obtain development and
commercialization rights with Program 2 in certain territories, and participation in a joint steering committee (“the JSC”) and determined that KKC could
not benefit from either of the research programs without the research license and participation in the JSC. As such, the combined license, research programs
and participation in the JSC were deemed to be the highest level of goods and services that can be deemed distinct for each of the Program 1 research and
Program  2  research.  We  concluded  that  the  options  to  obtain  additional  development  and  commercialization  rights  that  are  exercisable  by  KKC  under
certain circumstances are not performance obligations of the contract at inception because the option fees reflect the standalone selling price of the options,
and therefore, the options are not considered to be material rights.

At  the  outset  of  the  2019  KKC  Agreement,  we  determined  that  the  initial  transaction  price  was  $10.0  million  and  that  revenue  associated  with  the
combined performance obligations should be recognized as services are provided using the input method. Since transfer of control occurs over time, in
management’s judgment this input method is the best measure of progress towards satisfying the performance obligations and reflects a faithful depiction
of the transfer of goods and services. Revenue will be recognized over the Program 1 and Program 2 research periods. Management will re-evaluate the
estimates related to the transaction price at the end of each reporting period and as uncertain events are resolved or other changes in circumstances occur
and adjust the timing of revenue recognition as necessary.

During  the  years  ended  December  31,  2021  and  2020,  we  recognized  $4.2  million  and  $5.4  million,  respectively,  as  revenue  under  the  2019  KKC
Agreement  in  the  statement  of  operations  and  comprehensive  loss.  The  aggregate  amount  of  the  transaction  price  allocated  to  our  partially  unsatisfied
performance obligations as of December 31, 2021 and 2020 was zero and $4.2 million, which was presented in the Balance Sheet as deferred revenue for
each respective period. As of December 31,

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2021, we have no material future obligations under the 2019 KKC Agreement. There were no significant changes in estimates associated with the 2019
KKC Agreement during the twelve months ended December 31, 2021.

2017 KKC Agreement

In November 2017, we entered into an exclusive license agreement with KKC (the "2017 KKC Agreement") for the development, commercialization and
distribution of tenapanor in Japan for cardiorenal indications. We granted KKC an exclusive license to develop and commercialize certain sodium hydrogen
exchanger 3 ("NHE3") inhibitors, including tenapanor in Japan for the treatment of cardiorenal diseases and conditions, excluding cancer. We retained the
rights to tenapanor outside of Japan, and also retained the rights to tenapanor in Japan for indications other than those stated above. Pursuant to the License
Agreement, KKC is responsible for all of the development and commercialization costs for tenapanor in treatment of cardiorenal diseases and conditions,
excluding cancer in Japan. Under the 2017 KKC Agreement, we are responsible for supplying the tenapanor drug product for KKC’s use in development
and during commercialization until KKC has assumed such responsibility. Additionally, we are responsible for supplying the tenapanor drug substance for
KKC’s  use  in  development  and  commercialization  throughout  the  term  of  the  2017  KKC  Agreement,  provided  that  KKC  may  exercise  an  option  to
manufacture the tenapanor drug substance under certain conditions

We assessed these arrangements in accordance with ASC 606 and concluded that the contract counterparty, KKC, is a customer. Under the terms of the
2017 KKC Agreement, we received $30.0 million in up-front license fees which was recognized as revenue when the agreement was executed. Based on
our  assessment,  we  identified  that  the  license  and  the  manufacturing  supply  services  were  our  material  performance  obligations  at  the  inception  of  the
agreement,  and  as  such  each  of  the  performance  obligations  are  distinct.  Additionally,  on  January  1,  2018,  we  recorded  unbilled  revenue  under  current
assets of $5.0 million and an increase in uncharged license fees under current liabilities of $1.0 million related to the first milestone under the 2017 KKC
Agreement  that  KKC  achieved  in  February  2019,  reflecting  revenues  and  cost  of  revenue,  respectively,  that  would  have  been  recognized  in  the  fourth
quarter  2017  if  we  had  adopted  ASC  606  prior  to  January  1,  2018.  On  KKC’s  achievement  of  the  milestone  in  February  2019,  the  balance  related  to
unbilled  revenue  was  adjusted  to  zero.  Correspondingly,  the  $1.0  million  balance  related  to  uncharged  license  fees  that  we  owed  to  AstraZeneca  was
reclassified to accounts payable during the first quarter of 2019, and subsequently paid to AstraZeneca during the second quarter of 2019.

In  addition  to  the  up-front  license  fee  received  of  $30.0  million,  we  may  be  entitled  to  receive  up  to  $55.0  million  in  total  development  milestones,  of
which $10.0 million has been received to date, ¥8.5 billion Japanese yen for commercialization milestones, or approximately $73.9 million at the currency
exchange rate on December 31, 2021, as well as reimbursement of cost, plus a reasonable overhead for the supply of product and high-teen royalties on net
sales throughout the term of the agreement. The variable consideration related to the remaining development milestone payments has not been included in
the transaction price as these were fully constrained at December 31, 2021.

For the years ended December 31, 2021 and 2020, $0.9 million and $1.4 million, respectively, of product supply revenue was recorded for manufacturing
supply  of  tenapanor  and  other  materials  to  KKC  for  product  development  and  clinical  trials  in  Japan,  in  accordance  with  our  agreement  with  KKC,
including $0.5 million accounts receivable as of December 31, 2021

For the years ended December 31, 2021 and 2020, $5.0 million and zero, respectively, of licensing revenue was recorded. The 2021 licensing revenue was
recorded upon the initiation of phase 3 clinical studies by KKC in Japan to evaluate tenapanor for hyperphosphatemia.

During  the  twelve  months  ended  December  31,  2021,  we  received  a  $3.2  million  prepayment  from  KKC  for  the  manufacturing  of  tenapanor  drug
substance. In addition, we have unbilled prepayments of $1.5 million from KKC for the manufacturing of tenapanor drug product reflected within prepaid
and other current assets. Both amounts are reflected within our deferred revenue, non-current on our balance sheet as of December 31, 2021.

Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. , or Fosun Pharma

In December 2017, we entered into an exclusive license agreement with Fosun Pharma (the "Fosun Agreement") for the development, commercialization
and  distribution  of  tenapanor  in  China  for  both  hyperphosphatemia  and  IBS-C.  We  assessed  these  arrangements  in  accordance  with  ASC  606  and
concluded that the contract counterparty, Fosun Pharma, is a customer. Under the terms of the Fosun Agreement, we received $12.0 million in up-front
license  fees  which  was  recognized  as  revenue  when  the  agreement  was  executed.  Based  on  our  assessment,  we  identified  that  the  license  and  the
manufacturing supply services were its material performance obligations at the inception of the agreement, and as such each of the performance obligations
are distinct.

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In addition, we may be entitled to additional development and commercialization milestones of up to $110.0 million, as well as reimbursement of cost plus
a reasonable overhead for the supply of product and tiered royalties on net sales ranging from the mid-teens to 20%. The variable consideration related to
the remaining development milestone payments has not been included in the transaction price as these were fully constrained at December 31, 2021 and
2020.

For the years ended December 31, 2021 and 2020, no revenue was recorded related to the Fosun Agreement.

Knight Therapeutics, Inc.

In  March  2018,  we  entered  into  an  exclusive  license  agreement  with  Knight  Therapeutics,  Inc.,  (the  "Knight  Agreement")  for  the  development,
commercialization and distribution of tenapanor in Canada for hyperphosphatemia and IBS-C. We assessed these arrangements in accordance with ASC
606  and  concluded  that  the  contract  counterparty,  Knight,  is  a  customer.  Based  on  our  assessment,  it  identified  that  the  license  and  the  manufacturing
supply services were its material performance obligations at the inception of the agreement, and as such each of the performance obligations are distinct.

Under  the  terms  of  the  agreement,  we  received  a  $2.3  million  nonrefundable,  one-time  upfront  payment  in  March  2018  and  are  eligible  to  receive
additional  development  and  commercialization  milestone  payments  worth  up  to  CAD22.2  million,  or  $17.4  million  at  the  currency  exchange  rate  on
December  31,  2021,  reimbursement  of  supply  costs  on  a  schedule  specifying  cost  per  tablet,  with  a  reasonable  mark  up  for  overhead,  as  well  as  tiered
royalty rates on net sales ranging from the mid-single digits to the low twenties. The variable consideration related to the remaining development milestone
payments has not been included in the transaction price as these were fully constrained at December 31, 2021 and 2020.

For the years ended December 31, 2021 and 2020, $13 thousand and $0.7 million of licensing revenue was recorded, respectively, related to the Knight
Agreement.  For  the  years  ended  December  31,  2021  and  2020,  zero  and  $0.1  million  product  supply  revenue  was  recorded,  respectively,  related  to  the
Knight Agreement. Pursuant to the AstraZeneca Termination Agreement, $1.0 million and $0.1 million of cost of revenue was recorded during 2021 and
2020, respectively.

Xuanzhu (HK) Biopharmaceutical Limited, or XuanZhu

In  November  2019,  we  entered  into  a  license  agreement  with  XuanZhu  (“the  XuanZhu  Agreement")  for  a  license  to  certain  specific  patent  and  patent
applications. We assessed these arrangements in accordance with ASC 606 and concluded that the contract counterparty, XuanZhu, is a customer. Under the
terms  of  the  XuanZhu  Agreement,  we  recognized  $1.5  million  in  license  fees  when  the  agreement  was  executed,  of  which,  $0.8  million  was  received
upfront in November 2019 and achievement for the second $0.8 million payment was determined to be not materially at risk and probable of achievement
and it was included in the transaction price as the amount was not probable of revenue reversal. Based on our assessment, we determined that we had one
combined performance obligation, which is the license and the specific patent grant.

In  addition  to  the  license  fee  of  $1.5  million,  we  may  be  entitled  to  receive  milestone  payments.  The  variable  consideration  related  to  the  remaining
milestone payments has not been included in the transaction price as these were fully constrained at December 31, 2021 and 2020.

For the years ended December 31, 2021 and 2020, no license revenue was recorded related to the XuanZhu Agreement.

AstraZeneca

In June 2015, we entered into a termination agreement with AstraZeneca (the "AstraZeneca Termination Agreement") pursuant to which we remain liable
to pay AstraZeneca license fees for (i) future royalties at a royalty rate of 10% of net sales of tenapanor or other NHE3 products by us or our licensees, and
(ii) 20% of non-royalty revenue received from a licensee of tenapanor or certain other NHE3 inhibitors, up to a maximum of $75.0 million in aggregate for
(i) and (ii).

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To date in aggregate, we have recognized $11.6 million of the $75.0 million, recorded as cost of revenue, as follows (in thousands):

Year 2017

Year 2018

Year 2019

Year 2020

Year 2021

Total

Maximum payment per termination agreement

Remaining potential commitment

$

$

Cost of Revenue

Recognized

Amount Paid

9,400  * $

466 

600 

145 

1,000 
11,611 

$

$

6,000 

2,864 

1,002 

742 

1,003 

11,611 
75,000 
63,389 

* Includes $1.0 million adjustment recorded pursuant to the adoption of ASC 606, as discussed in Note 2.

Deferred Revenue

The following tables present changes in our current and non-current deferred revenue balances during the reporting period. The current deferred revenue
balance  is  attributable  entirely  to  the  2019  KKC  Agreement  and  the  non-current  deferred  revenue  balance  is  attributable  entirely  to  the  2017  KKC
Agreement (in thousands):

Deferred revenue - current
Balance at Balance at January 1,

Decreases due to revenue recognized in the period for which cash has been received

Balance at Balance at December 31,

Deferred revenue - non-current
Balance at Balance at January 1,

Increases due to cash received during the period
Increase due to unbilled prepayments recorded during the period

Balance at Balance at December 31,

6.     BORROWINGS

Solar Capital and Western Alliance Bank Loan Agreement

2021

2020

$

$

$

$

4,177 
(4,177)
— 

— 
3,242 
1,485 
4,727 

$

$

$

$

2021

4,541 
(364)
4,177 

— 
— 
— 
— 

2020

On May 16, 2018, we entered into a loan and security agreement (the "2018 Loan Agreement"), with Solar Capital Ltd. and Western Alliance Bank (the
"Lenders”). The 2018 Loan Agreement provides for a $50.0 million term loan facility with a maturity date of November 1, 2022 (the "2018 Term Loan”).
The  full  amount  of  the  2018  Term  Loan  was  funded  on  May  16,  2018.  We  received  net  proceeds  from  the  loan  of  approximately  $49.3  million,  after
deducting  the  closing  fee,  legal  expenses  and  issuance  costs.  On  October  9,  2020,  we  and  the  Lenders  entered  into  an  amendment  to  the  2018  Loan
Agreement  (“the  2020  Amendment”)  to  extend  the  date  through  which  we  were  permitted  to  make  interest-only  payments  on  the  2018  Term  Loan  by
twelve months to December 1, 2021 subject to the repayment terms noted below.

Borrowings  under  the  2018  Term  Loan  bear  interest  at  a  floating  per  annum  rate  equal  to  7.45%  plus  the  one-month  London  Inter-bank  Offered  Rate
("LIBOR"). We were permitted to make interest-only payments on the 2018 Term Loan through June 1, 2020, or until we achieved our primary endpoint in
the Phase 3 study of tenapanor for the treatment of hyperphosphatemia in end-stage renal disease patients on dialysis prior to June 1, 2020, in which case
we would have been permitted to make interest-only payments on the 2018 Term Loan through December 1, 2020. On December 3, 2019, we reported
positive topline results for PHREEDOM, a long-term Phase 3 study evaluating the efficacy and safety of tenapanor as monotherapy for the treatment of
hyperphosphatemia in adult patients with CKD on dialysis. The Lenders were in agreement that these positive data from the Phase 3 PHREEDOM study
achieve the “Phase 3 Endpoint” required by the 2018 Term Loan to extend the interest only period by six months to December 1, 2020. Subsequent to the
2020 Amendment, the interest only period was extended an additional twelve months to December 1, 2021. Accordingly, beginning on December 1, 2021
through

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the maturity date, we would have been required to make monthly payments of interest plus repayment of the 2018 Term Loan in consecutive equal monthly
installments of principal. If however, either the FDA did not approve our NDA for tenapanor for control of serum phosphorus in adult patients with CKD
on dialysis on or before May 31, 2021 or the FDA issued a Complete Response Letter ("CRL") for tenapanor for the control of serum phosphorus in adult
CKD on dialysis, then we would begin principal payments on the earlier of June 1, 2021 or the first day of the month immediately following the date that
the FDA issued a CRL to us.

In May and July 2021, we and the Lenders entered into additional amendments to the 2018 Loan Agreement (“the 2021 Amendments”) which together
extended the period of time that we were permitted to make interest-only payments on the 2018 Term Loan to December 1, 2021; provided that if we had
not received FDA approval for our NDA for tenapanor for the control of serum phosphorus in adult patients with CDK on dialysis on or before October 25,
2021,  the  interest-only  period  would  expire  and  principal  repayments  would  be  required  to  begin  on  November  1,  2021.  If  principal  repayments  were
required to begin prior to December 1, 2021 under the 2021 Amendments, then the first such repayment was required include all payments that would have
been due if monthly principal repayment had begun on June 1, 2021. Accordingly, during November 2021, in compliance with the terms of our 2018 Loan
Agreement, we paid the first principal repayment on the 2018 Term Loan in the amount of $16.7 million and have paid all other subsequently due principal
payments through December 31, 2021.

We paid a closing fee of $0.5 million, upon the closing of the 2018 Term Loan and $0.1 million upon closing of the 2020 Amendment. Under the 2018
Term Loan, we were obligated to pay a final fee equal to 3.95% of the 2018 Term Loan upon the earliest to occur of the maturity date, the acceleration of
the 2018 Term Loan, the prepayment or repayment of the 2018 Term Loan or the termination of the 2018 Loan Agreement. Under the 2020 Amendment,
the  final  fee  was  increased  to  4.95%  of  the  2018  Term  Loan.  We  may  voluntarily  prepay  the  outstanding  2018  Term  Loan,  subject  to  a  prepayment
premium of (i) 3% of the principal amount of the 2018 Term Loan if prepaid prior to or on the first anniversary of the Closing Date, (ii) 2% of the principal
amount of the 2018 Term Loan if prepaid after the first anniversary of the Closing Date through and including the second anniversary of the Closing Date,
or (iii) 1% of the principal amount of the 2018 Term Loan if prepaid after the second anniversary of the Closing Date and prior to the maturity date. The
2018 Term Loan is secured by substantially all of our assets, except for our intellectual property and certain other customary exclusions. Additionally, in
connection with the 2018 Term Loan, we entered into the 2018 Exit Fee Agreement, as discussed in Note 7 - Derivative Liability.

The 2018 Loan Agreement contains customary representations and warranties and customary affirmative and negative covenants, including restrictions on
payment  of  dividends  for  our  common  stock.  As  of  December  31,  2021,  we  were  in  compliance  with  all  of  the  covenants  set  forth  in  the  2018  Loan
Agreement.

In  addition,  the  2018  Loan  Agreement  contains  customary  events  of  default  that  entitle  the  Lender  to  cause  our  indebtedness  under  the  2018  Loan
Agreement to become immediately due and payable, and to exercise remedies against us and the collateral securing the 2018 Term Loan, including its cash.
Upon the occurrence and for the duration of an event of default, an additional default interest rate equal to 4.0% per annum will apply to all obligations
owed under the 2018 Loan Agreement. As of December 31, 2021, to our knowledge, there were no facts or circumstances in existence that would give rise
to an event of default.

As discussed in Note 18 - Subsequent Events, on February 23, 2022 (the “Closing Date”), we entered into a loan and security agreement (the “2022 Loan
Agreement”)  with  SLR  Investment  Corp.  as  collateral  agent  (the  “Agent”),  and  the  lenders  listed  in  the  2022  Loan  Agreement  (collectively  the  “2022
Lenders”). The 2022 Loan Agreement provides for a senior secured term loan facility, with $27.5 million (the “Term A Loan”) funded on the Closing Date
and an additional $22.5 million that we may borrow on or prior to July 25, 2023; provided that (i) we have received approval by the FDA for our NDA for
tenapanor the control of serum phosphorus in chronic kidney disease patients on dialysis by December 31, 2022, and (ii) we have achieved certain product
revenue milestone targets described in the 2022 Loan Agreement (the “Term B Loan”, and collectively, the Term A Loan and the Term B Loan, the “2022
Term  Loan”).  The  Term  A  Loan  funds  are  being  used  to  repay  the  Term  Loan  with  the  Lenders  as  discussed  in  Note  6  -  Borrowings  and  to  fund  our
ongoing operations. We had $25.0 million principal from the 2018 Term Loan outstanding as of the Closing Date. We have continued to classify the 2018
Term  Loan  balance  as  a  current  liability  as  of  December  31,  2021  due  to  the  determination  of  the  existence  of  substantial  doubt  about  our  ability  to
continue  operating  as  a  going  concern  discussed  in  Note  2  –  Summary  of  Significant  Accounting  Policies  and  our  assessment  that  the  material  adverse
change clause under the 2022 Loan Agreement is not within the Company's control. The lender has not invoked the material adverse change clause as of
the date of issuance of these financial statements.

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Total repayment obligations

Less: Unamortized discount and debt issuance costs
Less: Unaccreted value of final fee

Loan payable
Less: Loan payable, current portion
Loan payable, net of current portion

As of December 31, 2021, prior to restructuring our debt as discussed in Note 18 - Subsequent Events, our future payment obligations towards the 2018
Term Loan principal and final fee, excluding interest payments and the 2018 Exit Fee were as follows (in thousands):
2022

$
$

$

33,031 
33,031 
(235)
(532)
32,264 
(32,264)
— 

Subsequent to restructuring the 2018 Term Loan, we will have no debt repayment obligations in 2022 or 2023. We will be required to repay $6.9 million,
$9.2 million, $9.2 million, and $2.3 million in Term A Loan principal repayments per year during 2024, 2025, 2026 and 2027, respectively, as well as a
final fee in the amount of $1.4 million in 2027.

7.    DERIVATIVE LIABILITY

Exit Fee

In May 2018, in connection with entering into the 2018 Loan Agreement, as defined and discussed in Note 6 - Borrowing, we entered into an agreement
pursuant to which we agreed to pay $1.5 million in cash (the "2018 Exit Fee") upon any change of control transaction in respect of the Company or if we
obtain  both  (i)  FDA  approval  of  tenapanor  for  the  treatment  of  hyperphosphatemia  in  adult  patients  with  CKD  on  dialysis  and  (ii)  FDA  approval  of
tenapanor for the treatment of patients with IBS-C, which was obtained on September 12, 2019 when the FDA approved IBSRELA, a 50 mg, twice daily
oral pill for the treatment of IBS-C in adults (the “2018 Exit Fee Agreement”). Notwithstanding the prepayment or termination of the 2018 Term Loan, our
obligation  to  pay  the  2018  Exit  Fee  will  expire  on  May  16,  2028.  We  concluded  that  the  2018  Exit  Fee  is  a  freestanding  derivative  which  should  be
accounted for at fair value on a recurring basis. The estimated fair value of the 2018 Exit Fee is recorded as a derivative liability and included in accrued
expense and other current liabilities on the accompanying balance sheets.

The fair value of the derivative liability was determined using a discounted cash flow analysis and is classified as a Level 3 measurement within the fair
value hierarchy since our valuation utilized significant unobservable inputs. Specifically, the key assumptions included in the calculation of the estimated
fair value of the derivative instrument include: i) our estimates of both the probability and timing of a potential $1.5 million payment to Solar Capital Ltd.
and  Western  Alliance  Bank  as  a  result  of  the  FDA  approvals,  and  ii)  a  discount  rate  which  was  derived  from  our  estimated  cost  of  debt,  adjusted  with
current  LIBOR.  Generally,  increases  or  decreases  in  the  probability  of  occurrence  would  result  in  a  directionally  similar  impact  in  the  fair  value
measurement of the derivative instrument and it is estimated that a 10% increase (decrease), not to exceed 100%, in the probability of occurrence would
result in a fair value fluctuation of no more than $0.1 million.

Changes in the fair value of recurring measurements included in Level 3 of the fair value hierarchy are presented as other income (expense), net in our
Statements of Operations and were as follows for the years ended December 31, 2021, 2020 and 2019 (in thousands):

Fair value of exit fee derivative liability at January 1

Change in estimated fair value of derivative liability

Fair value of exit fee derivative liability at December 31

2021

2020

2019

$
$
$

1,376  $
(678) $
698  $

969  $
407  $
1,376  $

533 
436 
969 

As discussed in Note 18 - Subsequent Events, on February 23, 2022, we entered into an additional exit fee agreement with Solar whereby we agreed to pay
an exit fee in the amount 2% of the 2022 Term Loan funded upon the first to occur of a specified exit event or revenue achievement event.

8.     LEASES

We  have  recorded  right-of-use  operating  lease  assets  under  three  lease  agreements.  We  have  evaluated  our  facility  leases  and  determined  that,  effective
upon the adoption of Topic 842, the leases evaluated are all operating leases. We have performed

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an evaluation of our other contracts with suppliers and collaborators in accordance with Topic 842 and have determined that, except for the facility leases
described below, none of our contracts contain a lease.

We  have  recorded  a  right-of-use  operating  lease  asset  located  in  Fremont,  California  under  a  lease  agreement  entered  into  in  September  2008  that  was
amended in December 2012 to extend the lease agreement to September 2016. In September 2014, we signed the second amendment to our facility lease
agreement to add space and to extend the lease term through September 2019. In May 2016, we signed a third amendment to our facility lease agreement in
Fremont, California to add space and to extend the lease term through September 2021 (the “Third Amendment”). During May 2021, we entered into an
additional  amendment  to  the  lease  for  our  Fremont,  California  facility  that  extended  the  term  of  the  lease  to  March  2025.  The  office  space  consists  of
72,500  square  feet,  which  includes  10,716  square  feet  added  in  September  2019.  We  do  not  have  an  option  to  renew  the  lease  at  our  current  Fremont
location beyond March 2025.

We have recorded a right-of-use operating lease asset located in Waltham, Massachusetts under a lease agreement entered into in October 2018. The office
space  consisted  of  3,520  square  feet  with  the  lease  terminating  in  September  2021.  We  did  not  renew  the  lease  at  our  original  Waltham,  Massachusetts
facility.  During  April  2021  and  May  2021,  we  recorded  right-of-use  operating  lease  assets  for  a  new  facility  in  Waltham,  Massachusetts  under  a  lease
agreement entered into during December 2020 with lease commencement dates during April and May 2021. The office space consists of 12,864 square feet
with the lease terminating in June 2026. We have an option to extend the lease term for one additional five year period. This option to extend the lease term
has  not  been  included  in  the  calculation  since  currently  the  exercise  of  the  option  is  uncertain  and  therefore  deemed  not  probable.  We  recorded  a  $1.6
million right-of-use asset and lease liability for the Waltham lease upon commencement of the lease.

We have recorded a right-of-use operating lease asset located in Milwaukee, Wisconsin under a lease agreement entered into in October 2020 with a lease
commencement date in November 2020. The office space consists of 4,768 square feet with the lease terminating in February 2026. We have an option to
extend the lease term by one additional five-year period. This option to extend the lease term has not been included in the calculation since currently the
exercise of the option is uncertain and therefore deemed not probable. We recorded a $0.4 million right-of use asset and lease liability for the Milwaukee
lease upon commencement of the lease.

All of our leases are operating leases and each contain customary rent escalation clauses. Certain of the leases have both lease and non-lease components.
We  have  as  elected  to  account  for  each  separate  lease  component  and  the  non-lease  components  associated  with  that  lease  component  as  a  single  lease
component for all classes of underlying assets.

The following table provides additional details of the leases presented in the balance sheets (dollars in thousands):

Facilities

Right-of-use assets

Current portion of lease liabilities
Operating lease liability, net of current portion

Total

Weighted-average remaining life (years)
Weighted-average discount rate

$

$

As of Dec 31,

2021

2020

12,752 

$

2,274 

3,492 
9,748 
13,240 

$

3.40
6.9 %

2,117 
413 
2,530 

1.50
11.7 %

The lease costs, which are included in operating expenses in our statements of operations, were as follows (in thousands):

Operating lease expense
Cash paid for operating lease

2021

Year Ended December 31,
2020

2019

$
$

3,671  $
3,438  $

2,608  $
3,065  $

2,592 
2,645 

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The following table summarizes our undiscounted cash payment obligations for our operating lease liabilities as of December 31, 2021 (in thousands):

Ending December 31,
2022
2023
2024
2025
2026
Thereafter
Total undiscounted operating lease payments
Imputed interest expenses

Total operating lease liabilities

Less: Current portion of operating lease liability

Operating lease liability, net of current portion

9.     STOCKHOLDERS’ EQUITY

$

$

4,292 
4,440 
4,589 
1,321 
252 
— 
14,894 
(1,654)
13,240 
(3,492)
9,748 

In July 2020, we filed a Form S-3 registration statement, which became effective in August 2020, containing (i) a base prospectus for the offering, issuance
and sale by us of up to a maximum aggregate offering price of $250.0 million of our common stock, preferred stock, debt securities, warrants and/or units,
from  time  to  time  in  one  or  more  offerings;  and  (ii)  a  prospectus  supplement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a  maximum  aggregate
offering price of $100.0 million of its common stock that may be issued and sold, from time to time, under an Open Market Sales Agreement with Jefferies
LLC,  as  sales  agent,  deemed  to  be  “at-the-market  offerings”  (the  "2020  Open  Market  Sales  Agreement").  Pursuant  to  the  2020  Open  Market  Sales
Agreement, Jefferies, as sales agent, received a commission of up to 3.0% of the gross sales price for shares of common stock sold under the 2020 Open
Market Sales Agreement. We sold 8.2 million shares of our common stock between the dates of November 13, 2020 through February 19, 2021, 4.0 million
shares between the dates of May 11, 2021 through June 18, 2021, 3.3 million shares between the dates of August 24, 2021 through September 10, 2021 and
7.7 million between the dates of October 21, 2021 through December 31, 2021 for a cumulative total of 23.3 million shares and gross proceeds of $100.0
million at a weighted average sales price of approximately $4.30 per share which resulted in full utilization of the $100.0 million authorized amount under
the 2020 Open Market Sales Agreement.

In  August  2021,  we  filed  an  additional  prospectus  supplement  under  the  Registration  Statement  for  the  offering,  issuance  and  sale  by  us  of  up  to  a
maximum  aggregate  offering  price  of  $150.0  million  of  our  common  stock  that  may  be  issued  and  sold,  from  time  to  time,  under  an  additional  sales
agreement  we  entered  into  with  Jefferies  (the  "2021  Open  Market  Sales  Agreement"),  pursuant  to  which  we  may,  from  time  to  time,  sell  up  to  $150.0
million in shares of our common stock through Jefferies. We are not required to sell shares under the 2021 Open Market Sales Agreement. Pursuant to the
2021 Open Market Sales Agreement, Jefferies, as our sales agent, receives a commission of up to 3.0% of the gross sales price for shares of common stock
sold  under  the  2021  Open  Market  Sales  Agreement.  As  of  December  31,  2021  we  have  sold  15.7  million  shares  and  received  gross  proceeds  of  $25.0
million at a weighted average sales price of approximately $1.60 per share under the 2021 Open Market Sales Agreement.

On  December  9,  2019,  we  completed  an  underwritten  public  offering  of  20.0  million  shares  of  common  stock  at  a  price  of  $6.25  per  share  before
underwriting discounts and commissions (the "2019 Offering"). In connection with the 2019 Offering, we entered into an underwriting agreement, or the
2019 Underwriting Agreement, with Citigroup Global Markets Inc., Cowen and Company LLC, SVB Leerink LLC and Piper Jaffray & Co., or collectively
the 2019 Underwriters, pursuant to which we granted to the 2019 Underwriters a 30-day option to purchase up to an additional 3.0 million shares of our
common stock, or the 2019 Overallotment. We completed the sale of 23.0 million shares, inclusive of the 2019 Overallotment, to the 2019 Underwriters
and  that  sale  resulted  in  the  receipt  by  us  of  aggregate  gross  proceeds  of  approximately  $143.8  million,  less  underwriting  discounts,  commissions  and
offering expenses totaling approximately $8.9 million, which resulted in net proceeds of approximately $134.9 million.

On November 22, 2019, we and KKC entered into a stock purchase agreement, pursuant to which we sold an aggregate of approximately 2.9 million shares
of  its  common  stock  at  $6.96  per  share  for  net  proceeds  of  approximately  $20.0  million,  or  the  Private  Placement.  The  Private  Placement  closed  on
November 25, 2019.

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10.    EQUITY INCENTIVE PLANS

2008 Plan

We granted options under its 2008 Stock Incentive Plan (the “2008 Plan”) until June 2014 when it was terminated as to future awards, although it continues
to govern the terms of options that remain outstanding under the 2008 Plan. The 2008 Plan provided for the granting of incentive and non-qualified stock
options, and stock purchase rights to employees, directors and consultants at the discretion of the Board of Directors. Stock options granted generally vest
over a period of four years from the date of grant. In connection with the Board of Directors and stockholders’ approval of the 2014 Plan, all remaining
shares available for future award under the 2008 Plan were transferred to 2014 Plan, and the 2008 Plan was terminated.

2014 Plan

The 2014 Equity Incentive Award Plan (the “2014 Plan”) became effective on June 18, 2014. Under the 2014 Plan, 1.4 million shares of common stock
were initially reserved for issuance pursuant to a variety of stock-based compensation awards, including stock options, stock appreciation rights ("SARs"),
restricted  stock  awards,  service-based  restricted  stock  unit  (“RSU”)  awards,  performance-based  restricted  stock  unit  (“PRSU”)  awards,  deferred  stock
awards, deferred stock unit awards, dividend equivalent awards, stock payment awards and performance awards. In addition, 35 thousand shares that had
been available for future awards under the 2008 Plan as of June 18, 2014, were added to the initial reserve available under the 2014 Plan, bringing the total
reserve upon the effective date of the 2014 Plan to 1.5 million shares. The number of shares initially reserved for issuance or transfer pursuant to awards
under the 2014 Plan will be increased by (i) the number of shares represented by awards outstanding under 2008 Plan on June 18, 2014, that are either
forfeited or lapse unexercised or that are repurchased for the original purchase price thereof, up to a maximum of 1.2 million shares, and (ii) if approved by
the Administrator of the 2014 Plan, an annual increase on the first day of each fiscal year ending in 2024 equal to the lesser of (A) four percent (4.0%) of
the shares of stock outstanding (on an as converted basis) on the last day of the immediately preceding fiscal year and (B) such smaller number of shares of
stock  as  determined  by  our  board  of  directors;  provided,  however,  that  no  more  than  10.7  million  shares  of  stock  may  be  issued  upon  the  exercise  of
incentive stock options.

2016 Plan

In  November  2016,  our  board  of  directors  approved  the  2016  Employment  Commencement  Incentive  Plan  (the  “Inducement  Plan”)  under  which  1.0
million  shares  were  reserved.  In  January  2021  and  2022,  0.5  million  and  2.0  million  shares,  respectively,  were  added  to  the  Inducement  Plan.  As  of
December 31, 2021, 0.4 million shares of our common stock were subject to inducement grants that were issued pursuant to the Inducement Plan.

Stock Options

The following table summarizes activity under the 2008 Plan and the 2014 Plan, including grants issued to nonemployees, in the year ended December 31,
2021:

Options Issued and Outstanding

Shares Available
for Grant

Number of Shares

Weighted-Average
Exercise Price 
per Share

Weighted
Average
Remaining
Contractual Term

(in Years)

Aggregate
Intrinsic Value

(in thousands)

Balance at December 31, 2020
Options authorized
Options granted
Options exercised
Options canceled
Issuance of common stock for services

Balance at December 31, 2021

Vested and expected to vest at December 31, 2021

Exercisable at December 31, 2021

1,757,058 
4,201,766 
(3,409,719)
— 
2,451,306 
(25,989)
4,974,422 

9,790,049  $
—  $
3,409,719  $
(331,310) $
(2,451,306) $

— 

10,417,152  $
10,417,152  $
6,772,289  $

6.76 
— 
6.60 
1.96 
6.17 
— 

7.00 

7.00 

7.39 

6.57 $

6.57 $

5.58 $

— 

— 

— 

The aggregate intrinsic value represents the difference between the total pre-tax value (i.e., the difference between our stock price and the exercise price) of
stock options outstanding as of December 31, 2021, based on our common stock closing

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price of $1.10 per share, which would have been received by the option holders had all their in-the-money options been exercised as of that date.

The  intrinsic  value  of  options  exercised  during  the  years  ended  December  31,  2021,  2020  and  2019,  was  $1.7  million,  $2.7  million,  and  $0.4  million,
respectively.

The weighted-average grant-date estimated fair value of options granted during the years ended December 31, 2021, 2020 and 2019 was $3.92, $4.82 and
$1.79 per share, respectively. The estimated grant date fair value of employee stock options was calculated using the Black-Scholes option-pricing model,
based on the following weighted-average assumptions:

Expected term (years)
Expected volatility
Risk-free interest rate
Dividend yield

2021

Year Ended December 31,
2020

2019

4.97
77 %
4.69 %
— %

6.00
83 %
1.07 %
— %

6.00
81 %
2.42 %
— %

Expected Term—We  have  limited  historical  information  to  develop  reasonable  expectations  about  future  exercise  patterns  and  post-vesting  employment
termination behavior for its stock-option grants. As such, the expected term has been estimated using the simplified method whereby the expected term
equals the arithmetic average of the vesting term and the original contractual term of the option. Beginning in 2021, we estimate the expected term of our
options  based  upon  historical  exercises  and  post-vesting  termination  behavior,  which  has  not  resulted  in  a  material  difference  as  compared  to  using  the
simplified method.

Expected Volatility—Since  January  1,  2017,  we  use  the  historic  volatility  of  our  own  stock  over  the  retrospective  period  corresponding  to  the  expected
remaining term of the options, or the period since our shares were first quoted on The Nasdaq Global Market, if that is shorter, to compute our expected
stock price volatility.

Risk-Free Interest Rate—The risk-free interest rate assumption is based on the zero-coupon U.S. treasury instruments on the date of grant with a maturity
date consistent with the expected term of our stock option grants.

Dividend Yield—To  date,  we  have  not  declared  or  paid  any  cash  dividends  and  does  not  have  any  plans  to  do  so  in  the  future.  Therefore,  we  use  an
expected dividend yield of zero.

Restricted Stock Units

The following table summarizes restricted stock unit activity under the 2014 Plan in the year ended December 31, 2021, and includes restricted stock units
with time or service-based vesting and those restricted stock units with performance-based vesting:

Non-vested restricted stock units at December 31, 2020

Granted
Vested
Forfeited

Non-vested restricted stock units at December 31, 2021

Number of
RSUs

Weighted-Average
Grant Date Fair
Value Per Share

158,626  $
4,144,051  $
(193,147) $
(580,848) $
3,528,682  $

5.64 
2.71 
6.39 
6.38 

2.04 

In  July  2018,  we  granted  0.9  million  PRSUs  to  our  employees  that  vested  upon  the  achievement  of  certain  performance  conditions,  subject  to  the
employees’ continued service relationship with us through the achievement date. During 2020, we granted an additional 30 thousand PRSUs subject to the
same  performance  conditions.  All  0.9  million  of  these  PRSUs  vested  in  September  2020.  None  of  these  PRSUs  vested  during  the  years  ended
December 31, 2019 or 2018. We recognized zero and $1.2 million of related expense during the years ended December 31, 2021 and 2020, respectively.

The  total  estimated  fair  value  of  RSUs  vested  during  the  years  ended  December  31,  2021,  2020  and  2019  was  $0.8  million,  zero  and  $0.2  million,
respectively.

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Issuance of Common Stock for Services

During the years ended December 31, 2021, 2020 and 2019, we issued approximately 26 thousand, 42 thousand and 113 thousand shares, respectively, of
common stock to members of the board of directors who elected to receive stock in lieu of their cash fees under our Non-Employee Director Compensation
Program. The shares issued during the years ended December 31, 2021, 2020 and 2019 were valued at $0.2 million, $0.3 million and $0.3 million for each
year, respectively, based on the fair value of the common stock on the date of grant.

Employee Stock Purchase Plan

We adopted the 2014 Employee Stock Purchase Plan (“ESPP”) and initially reserved approximately 0.2 million shares of common stock as of its effective
date of June 18, 2014. If approved by the Administrator of the ESPP, on the first day of each calendar year, ending in 2024, the number of shares in the
reserve  will  increase  by  an  amount  equal  to  the  lesser  of  (i)  one  percent  (1.0%)  of  the  shares  of  common  stock  outstanding  on  the  last  day  of  the
immediately preceding fiscal year and (ii) such number of shares of common stock as determined by the board of directors; provided, however, no more
than $2.2 million shares of our common stock may be issued under the ESPP.

The following table summarizes our ESPP activity during the year ended December 31, 2021:

Balance at December 31, 2020

Shares purchased

Balance at December 31, 2021

Shares Available
for Grant

Number of Shares
Purchased

Average Purchase Price
per Share

Gross Proceeds
(in thousands)

349,647 
(386,664)
898,982 

661,611 
386,664  $

1,048,275 

2.12  $

819 

The following table illustrates the weighted-average assumptions for the Black-Scholes option-pricing model used in determining the fair value of ESPP
purchase rights granted to our employees:

Expected term (years)
Expected volatility
Risk-free interest rate
Dividend yield

Stock-based Compensation Expense

Total stock-based compensation recognized was as follows (in thousands):

Research and development
General and administrative

Total

2021

Year Ended December 31,
2020

2019

0.50
123 %
0.65 %
— %

0.50
79 %
0.48 %
— %

0.50
69 %
2.00 %
— %

2021

Year Ended December 31,
2020

2019

$

$

4,116  $
7,923 
12,039  $

4,061  $
6,522 
10,583  $

4,104 
5,832 
9,936 

At December 31, 2021, the Company had total unrecognized stock-based compensation expense, net of estimated forfeitures, of the following (dollars in
thousands):

Stock options grant
RSU grants
ESPP

December 31, 2021

Unrecognized Compensation Expense

14,506 
2,262 
44 

Average Remaining Vesting Period
(Years)
2.4
0.8
0.1

$
$
$

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11.     RESTRUCTURING

On July 29, 2021, our Board of Directors approved, and on August 2, 2021, we began implementing a restructuring plan to better align our workforce and
anticipated  commercial  and  development  spend  with  our  capital  resources  and  the  needs  of  our  business  following  the  receipt  of  the  CRL.  Under  the
restructuring plan, we reduced our workforce by 83 employees (approximately 33%). Impacted employees received cash payments equal to their base pay
for a notice period of sixty (60) days and Company funded COBRA premiums through such notice period.

Following the conclusion of an End of Review Type A meeting with the FDA, on October 8, 2021, our Board of Directors approved and, on October 12,
2021,  we  began  to  implement  an  additional  restructuring  plan  to  further  reduce  operating  costs  and  better  align  our  workforce  with  the  needs  of  our
business. Under the additional restructuring plan, we planned to reduce our workforce by approximately 100 of our remaining employees (approximately
60%). The impacted employees received notice that their positions would be eliminated during December 2021.

On November 30, 2021, we announced plans to launch IBSRELA, our approved treatment for IBS-C in adults. In connection with the planned launch of
IBSRELA, which we currently expect to commence in April 2022, we retained 28 of the employees whose positions were originally eliminated as part of
the additional restructuring plan, thereby reducing the number of employees terminated as part of the restructuring plan to 72. The additional restructuring
plan,  which  resulted  in  the  elimination  of  our  research  organization  and  significantly  altered  our  commercial  sales  and  marketing  organizations,  was
substantially completed in December 2021.

Impacted  employees  were  eligible  to  receive  severance  benefits  and  additional  Company  funded  COBRA  premiums,  contingent  upon  an  impacted
employee’s  execution  (and  non-revocation)  of  a  separation  agreement,  which  included  a  general  release  of  claims  against  us.  In  connection  with
restructuring, we have incurred restructuring charges of $6.2 million, which were recorded during the twelve months ended December 31, 2021, related to
one-time termination notice and severance payments and other employee-related costs. We did not incur any significant contract termination costs pursuant
to  restructuring.  Of  the  charges,  $2.7  million  was  recorded  in  research  and  development  expenses,  and  $3.5  million  was  recorded  in  general  and
administrative  expense  in  the  accompanying  statements  of  operations  and  comprehensive  loss.  Most  of  the  cash  payments  related  to  the  reduction  in
workforce  were  disbursed  during  the  twelve  months  ended  December  31,  2021.  We  have  reported  the  remaining  estimated  restructuring  liability  of
$0.5 million as accrued compensation and benefits in our Balance Sheet as of December 31, 2021.

In addition, on October 8, 2021, our Board approved, and management has implemented a retention program consisting of cash payments and grants of
RSUs to our employees, including our executives, not impacted by the reduction in force.

12.     PROPERTY AND EQUIPMENT, NET

Property and equipment consist of the following (in thousands):

Laboratory equipment
Office equipment and furniture
Leasehold improvements

Property and equipment, gross
Less: accumulated depreciation

Total property and equipment, net

December 31,

2021

2020

$

$

7,474  $
2,034 
8,745 
18,253 
(15,891)

2,362  $

7,268 
1,133 
7,985 
16,386 
(14,450)
1,936 

We recognized depreciation expense in the amount of $1.4 million, $1.8 million, and $2.5 million for the years ended December 31, 2021, 2020 and 2019,
respectively.

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13.     ACCRUED EXPENSES AND OTHER CURRENT LIABILITIES

Accrued expenses and other current liabilities consist of the following (in thousands):

Accrued clinical expenses
Accrued contract manufacturing expenses
Derivative liability for exit fee
Accrued professional and consulting services
Accrued sales and marketing expenses
Accrued interest expense
Other

Total accrued expenses and other current liabilities

14.    INCOME TAXES

December 31,

2021

2020

$

$

2,522  $
2,485 
698 
597 
256 
203 
605 
7,366  $

2,197 
1,840 
1,376 
243 
593 
123 
285 
6,657 

2 
301 
303 

— 
— 
303 

The components of our provision for income taxes for the year ended December 31, 2021, 2020 and 2019, are as follows (in thousands):

Current:
State
Foreign
Total current

Deferred:
Federal
Total deferred

Provision for income taxes

Year Ended December 31,
2020

2021

2019

4  $

2  $

— 
4 

— 
— 

— 
2 

— 
— 

4  $

2  $

$

$

The following is a reconciliation of the statutory federal income tax rate to our effective tax rate:

Change in valuation allowance
Income tax at the federal statutory rate
Tax credits
State taxes, net of federal benefit
Stock based compensation
Executive compensation disallowed under IRC Sec 162(m)
Other

Income tax provision

97

Year Ended December 31,
2020

2021

2019

(20.0)%
21.0 
1.0 
0.4 
(1.3)
(1.1)
— 
— %

(22.3)%
21.0 
1.3 
0.7 
(0.1)
(0.5)
(0.1)

— %

(21.9)%
21.0 
1.6 
0.3 
(0.4)
(0.5)
(0.4)
(0.3)%

Table of Contents

Deferred income taxes reflect the tax effects of temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes
and the amounts used for income tax purposes. Significant components of our deferred tax assets are as follows as of December 31, 2021 and 2020 (in
thousands):

Deferred tax assets:

Amortization and depreciation
Net operating loss carryforwards
Tax credits
Stock-based compensation
Other

Gross deferred tax assets

Valuation allowance

Deferred tax assets net of valuation allowance

Deferred tax liabilities:
Right-of-use asset
Other

Net deferred tax assets

December 31,

2021

2020

$

$

61,098  $
74,989 
13,827 
4,054 
3,867 
157,835 
(155,141)
2,694 

(2,689)
(5)
—  $

51,370 
53,436 
11,777 
5,524 
1,804 
123,911 
(123,402)
509 

(479)
(30)
— 

Realization of deferred tax assets is dependent on future taxable income, if any, the timing and the amount of which are uncertain. We assess the available
positive and negative evidence to estimate whether sufficient future taxable income will be generated to permit use of the existing deferred tax assets. A
significant component of objective negative evidence evaluated was our cumulative loss incurred over the three-year period ended December 31, 2021.
Such objective evidence limits the ability to consider other subjective evidence, such as our projections for future growth. On the basis of this evaluation, as
of December 31, 2021, December 31, 2020 and December 31, 2019, a full valuation allowance has been recorded against our net deferred tax asset. The
amount of the deferred tax asset considered realizable, however, could be adjusted if estimates of future taxable income during the carryforward period are
reduced or increased or if objective negative evidence in the form of cumulative losses is no longer present and additional weight is given to subjective
evidence such as our projections for growth.

As  of  December  31,  2021,  we  had  net  operating  loss  carryforwards  for  federal  income  tax  purposes  of  approximately  $386.3  million,  of  which
approximately $236.1 million can be carried forward indefinitely and the remaining net operating losses expire beginning in 2030, if not utilized. Federal
research  and  development  tax  credit  carryforwards  of  approximately  $16.4  million  that  expire  beginning  in  2027,  if  not  utilized,  and  foreign  tax  credit
carryforwards of approximately $1.2 million that expire in 2027, if not utilized.

In addition, we had net operating loss carryforwards for California income tax purposes of approximately $88.3 million that expire beginning of 2030, if
not utilized, and state research and development tax credit carryforwards of approximately $8.4 million which can be carried forward indefinitely. We had
approximately $0.1 million of minimum tax credit carryovers for California income tax purposes. The minimum tax credits have no expiration date. We
had other state net operating losses of approximately $4.5 million that begin to expire in 2035.

The future utilization of net operating loss and tax credit carryforwards and credits may be subject to an annual limitation, pursuant to Internal Revenue
Code Sections 382 and 383, as a result of ownership changes that may have occurred previously or that could occur in the future. Due to the existence of
the valuation allowance, limitations under Section 382 and 383 will not impact our effective tax rate.

On March 27, 2020, the Coronavirus Aid, Relief, and Economic Security Act (“CARES Act”) was enacted and signed into law in response to coronavirus
disease 2019 (“COVID-19”). The CARES Act, among other things, included several significant provisions that impacted corporate taxpayers’ accounting
for income taxes. Prior to the enactment of the CARES Act, the 2017 Tax Cuts and Jobs Act generally eliminated the ability to carryback net operating
losses (“NOLs”), and permitted the NOLs arising in tax years beginning after December 31, 2018 to be carried forward indefinitely, limited to 80% of the
taxpayer’s income. The CARES Act amended the NOL rules, suspending the 80% limitation on the utilization of NOLs generated after December 31, 2018
and before January 1, 2021. Additionally, the CARES Act allows corporate NOLs arising in taxable years beginning after December 31, 2018 and before
January 1, 2021, to be carried back to each of the five taxable years preceding

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the taxable year of the loss. Also, the CARES Act allows companies to defer making certain payroll tax payments until future years. With the enactment of
the CARES Act, the company does not expect a financial statement impact from income taxes.

A reconciliation of the beginning and ending amount of unrecognized tax benefits is as follows (in thousands):

Balance at beginning of year
Additions (subtractions) based on tax positions related to prior year
Additions based on tax positions related to current year

Balance at end of year

2021

December 31,
2020

23,624  $
(811)
1,613 
24,426  $

24,538  $
(1,388)
474 
23,624  $

$

$

2019

23,052 
755 
731 
24,538 

We recognize a tax benefit from an uncertain tax position when it is more likely than not that the position will be sustained upon examination, including
resolutions of any related appeals or litigation processes, based on the technical merits. Income tax positions must meet a more likely than not recognition
at the effective date to be recognized. None of our unrecognized tax benefits would impact the effective tax rate if recognized, because the benefit would be
offset by an increase in the valuation allowance.

We have elected to include interest and penalties as a component of tax expense. During the years ended December 31, 2021, 2020 and 2019, we did not
recognize accrued interest and penalties related to unrecognized tax benefits. Although the timing and outcome of an income tax audit is highly uncertain,
we do not anticipate that the amount of existing unrecognized tax benefits will significantly change during the next 12 months.

We file income tax returns in the U.S. federal, Alabama, Arizona, California, Colorado, Connecticut, DC, Florida, Georgia, Idaho, Illinois, Indiana, Kansas,
Kentucky, Massachusetts, Maryland, Michigan, Missouri, Kansas City (MO), Mississippi, New York & New York MTA, New York City, Nebraska, New
Jersey,  New  Mexico,  North  Carolina,  Cincinnati  (OH),  Maineville  (OH),  Oklahoma,  Pennsylvania,  Tennessee,  Texas,  Virginia  and  Wisconsin  tax
jurisdictions. Due to our net operating loss and tax credit carryforwards, the income tax returns remain open to U.S. federal and state tax examinations. The
Company is not currently under examination in any tax jurisdiction.

15.    GEOGRAPHIC INFORMATION AND CONCENTRATIONS

Revenues are attributed to geographical areas based on the domicile of our collaboration partners. Our revenue by geographic areas for the years ended
December 31, 2021, 2020 and 2019, are as follows (in thousands):

United States
International:

North America (1)
Asia Pacific (2) (3)

Total revenue

2021

Year Ended December 31,
2020

—  $

—  $

2019

13 
10,084 
10,097  $

806 
6,765 
7,571  $

— 

— 
5,281 
5,281 

$

$

_________________________________
(1) Revenues from North America are comprised of amounts earned from Canada in accordance with the Knight Agreement.
(2) Revenues from Asia Pacific in 2021 and 2020 are comprised of amounts earned from Japan in accordance with the 2017 KKC Agreement and 2019

KKC Agreement.

(3) Revenues from Asia Pacific in 2019 were comprised of $0.8 million from Japan in accordance with the 2017 KKC Agreement and 2019 KKC

Agreement, $1.5 million from Hong Kong in accordance with the XuanZhu Agreement and $3.0 million from China in accordance with the Fosun
Agreement.

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Revenues recorded in the years ended December 31, 2021, 2020 and 2019, were wholly from collaboration partnerships. Collaboration partnerships
accounting for more than 10% of total revenues during the years ended December 31, 2021, 2020 and 2019 are as follows:

KKC
Knight
Fosun Pharma
XuanZhu

Year Ended December 31,
2020

2021

2019

100 %
— %
— %
— %

89 %
11 %
— %
— %

15 %
— %
57 %
28 %

Historically, we have not experienced credit losses from our accounts receivable. We have not recorded a reserve for credit losses as of December 31, 2021
and 2020.

16.    NET LOSS PER SHARE

Basic net loss per share is calculated by dividing net loss by the weighted-average number of common shares outstanding during the period, less shares
subject to repurchase, and excludes any dilutive effects of stock-based awards and warrants. Diluted net loss per common share is computed giving effect to
all potential dilutive common shares, including common stock issuable upon exercise of stock options, and unvested restricted common stock and stock
units. As we had net losses for the years ended December 31, 2021, 2020 and 2019, all potential common shares were determined to be anti-dilutive.

The following table sets forth the computation of net loss per common share (in thousands, except per share amounts):

Numerator:

Net loss
Denominator:

Weighted average common shares outstanding - basic and diluted

Net loss per share - basic and diluted

Year Ended December 31,
2020

2021

2019

(158,165) $

(94,313) $

(94,940)

104,205,645 

89,582,138 

64,478,066 

(1.52) $

(1.05) $

(1.47)

$

$

For the years ended December 31, 2021, 2020 and 2019, the total numbers of securities that could potentially dilute net income per share in the future that
were not considered in the diluted net loss per share calculations because the effect would have been anti-dilutive were as follows:

Options to purchase common stock
Restricted stock units
ESPP shares issuable
Warrants to purchase common stock
Performance-based restricted stock units

Total

Year Ended December 31,
2020
9,246,047 
26,121 
94,466 
932,091 
— 
10,298,725 

2021
11,870,778 
1,602,384 
206,522 
— 
— 
13,679,684 

2019
7,128,247 
— 
78,761 
2,172,899 
867,506 
10,247,413 

The number of potential common shares that would have been included in diluted income per share had it not been for the anti-dilutive effect caused by the
net  loss,  computed  by  converting  these  securities  using  the  treasury  stock  method  during  the  years  ended  December  31,  2021,  2020  and  2019,  was
approximately 1.1 million, 2.1 million and 1.1 million, respectively.

17.    COMMITMENTS AND CONTINGENCIES

Guarantees and Indemnifications

We indemnify each of our officers and directors for certain events or occurrences, subject to certain limits, while the officer or director is or was serving at
our request in such capacity, as permitted under Delaware law and in accordance with our

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certificate of incorporation and bylaws. The term of the indemnification period lasts as long as an officer or director may be subject to any proceeding
arising out of acts or omissions of such officer or director in such capacity.

The maximum amount of potential future indemnification is unlimited; however, we currently hold director and officer liability insurance, which allows the
transfer of risk associated with our exposure and may enable us to recover a portion of any future amounts paid. We believe that the fair value of these
indemnification obligations is minimal. Accordingly, we have not recognized any liabilities relating to these obligations for any period presented.

Legal Proceedings and Claims

From time to time we may be involved in claims arising in connection with our business. Based on information currently available, management believes
that the amount, or range, of reasonably possible losses in connection with any pending actions against us will not be material to our financial condition or
cash flows, and no contingent liabilities were accrued as of December 31, 2021 or 2020.

18.    SUBSEQUENT EVENTS

On February 23, 2022 (the “Closing Date”), we entered into a loan and security agreement (the “2022 Loan Agreement”) with SLR Investment Corp. as
collateral agent (the “Agent”), and the lenders listed in the 2022 Loan Agreement (collectively the “2022 Lenders”). The 2022 Loan Agreement provides
for a senior secured term loan facility, with $27.5 million (the “Term A Loan”) funded on the Closing Date and an additional $22.5 million that we may
borrow on or prior to July 25, 2023; provided that (i) we have received approval by the FDA for our NDA for the control of serum phosphorus in chronic
kidney disease patients on dialysis by December 31, 2022, and (ii) we have achieved certain product revenue milestone targets described in the 2022 Loan
Agreement (the “Term B Loan”, and collectively, the Term A Loan and the Term B Loan, the “2022 Term Loan”). The 2022 Term A Loan funds are being
used to repay the 2018 Term Loan with the Lenders as discussed in Note 6 - Borrowings and to fund our ongoing operations. We owed $25.0 million in
principal payments from the 2018 Term Loan as of the Closing Date. The 2022 Term Loan has a maturity date of March 1, 2027.

Borrowings under the 2022 Term Loan bear interest at a floating per annum rate equal to 7.95% plus the greater of (i) one tenth percent (0.10%) and (ii)
one-month LIBOR. We are permitted to make interest-only payments on the 2022 Term Loan through March 31, 2024. Accordingly, beginning on April 1,
2024, we will be required to make monthly payments of interest plus repay the 2022 Term Loan in consecutive equal monthly installments of principal. We
were obligated to pay $0.2 million, upon the closing of the Term A Loan, and we are obligated to pay $0.1 million on the earliest of (i) the funding date of
the Term B Loan, (ii) July 25, 2023, and (iii) the prepayment, refinancing, substitution, or replacement of the Term A Loan on or prior to July 25, 2023. We
are  obligated  to  pay  a  fee  equal  to  4.95%  of  the  aggregate  original  principal  amount  of  the  2022  Term  Loan  funded  upon  the  earliest  to  occur  of  the
maturity  date,  the  acceleration  of  the  2022  Term  Loan,  and  the  prepayment,  refinancing,  substitution,  or  replacement  of  the  2022  Term  Loan.  We  may
voluntarily prepay the outstanding 2022 Term Loan, subject to a prepayment premium of (i) 3% of the principal amount of the 2022 Term Loan if prepaid
prior to or on the first anniversary of the Closing Date, (ii) 2% of the principal amount of the 2022 Term Loan if prepaid after the first anniversary of the
Closing Date through and including the second anniversary of the Closing Date, or (iii) 1% of the principal amount of the 2022 Term Loan if prepaid after
the second anniversary of the Closing Date and prior to the maturity date. The 2022 Term Loan is secured by substantially all of our assets, except for our
intellectual property and certain other customary exclusions. Additionally, in connection with the 2022 Term Loan, we entered into an agreement, whereby
we agreed to pay an exit fee in the amount 2% of the 2022 Term Loan funded (the “2022 Exit Fee”) upon (i) any change of control transaction or (ii) our
achievement of net revenue from the sale of any products equal to or greater than $100.0 million, measured on a six (6) months basis, tested monthly at the
end of each month. Notwithstanding the prepayment or termination of the 2022 Term Loan, the 2022 Exit Fee will expire 10 years from the Closing Date.

The 2022 Loan Agreement contains customary representations and warranties and customary affirmative and negative covenants, including, among others,
requirements as to financial reporting and insurance and restrictions on our ability to dispose of our business or property, to change our line of business, to
liquidate or dissolve, to enter into any change in control transaction, to merge or consolidate with any other entity or to acquire all or substantially all the
capital stock or property of another entity, to incur additional indebtedness, to incur liens on our property, to pay any dividends or other distributions on
capital stock other than dividends payable solely in capital stock or to redeem capital stock. We have agreed to not allow our cash and cash equivalents to
be less than the eighty percent (80%) of the outstanding 2022 Term Loan balance for any period in which our net revenue from the sale of any products,
calculated on a trailing six (6) month basis and tested monthly, is less than sixty percent (60%) of the outstanding 2022 Term Loan balance.

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In  addition,  the  2022  Loan  Agreement  contains  customary  events  of  default  that  entitle  the  Agent  to  cause  our  indebtedness  under  the  2022  Loan
Agreement to become immediately due and payable, and to exercise remedies against us and the collateral securing the 2022 Term Loan, including our
cash. Under the 2022 Loan Agreement, an event of default will occur if, among other things, we fail to make payments under the 2022 Loan Agreement,
we  breach  any  of  our  covenants  under  the  2022  Loan  Agreement,  subject  to  specified  cure  periods  with  respect  to  certain  breaches,  certain  Lenders
determine that a material adverse change has occurred, we or our assets become subject to certain legal proceedings, such as bankruptcy proceedings, we
are unable to pay our debts as they become due or we default on contracts with third parties which would permit the holder of indebtedness to accelerate
the maturity of such indebtedness or that could have a material adverse change on us. Upon the occurrence and for the duration of an event of default, an
additional default interest rate equal to 4% per annum will apply to all obligations owed under the 2022 Loan Agreement.

ITEM 9.    CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE

None.

ITEM 9A.    CONTROLS AND PROCEDURES

Conclusions Regarding the Effectiveness of Disclosure Controls and Procedures

As of December 31, 2021, management, with the participation of our Chief Executive Officer and Chief Financial Officer, performed an evaluation of the
effectiveness of the design and operation of our disclosure controls and procedures as defined in Rules 13a-15(e) and 15d-15(e) of the Exchange Act. Our
disclosure controls and procedures are designed to ensure that information required to be disclosed in the reports we file or submit under the Exchange Act
is recorded, processed, summarized and reported within the time periods specified in the Securities and Exchange Commission’s rules and forms, and that
such information is accumulated and communicated to our management, including the Chief Executive Officer and the Chief Financial Officer, to allow
timely decisions regarding required disclosures.

Any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving the desired control objective
and management necessarily applies its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on this evaluation,
our Chief Executive Officer and Chief Financial Officer concluded that, as of December 31, 2021, the design and operation of our disclosure controls and
procedures were effective at a reasonable assurance level.

Management’s Annual Report on Internal Control Over Financial Reporting

Our management is responsible for establishing and maintaining adequate internal control over financial reporting. Internal control over financial reporting
is  a  process  designed  by,  or  under  the  supervision  of,  our  CEO  and  CFO,  and  effected  by  our  Board  of  Directors,  management  and  other  personnel,  to
provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance
with generally accepted accounting principles and includes those policies and procedures that:

•

•

•

Pertain  to  the  maintenance  of  records  that  accurately  and  fairly  reflect  in  reasonable  detail  the  transactions  and  dispositions  of  the  assets  of  our
company;

Provide  reasonable  assurance  that  transactions  are  recorded  as  necessary  to  permit  preparation  of  financial  statements  in  accordance  with  generally
accepted accounting principles, and that our receipts and expenditures are being made only in accordance with authorizations of our management and
directors; and

Provide reasonable assurances regarding prevention or timely detection of unauthorized acquisition, use or disposition of our assets that could have a
material adverse effect on our financial statements.

Our management assessed our internal control over financial reporting as of December 31, 2021, the end of the period covered by this Annual Report on
Form  10-K.  Management  based  its  assessment  on  criteria  established  in  “Internal  Control—Integrated  Framework  (2013)”  issued  by  the  Committee  of
Sponsoring Organizations of the Treadway Commission. Based on management’s assessment of our internal control over financial reporting, management
concluded that, as of December 31, 2021, our internal control over financial reporting was effective.

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Changes in Internal Control over Financial Reporting

There were no changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) during the
quarter ended December 31, 2021 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

Attestation Report of Independent Registered Public Accounting Firm

Our independent registered public accounting firm, Ernst & Young LLP, has audited our Financial Statements included in Item 8 of this Annual Report on
Form 10-K and have issued a report on our internal control over financial reporting as of December 31, 2021. Their report on the audit of internal control
over financial reporting appears below.

To the Stockholders and the Board of Directors of Ardelyx, Inc.
Opinion on Internal Control over Financial Reporting

Report of Independent Registered Public Accounting Firm

We  have  audited  Ardelyx,  Inc.’s  internal  control  over  financial  reporting  as  of  December  31,  2021,  based  on  criteria  established  in  Internal  Control—
Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (“the COSO criteria”). In our
opinion, Ardelyx, Inc. (“the Company”) maintained, in all material respects, effective internal control over financial reporting as of December 31, 2021,
based on the COSO criteria.
We  also  have  audited,  in  accordance  with  the  standards  of  the  Public  Company  Accounting  Oversight  Board  (United  States)  (“PCAOB”),  the  balance
sheets of the Company as of December 31, 2021 and 2020, the related statements of operations and comprehensive loss, stockholders’ equity, and cash
flows  for  each  of  the  three  years  in  the  period  ended  December  31,  2021,  and  the  related  notes  and  our  report  dated  February  28,  2022  expressed  an
unqualified opinion thereon that included an explanatory paragraph regarding the Company’s ability to continue as a going concern.

Basis for Opinion

The Company’s management is responsible for maintaining effective internal control over financial reporting and for its assessment of the effectiveness of
internal control over financial reporting included in the accompanying Management's Annual Report on Internal Control Over Financial Reporting. Our
responsibility  is  to  express  an  opinion  on  the  Company’s  internal  control  over  financial  reporting  based  on  our  audit.  We  are  a  public  accounting  firm
registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the
applicable rules and regulations of the Securities 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 effective internal control over financial reporting was maintained in all material respects.

Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, testing and
evaluating the design and operating effectiveness 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.

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Definition and Limitations of Internal Control Over Financial Reporting

A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting
and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control
over financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly
reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit
preparation  of  financial  statements  in  accordance  with  generally  accepted  accounting  principles,  and  that  receipts  and  expenditures  of  the  company  are
being  made  only  in  accordance  with  authorizations  of  management  and  directors  of  the  company;  and  (3)  provide  reasonable  assurance  regarding
prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial
statements.

Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of
effectiveness  to  future  periods  are  subject  to  the  risk  that  controls  may  become  inadequate  because  of  changes  in  conditions,  or  that  the  degree  of
compliance with the policies or procedures may deteriorate.

/s/ Ernst & Young LLP

Redwood City, California

February 28, 2022

ITEM 9B.    OTHER INFORMATION

None.

ITEM 9C.    DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS

Not Applicable.

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ITEM 10.    DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE

PART III

Information required by this item will be contained in our definitive proxy statement to be filed with the Securities and Exchange Commission on Schedule
14A in connection with our 2022 Annual Meeting of Stockholders (the “Proxy Statement”), which will be filed not later than 120 days after the end of our
fiscal  year  ended  December  31,  2021,  under  the  headings  “Executive  Officers,”  “Election  of  Directors,”  “Corporate  Governance,”  and  “
Section 16(a) Beneficial Ownership Reporting Compliance,” and is incorporated herein by reference.

We  have  adopted  a  Code  of  Business  Conduct  and  Ethics  that  applies  to  our  officers,  directors  and  employees  which  is  available  on  our  website  at
www.ardelyx.com.  The  Code  of  Business  Conduct  and  Ethics  is  intended  to  qualify  as  a  “code  of  ethics”  within  the  meaning  of  Section  406  of  the
Sarbanes-Oxley Act of 2002 and Item 406 of Regulation S-K. In addition, we intend to promptly disclose (1) the nature of any amendment to our Code of
Business Conduct and Ethics that applies to our principal executive officer, principal financial officer, principal accounting officer or controller or persons
performing similar functions and (2) the nature of any waiver, including an implicit waiver, from a provision of our code of ethics that is granted to one of
these specified officers, the name of such person who is granted the waiver and the date of the waiver on our website in the future.

ITEM 11.    EXECUTIVE COMPENSATION

The information required by this item regarding executive compensation will be incorporated by reference to the information set forth in the sections titled
“Executive Compensation” in our Proxy Statement.

ITEM 12.    SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER

MATTERS

The information required by this item regarding security ownership of certain beneficial owners and management will be incorporated by reference to the
information  set  forth  in  the  section  titled  “Security  Ownership  of  Certain  Beneficial  Owners  and  Management”  and  “Equity  Compensation  Plan
Information” in our Proxy Statement.

ITEM 13.    CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS, AND DIRECTOR INDEPENDENCE

The information required by this item regarding certain relationships and related transactions and director independence will be incorporated by reference
to the information set forth in the sections titled “Certain Relationships and Related Party Transactions” and “Election of Directors”, respectively, in our
Proxy Statement.

ITEM 14.    PRINCIPAL ACCOUNTING FEES AND SERVICES

The information required by this item regarding principal accountant fees and services will be incorporated by reference to the information set forth in the
section titled “Principal Accountant Fees and Services” in our Proxy Statement.

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PART IV

ITEM 15.    EXHIBITS, FINANCIAL STATEMENT SCHEDULES

(a) The following documents are filed as part of this report:

1. Financial Statements

See Index to Financial Statements at Item 8 herein.

2. Financial Statement Schedules

All  schedules  are  omitted  because  they  are  not  applicable  or  the  required  information  is  shown  in  the  financial  statements  or  notes

thereto.

3. Exhibits

See the Exhibit Index immediately following this page.

ITEM 16.    FORM 10-K SUMMARY

None.

Exhibit
Number

3.1

3.2

4.1

4.2

4.4

10.1

10.2

10.3(a)

10.3(b)

10.3(c)

10.3(d)

10.3(e)

10.4(a)#

10.4(b)#

10.4(c)#

Exhibit Index

Form

8-K

8-K

Incorporated by Reference

Date

Number

Filed
Herewith

Amended and Restated Certificate of Incorporation

Exhibit Description

Amended and Restated Bylaws

Reference is made to Exhibits 3.1 and 3.2

Form of Common Stock Certificate

Description of the Registrant’s Securities Registered Pursuant to Section 12 of the
Securities Exchange Act of 1934

Termination Agreement, dated June 2, 2015, by and between AstraZeneca AB and
Ardelyx, Inc.

Amendment No. 1 to Termination Agreement and to Manufacturing and Supply
Agreement, dated November 2, 2015 by and between AstraZeneca AB and
Ardelyx, Inc.

Lease, dated August 8, 2008, by and between 34175 Ardenwood Venture, LLC and
Ardelyx, Inc.

First Amendment to Lease, dated December 20, 2012, by and between 34175
Ardenwood Venture, LLC and Ardelyx, Inc.

Second Amendment to Lease, dated September 5, 2014, by and between
Ardelyx, Inc. and 34175 Ardenwood Venture, LLC

Third Amendment to Lease, dated April 28, 2016, by and between Ardelyx, Inc. and
34175 Ardenwood Venture, LLC

Fifth Amendment to Lease, dated May 25, 2021, by and between Ardelyx, Inc. and
34175 Ardenwood Venture, LLC

Ardelyx, Inc. 2008 Stock Incentive Plan, as amended

Form of Stock Option Grant Notice and Stock Option Agreement under the 2008
Stock Incentive Plan, as amended

Form of Restricted Stock Purchase Grant Notice and Restricted Stock Purchase
Agreement under the 2008 Stock Incentive Plan, as amended

6/24/2014

6/24/2014

S-1/A

10-K

6/18/2014

3/8/2021

3.1

3.2

4.2

4.4

10-Q

8/12/2015

10.1

10-K

3/4/2016

10.1(d)

S-1

S-1

5/19/2014

10.4(a)

5/19/2014

10.4(b)

8-K

9/9/2014

10-Q

8/8/2016

8-K

6/1/2021

10.1

10.3

10.1

S-1

S-1

S-1

S-8

5/19/2014

5/19/2014

10.5(a)

10.5(b)

5/19/2014

10.5(c)

7/14/2014

99.3

10.5(a)#

Ardelyx, Inc. 2014 Equity Incentive Award Plan

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Table of Contents

Exhibit
Number

10.5(b)#

10.5(c)#

10.6#

10.7#

10.8#

10.9#

10.11#

10.12#

10.13#

10.14#

10.15#

10.16#

10.17#

10.18#

10.19#

10.20#

10.21#

10.22#

10.23#

10.24(a)#

10.24(b)#

10.24(c)#

10.25

10.26

10.27(a)#

10.27(b)#

10.27(c)#

Exhibit Description

Form of Stock Option Grant Notice and Stock Option Agreement under the 2014
Equity Incentive Award Plan

Form of Restricted Stock Award Agreement and Restricted Stock Unit Award Grant
Notice under the 2014 Equity Incentive Award Plan

Form of Indemnification Agreement for directors and officers

Amended and Restated Executive Employment Agreement, dated June 6, 2014, by
and between Ardelyx, Inc. and Michael Raab

Retention Agreement, dated October 25, 2021, by and between Ardelyx, Inc. and
Mike Raab

Offer Letter, dated December 28, 2009, by and between Ardelyx, Inc. and David
Rosenbaum, Ph.D.

Second Amended and Restated Change in Control and Severance Agreement by and
between Ardelyx, Inc. and David P. Rosenbaum, Ph.D.

Offer Letter, dated November 21, 2012, by and between Ardelyx, Inc. and Elizabeth
Grammer, Esq.

Second Amended and Restated Change in Control and Severance Agreement by and
between Ardelyx, Inc. and Elizabeth Grammer.

Offer Letter, dated April 27, 2020, by and between Ardelyx, Inc. and Susan
Rodriguez

Change in Control Severance Agreement dated June 2, 2020, by and between
Ardelyx, Inc. and Susan Rodriguez

Retention Agreement, dated October 25, 2021, by and between Ardelyx, Inc. and
Susan Rodriguez

Offer Letter, dated June 2, 2020, by and between Ardelyx, Inc. and Justin Renz

Change in Control Severance Agreement, dated June 8, 2020, by and between
Ardelyx, Inc. and Justin Renz

Retention Agreement, dated October 25, 2021, by and between Ardelyx, Inc. and
Justin Renz

Amendment Number One to Second Amended and Restated Change in Control
Severance Agreement and Retention Agreement dated December 1, 2021 between
Ardelyx, Inc. and David Rosenbaum

Form of Executive Retention Agreement Version 1

Form of Executive Retention Agreement Version 2

Ardelyx, Inc. 2014 Employee Stock Purchase Plan

Non-Employee Director Compensation Program

Description of amendments to Non-Employee Director Compensation Program

Amended and Restated Non-Employee Director Compensation Program.

Registration Rights Agreement by and among Ardelyx, Inc. and the investors
signatory thereto, dated June 2, 2015

Registration Rights Agreement by and among Ardelyx, Inc. and the investors
signatory thereto, dated July 14, 2016

Ardelyx, Inc. 2016 Employment Commencement Incentive Plan

Form of Stock Option Grant Notice and Stock Option Agreement under the 2016
Employment Commencement Incentive Plan

Form of Restricted Stock Unit Award Grant Notice and Restricted Stock Unit Award
Agreement under the 2016 Employment Commencement Incentive Plan

107

Incorporated by Reference

Form

S-1/A

Date

6/9/2014

Number

10.6(b)

Filed
Herewith

S-1/A

6/9/2014

10.6(c)

S-1/A

S-1/A

6/9/2014

6/9/2014

10.7

10.8

S-1/A

6/9/2014

10.13

10-Q

5/8/2018

10.10

S-1/A

6/9/2014

10.14

10-Q

5/8/2018

10.00

10-Q

8/6/2020

10.10

10-Q

8/6/2020

0.01

10-Q

10-Q

8/6/2020

8/6/2020

10.30

10.40

X

X

X

X

X

X

S-8

S-1/A

8-K

10-Q

S-3

7/14/2014

6/9/2014

3/9/2017

5/7/2019

7/13/2015

10-Q

8/8/2016

11/10/2016

11/10/2016

S-8

S-8

S-8

11/10/2016

99.3

99.6

10.21

N/A

10.1

99.1

10.2

99.1

99.2

Table of Contents

Exhibit
Number

10.27(d)#

10.28††

10.29††

10.30

10.31††

10.32

10.33

23.1

31.1

31.2

32.1

Form of Restricted Stock Award Grant Notice and Restricted Stock Award
Agreement under the 2016 Employment Commencement Incentive Plan

Exhibit Description

Incorporated by Reference

Form

S-8

Date

11/10/2016

Number

99.4

Filed
Herewith

License Agreement, dated November 27, 2017, by and between Kyowa Hakko Kirin
Co. , Ltd. and Ardelyx, Inc.

10-K

3/14/2018

10.35

License Agreement, dated December 11, 2017, by and between Shanghai Fosun
Pharmaceutical Industrial Development Co. Ltd. and Ardelyx, Inc.

Exit Fee Agreement, dated May 16, 2018, by and between the Company and Solar
Capital Ltd. and Western Alliance Bank.  

Manufacturing Services Agreement, dated May 18, 2020, between Ardelyx, Inc. and
Patheon Pharmaceuticals Inc.

Lease Agreement, dated December 30, 2020, by and between Ardelyx, Inc. and
Prospect Fifth Ave, LLC.

Open Market Sales Agreement, dated August 31, 2021 between Ardelyx, Inc. and
Jefferies LLC.

Consent of Independent Registered Public Accounting Firm

Certification of Principal Executive Officer Required Under Rule 13a-14(a) and 15d-
14(a) of the Securities Exchange Act of 1934, as amended

Certification of Principal Financial Officer Required Under Rule 13a-14(a) and 15d-
14(a) of the Securities Exchange Act of 1934, as amended

Certification of Principal Executive Officer and Principal Financial Officer Required
Under Rule 13a‑14(b) of the Securities Exchange Act of 1934, as amended, and 18
U.S.C §1350

101.SCH

101.CAL

101.DEF

101.LAB

101.PRE

Inline XBRL Taxonomy Extension Schema Document

Inline XBRL Taxonomy Extension Calculation Linkbase Document

Inline XBRL Taxonomy Extension Definition Linkbase Document

Inline XBRL Taxonomy Extension Label Linkbase Document

Inline XBRL Taxonomy Extension Presentation Linkbase Document

_______________________________

10-K

3/14/2018

10.36

10-Q

8/7/2018

10-Q

8/6/2020

10.2

10.5

10-K

3/8/2021

10.31

8-K

8/17/2021

10.1

—

—

—

—

—

—

—

—

—

X

X

X

X

X

X

X

X

X

†    Confidential treatment granted as to portions of this Exhibit. The confidential portions of this Exhibit have been omitted and are marked by asterisks.

††    Certain portions have been omitted pursuant to a confidential treatment request. Omitted information has been filed separately with the Securities and

Exchange Commission.

#    Indicates management contract or compensatory plan.

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Table of Contents

Pursuant  to  the  requirements  of  the  Securities  Exchange  Act  of  1934,  the  Registrant  has  duly  caused  this  report  to  be  signed  on  its  behalf  by  the
undersigned, thereunto duly authorized.

SIGNATURES

Date: February 28, 2022

By:

/s/ Michael Raab

Ardelyx, Inc.

Michael Raab
President Chief Executive Officer and Director
(Principal Executive Officer)

POWER OF ATTORNEY

Each person whose individual signature appears below hereby authorizes and appoints Michael Raab and Justin Renz, and each of them, with full power of
substitution and resubstitution and full power to act without the other, as his or her true and lawful attorney-in-fact and agent to act in his or her name, place
and stead and to execute in the name and on behalf of each person, individually and in each capacity stated below, and to file any and all amendments to
this  annual  report  on  Form  10-K  and  to  file  the  same,  with  all  exhibits  thereto,  and  other  documents  in  connection  therewith,  with  the  Securities  and
Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act
and thing, ratifying and confirming all that said attorneys-in-fact and agents or any of them or their or his substitute or substitutes may lawfully do or cause
to be done by virtue thereof.

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Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the registrant
and in the capacities and on the dates indicated.

Signature

/s/ Michael Raab

Michael Raab

/s/ Justin Renz

Justin Renz

/s/ David Mott

David Mott

/s/ Robert Bazemore

Robert Bazemore

/s/ William Bertrand, Jr.

William Bertrand, Jr., J.D.

/s/ Muna Bhanji

Muna Bhanji, R.Ph

/s/ Geoffrey A. Block

Geoffrey A. Block, M.D.

/s/ Onaiza Cadoret-Manier

Onaiza Cadoret-Manier

/s/ Jan M. Lundberg

Jan M. Lundberg, Ph.D.

/s/ Richard Rodgers

Richard Rodgers

Title

Date

President, Chief Executive Officer and Director
(Principal Executive Officer)

Chief Financial Officer
(Principal Financial and Accounting Officer)

February 28, 2022

February 28, 2022

Chairman of the Board of Directors

February 28, 2022

February 28, 2022

February 28, 2022

February 28, 2022

February 28, 2022

February 28, 2022

February 28, 2022

February 28, 2022

Director

Director

Director

Director

Director

Director

Director

110

Exhibit 10.8

RETENTION AGREEMENT

This Retention Agreement (“Agreement”) is made and entered into by and between Ardelyx, Inc. (“Company”)

and Michael Raab (“Executive”), effective as of October 25, 2021 (“Effective Date”).

Recitals

A.

 The Company and the Board of Directors of the Company (“Board”) has determined that it is in the best

interests of the Company and its stockholders to execute a second reduction in force in order to reduce operating costs and better
align the Company’s workforce with the needs of the business following the receipt of a complete response letter (“CRL”) from
the U.S. Food and Drug Administration (“FDA”) on July 28, 2021. 

B.

The Board has determined that it is in the best interests of the Company and the stockholders to put in
place arrangements designed to provide that the Company will have the continued dedication and commitment of Executive,
notwithstanding the reduction in force, and to provide Executive with an incentive to continue Executive’s employment and
further align Executive’s incentives to maximize the value of the Company for the benefit of its stockholders. 

C.

The Executive and the Company are parties to that certain Executive Employment Agreement dated as of

February 17, 2009 (“Severance Agreement”). Capitalized terms not defined herein shall have the meaning assigned to them in the
Severance Agreement.

The parties hereto agree as follows:

1

2

Severance Agreement. Except as specifically modified by the provisions of this Agreement, the Severance Agreement shall
remain in full force and effect.
2021 Annual Bonus.
The Compensation Committee of the Board previously set the Executive’s annual target bonus for fiscal year 2021 at an
amount equal to sixty percent (60%) of the Executive’s base salary (“2021 Annual Bonus”). As an incentive to continue
Executive’s employment with the Company, subject to the terms of this Agreement, the Executive’s 2021 Annual Bonus shall
be earned and paid as follows: (a) fifty percent (50%) of the 2021 Annual Bonus shall be earned on the date in January 2022
when the Company pays annual bonuses to its employees, and (b) fifty percent (50%) of the 2021 Annual Bonus shall be
earned following the achievement of the 2021 Annual Bonus milestone described on Exhibit A hereto; provided, however,
that the second fifty percent (50%) of the 2021 Annual Bonus will not be earned earlier than April 1, 2022. 
The Executive shall not earn a portion of the 2021 Annual Bonus if the Executive voluntarily terminates his employment with
the Company for any reason or the Company terminates his employment for Cause prior to the date that such portion of the
2021 Annual Bonus is earned. 
Each portion of the 2021 Annual Bonus shall be paid in full, less applicable withholdings, as soon as practicable following
the date on which it is earned. 

3 Restricted Stock Unit

|

On October 8, 2021, the Company granted the Executive 300,000 restricted stock units (“RSUs”). The Executive has been or
will be provided with a Restricted Stock Unit Award Grant Notice (“Notice”) which sets forth the details of the RSUs and
provides the terms and conditions of the grant. Subject to the provisions of this Agreement and the Notice, the RSUs will vest
in full on the earliest of (a) June 1, 2022, (b) the closing of a Change in Control or (c) the date the Executive’s employment
with the Company is terminated by the Company without Cause , in each case, subject to the Executive remaining an
employee of the Company through such applicable vesting date.

4 Cash Bonus

The Executive shall earn a retention bonus in the aggregate amount of $300,000, subject to applicable tax withholding (“Cash
Bonus”) on the earliest of (a) the date of the achievement of the Cash Bonus milestone set forth on Exhibit A, (b) the closing
of a Change in Control or (c) the date the Executive’s employment with the Company is terminated by the Company without
Cause, subject to the Executive’s continued employment with the Company through such earliest date.
The Executive shall not earn the Cash Bonus if the Executive voluntarily terminates his employment with the Company or the
Company terminates the Executive’s employment for Cause prior to the date that the Cash Bonus is earned. 
The Cash Bonus shall be paid in full, less applicable withholdings, as soon as practicable following the date on which it is
earned. 

5 Nature of Agreement This Agreement is not a contract of employment for any specified term. Nothing contained in this

6

7

Agreement shall confer upon Executive any right to continue in the employ of the Company or interfere in any way with the
at-will nature of Executive’s employment with the Company (it being understood and agreed that (so long as it is done in
accordance with applicable law) the Company may terminate Executive’s employment at any time for any reason or for no
reason and that Executive may terminate his/her employment with the Company at any time for any reason or for no reason).
Full Agreement This Agreement, together with the Notice and the Severance Agreement referenced herein constitutes the
entire agreement of the parties with respect to the subject matter hereof, and supersedes all prior and contemporaneous
discussions, negotiations, or understandings, written or oral, relating thereto. This Agreement may not be amended or
modified except in a writing signed by both Executive and an authorized representative of the Company. 
Successors
Any successor to the Company (whether direct or indirect and whether by purchase, merger, consolidation, liquidation or
otherwise) to all or substantially all of the Company’s business and/or assets shall assume the obligations under this
Agreement and agree expressly to perform the obligations under this Agreement in the same manner and to the same extent as
the Company would be required to perform such obligations in the absence of a succession. For all purposes under this
Agreement, the term “Company” shall include any successor to the Company’s business and/or assets which executes and
delivers the assumption agreement described in the Severance Agreement or which becomes bound by the terms of this
Agreement by operation of law.

| ||

2

The terms of this Agreement and all rights of Executive hereunder shall inure to the benefit of, and be enforceable by,
Executive’s personal or legal representatives, executors, administrators, successors, heirs, distributees, devisees and legatees.

8 Choice of Law and Severability The validity, interpretation, construction and performance of this Agreement shall be
governed by the laws of the State of California. The invalidity or unenforceability of any provision or provisions of this
Agreement shall not affect the validity or enforceability of any other provision hereof, which shall remain in full force and
effect.

9 Date of Signature This Agreement shall be conveyed to Executive via DocuSign and in order to be effective, it must be

signed by Executive and delivered to the Company no later than November 15, 2021. Executive may elect to electronically
execute this Agreement using the DocuSign link provided, in which case this Agreement shall be automatically delivered to
Kelli Shaa and Mishu Nitulescu in Human Resources upon execution. Alternatively, Executive may elect to manually sign
this Agreement provided that such signature is delivered to Kelli Shaa in Human Resources no later than November 15,
2021.

Michael Raab

       /s/ Michael Raab

Signature

October 23, 2021
Dated

Ardelyx, Inc.

By:/s/ Elizabeth Grammer

Title: Chief Legal and Administrative Officer

Dated:October 23, 2021

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3

Exhibit 10.16

RETENTION AGREEMENT

This Retention Agreement (“Agreement”) is made and entered into by and between Ardelyx, Inc. (“Company”)

and Susan Rodriguez (“Executive”), effective as of October 25, 2021 (“Effective Date”).

Recitals

A.

 The Company and the Board of Directors of the Company (“Board”) has determined that it is in the best

interests of the Company and its stockholders to execute a second reduction in force in order to reduce operating costs and better
align the Company’s workforce with the needs of the business following the receipt of a complete response letter (“CRL”) from
the U.S. Food and Drug Administration (“FDA”) on July 28, 2021. 

B.

The Board has determined that it is in the best interests of the Company and the stockholders to put in
place arrangements designed to provide that the Company will have the continued dedication and commitment of Executive,
notwithstanding the reduction in force, and to provide Executive with an incentive to continue Executive’s employment and
further align Executive’s incentives to maximize the value of the Company for the benefit of its stockholders. 

C.

The Executive and the Company are parties to that certain Change in Control Severance Agreement dated
as of May 18, 2020 (“Severance Agreement”). Capitalized terms not defined herein shall have the meaning assigned to them in
the Severance Agreement.

The parties hereto agree as follows:

1

2

Severance Agreement. Except as specifically modified by the provisions of this Agreement, the Severance Agreement shall
remain in full force and effect.
2021 Annual Bonus.
The Compensation Committee of the Board previously set the Executive’s annual target bonus for fiscal year 2021 at an
amount equal to forty percent (40%) of the Executive’s base salary (“2021 Annual Bonus”). As an incentive to continue
Executive’s employment with the Company, subject to the terms of this Agreement, the Executive’s 2021 Annual Bonus shall
be earned and paid as follows: (a) fifty percent (50%) of the 2021 Annual Bonus shall be earned on the date in January 2022
when the Company pays annual bonuses to its employees, and (b) fifty percent (50%) of the 2021 Annual Bonus shall be
earned following the achievement of the 2021 Annual Bonus milestone described on Exhibit A hereto; provided, however,
that the second fifty percent (50%) of the 2021 Annual Bonus will not be earned earlier than April 1, 2022. 
The Executive shall not earn a portion of the 2021 Annual Bonus if the Executive voluntarily terminates her employment
with the Company for any reason or the Company terminates her employment for Cause prior to the date that such portion of
the 2021 Annual Bonus is earned. 
Each portion of the 2021 Annual Bonus shall be paid in full, less applicable withholdings, as soon as practicable following
the date on which it is earned. 

3 Restricted Stock Unit

|

On October 8, 2021, the Company granted the Executive 150,000 restricted stock units (“RSUs”). The Executive has been or
will be provided with a Restricted Stock Unit Award Grant Notice (“Notice”) which sets forth the details of the RSUs and
provides the terms and conditions of the grant. Subject to the provisions of this Agreement and the Notice, the RSUs will vest
in full on the earliest of (a) June 1, 2022, (b) the closing of a Change in Control or (c) the date the Executive’s employment
with the Company is terminated by the Company without Cause , in each case, subject to the Executive remaining an
employee of the Company through such applicable vesting date.

4 Cash Bonus

The Executive shall earn a retention bonus in the aggregate amount of $150,000, subject to applicable tax withholding (“Cash
Bonus”) on the earliest of (a) the date of the achievement of the Cash Bonus milestone set forth on Exhibit A, (b) the closing
of a Change in Control or (c) the date the Executive’s employment with the Company is terminated by the Company without
Cause, subject to the Executive’s continued employment with the Company through such earliest date.
The Executive shall not earn the Cash Bonus if the Executive voluntarily terminates her employment with the Company or
the Company terminates the Executive’s employment for Cause prior to the date that the Cash Bonus is earned. 
The Cash Bonus shall be paid in full, less applicable withholdings, as soon as practicable following the date on which it is
earned. 

5 Nature of Agreement This Agreement is not a contract of employment for any specified term. Nothing contained in this

6

7

Agreement shall confer upon Executive any right to continue in the employ of the Company or interfere in any way with the
at-will nature of Executive’s employment with the Company (it being understood and agreed that (so long as it is done in
accordance with applicable law) the Company may terminate Executive’s employment at any time for any reason or for no
reason and that Executive may terminate his/her employment with the Company at any time for any reason or for no reason).
Full Agreement This Agreement, together with the Notice and the Severance Agreement referenced herein constitutes the
entire agreement of the parties with respect to the subject matter hereof, and supersedes all prior and contemporaneous
discussions, negotiations, or understandings, written or oral, relating thereto. This Agreement may not be amended or
modified except in a writing signed by both Executive and an authorized representative of the Company. 
Successors
Any successor to the Company (whether direct or indirect and whether by purchase, merger, consolidation, liquidation or
otherwise) to all or substantially all of the Company’s business and/or assets shall assume the obligations under this
Agreement and agree expressly to perform the obligations under this Agreement in the same manner and to the same extent as
the Company would be required to perform such obligations in the absence of a succession. For all purposes under this
Agreement, the term “Company” shall include any successor to the Company’s business and/or assets which executes and
delivers the assumption agreement described in the Severance Agreement or which becomes bound by the terms of this
Agreement by operation of law.

| ||

2

The terms of this Agreement and all rights of Executive hereunder shall inure to the benefit of, and be enforceable by,
Executive’s personal or legal representatives, executors, administrators, successors, heirs, distributees, devisees and legatees.

8 Choice of Law and Severability The validity, interpretation, construction and performance of this Agreement shall be
governed by the laws of the State of California. The invalidity or unenforceability of any provision or provisions of this
Agreement shall not affect the validity or enforceability of any other provision hereof, which shall remain in full force and
effect.

9 Date of Signature This Agreement shall be conveyed to Executive via DocuSign and in order to be effective, it must be

signed by Executive and delivered to the Company no later than November 15, 2021. Executive may elect to electronically
execute this Agreement using the DocuSign link provided, in which case this Agreement shall be automatically delivered to
Kelli Shaa and Mishu Nitulescu in Human Resources upon execution. Alternatively, Executive may elect to manually sign
this Agreement provided that such signature is delivered to Kelli Shaa in Human Resources no later than November 15,
2021.

Susan Rodriguez

        /s/ Susan Rodriguez

Signature

October 25, 2021
Dated

Ardelyx, Inc.

By: /s/ Michael Raab

Title: Chief Executive Officer

Dated: October 23, 2021

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3

Exhibit 10.19

RETENTION AGREEMENT

and Justin Renz (“Executive”), effective as of October 25, 2021 (“Effective Date”).

This Retention Agreement (“Agreement”) is made and entered into by and between Ardelyx, Inc. (“Company”)

A.

 The Company and the Board of Directors of the Company (“Board”) has determined that it is in the best

Recitals

interests of the Company and its stockholders to execute a second reduction in force in order to reduce operating costs and better
align the Company’s workforce with the needs of the business following the receipt of a complete response letter (“CRL”) from
the U.S. Food and Drug Administration (“FDA”) on July 28, 2021. 

B.

The Board has determined that it is in the best interests of the Company and the stockholders to put in
place arrangements designed to provide that the Company will have the continued dedication and commitment of Executive,
notwithstanding the reduction in force, and to provide Executive with an incentive to continue Executive’s employment and
further align Executive’s incentives to maximize the value of the Company for the benefit of its stockholders. 

C.

The Executive and the Company are parties to that certain Second Amended and Restated Change in

Control Severance Agreement dated as of March 9, 2021 (“Severance Agreement”). Capitalized terms not defined herein shall
have the meaning assigned to them in the Severance Agreement.

The parties hereto agree as follows:

1

2

Severance Agreement. Except as specifically modified by the provisions of this Agreement, the Severance Agreement shall
remain in full force and effect.
2021 Annual Bonus.
The Compensation Committee of the Board previously set the Executive’s annual target bonus for fiscal year 2021 at an
amount equal to forty percent (40%) of the Executive’s base salary (“2021 Annual Bonus”). As an incentive to continue
Executive’s employment with the Company, subject to the terms of this Agreement, the Executive’s 2021 Annual Bonus shall
be earned and paid as follows: (a) fifty percent (50%) of the 2021 Annual Bonus shall be earned on the date in January 2022
when the Company pays annual bonuses to its employees, and (b) fifty percent (50%) of the 2021 Annual Bonus shall be
earned following the achievement of the 2021 Annual Bonus milestone described on Exhibit A hereto; provided, however,
that the second fifty percent (50%) of the 2021 Annual Bonus will not be earned earlier than April 1, 2022. 
The Executive shall not earn a portion of the 2021 Annual Bonus if the Executive voluntarily terminates his employment with
the Company for any reason or the Company terminates his employment for Cause prior to the date that such portion of the
2021 Annual Bonus is earned. 
Each portion of the 2021 Annual Bonus shall be paid in full, less applicable withholdings, as soon as practicable following
the date on which it is earned. 

|

3 Restricted Stock Unit

On October 8, 2021, the Company granted the Executive 250,000 restricted stock units (“RSUs”). The Executive has been or
will be provided with a Restricted Stock Unit Award Grant Notice (“Notice”) which sets forth the details of the RSUs and
provides the terms and conditions of the grant. Subject to the provisions of this Agreement and the Notice, the RSUs will vest
in full on the earliest of (a) June 1, 2022, (b) the closing of a Change in Control or (c) the date the Executive’s employment
with the Company is terminated by the Company without Cause , in each case, subject to the Executive remaining an
employee of the Company through such applicable vesting date.

4 Cash Bonus

The Executive shall earn a retention bonus in the aggregate amount of $250,000, subject to applicable tax withholding (“Cash
Bonus”) on the earliest of (a) the date of the achievement of the Cash Bonus milestone set forth on Exhibit A, (b) the closing
of a Change in Control or (c) the date the Executive’s employment with the Company is terminated by the Company without
Cause, subject to the Executive’s continued employment with the Company through such earliest date.
The Executive shall not earn the Cash Bonus if the Executive voluntarily terminates his employment with the Company or the
Company terminates the Executive’s employment for Cause prior to the date that the Cash Bonus is earned. 
The Cash Bonus shall be paid in full, less applicable withholdings, as soon as practicable following the date on which it is
earned. 

5 Nature of Agreement This Agreement is not a contract of employment for any specified term. Nothing contained in this

6

7

Agreement shall confer upon Executive any right to continue in the employ of the Company or interfere in any way with the
at-will nature of Executive’s employment with the Company (it being understood and agreed that (so long as it is done in
accordance with applicable law) the Company may terminate Executive’s employment at any time for any reason or for no
reason and that Executive may terminate his/her employment with the Company at any time for any reason or for no reason).
Full Agreement This Agreement, together with the Notice and the Severance Agreement referenced herein constitutes the
entire agreement of the parties with respect to the subject matter hereof, and supersedes all prior and contemporaneous
discussions, negotiations, or understandings, written or oral, relating thereto. This Agreement may not be amended or
modified except in a writing signed by both Executive and an authorized representative of the Company. 
Successors
Any successor to the Company (whether direct or indirect and whether by purchase, merger, consolidation, liquidation or
otherwise) to all or substantially all of the Company’s business and/or assets shall assume the obligations under this
Agreement and agree expressly to perform the obligations under this Agreement in the same manner and to the same extent as
the Company would be required to perform such obligations in the absence of a succession. For all purposes under this
Agreement, the term “Company” shall include any successor to the Company’s business and/or assets which executes and
delivers the assumption agreement described in the Severance Agreement or which becomes bound by

| ||

2

the terms of this Agreement by operation of law.
The terms of this Agreement and all rights of Executive hereunder shall inure to the benefit of, and be enforceable by,
Executive’s personal or legal representatives, executors, administrators, successors, heirs, distributees, devisees and legatees.

8 Choice of Law and Severability The validity, interpretation, construction and performance of this Agreement shall be
governed by the laws of the State of California. The invalidity or unenforceability of any provision or provisions of this
Agreement shall not affect the validity or enforceability of any other provision hereof, which shall remain in full force and
effect.

9 Date of Signature This Agreement shall be conveyed to Executive via DocuSign and in order to be effective, it must be

signed by Executive and delivered to the Company no later than November 15, 2021. Executive may elect to electronically
execute this Agreement using the DocuSign link provided, in which case this Agreement shall be automatically delivered to
Kelli Shaa and Mishu Nitulescu in Human Resources upon execution. Alternatively, Executive may elect to manually sign
this Agreement provided that such signature is delivered to Kelli Shaa in Human Resources no later than November 15,
2021.

Justin Renz

/s/ Justin Renz
Signature

Dated: October 24, 2021

Ardelyx, Inc.

By: /s/ Michael Raab

Title: Chief Executive Officer

Dated: October 23, 2021

| ||

3

Exhibit 10.20

Amendment Number One
To
Second Amended and Restated Change in Control Severance Agreement and to Retention Agreement

    This Amendment Number One to Second Amended and Restated Change in Control Severance Agreement and to Retention Agreement
(“Amendment Number One”) is made and entered into this first day of December, 2021, by and between David P. Rosenbaum (the
“Executive”) and Ardelyx, Inc. (the “Company”).

    Whereas, the Company and the Executive are parties to that certain Second Amended and Restated Change in Control Severance
th
Agreement made and entered into the 7  day of May 2018 (the “Agreement”);

Whereas, the Company and the Executive are parties to that certain Retention Agreement made and entered into the 23  day of

rd

October 2021 (the “Retention Agreement”); and

Whereas, the Board of Directors of the Company (the “Board”) has determined that it is in the best interest of the Company and the
stockholders to amend the Agreement and the Retention Agreement in order to ensure that the Company will continue to have the dedication
and commitment of the Executive and to provide the Executive with an incentive to continue Executive’s employment and further align
Executive’s incentives to maximize the value of the Company for the benefit of its stockholders;

The parties hereto agree as follows:

1.

 Definition of Covered Termination. The definition of Covered Termination set forth in Section 7 (e) of the Agreement shall be
revised to read in full as follows:

(e)  Covered Termination. “Covered Termination” means (a) Executive’s voluntary resignation for any reason; provided that (i)

written notice of such voluntary resignation is delivered in writing to the Company in the sixty (60) day period after the Cash
Bonus (as defined in the Retention Agreement) is earned by the Executive and (ii) such resignation is effective no later than
February 15 of the year following the year in which the Cash Bonus is earned (it being understood that the effective resignation
timing requirement of subclause (ii) may require written notice to be provided earlier than would otherwise apply under
subclause (i)); (b) an Involuntary Termination Without Cause; or (c) a Voluntary Resignation for Good Reason, provided that
such termination or resignation constitutes a Separation from Service.

2. Timing of Effective and Irrevocable Delivery of Release of Claims. The initial clause of each of Section 3 and Section 4 of the
Agreement shall be modified in their entirety as set forth below. The remaining provisions of each of Section 3 and Section 4 shall
remain unchanged. 

a. 3.    Covered Termination Other Than During a Change in Control Period. If Executive experiences a Covered

Termination other than during a Change in Control Period, and if Executive delivers to the Company a general release of all
claims against the Company and its affiliates in a form acceptable to the Company (“a Release of Claims”) that becomes
effective and irrevocable within twenty-eight (28) days, or such shorter period of time specified by the Company, following
such Covered Termination, then in addition to any accrued but unpaid salary, bonus, vacation and expense reimbursement
payable in accordance with applicable law, the Company shall provide Executive with the following:”

b. 4.    Covered Termination During a Change in Control Period. If Executive experiences a Covered Termination during a

Change in Control Period, and if Executive delivers to the Company a Release of Claims that becomes effective and
irrevocable within twenty-eight (28) days, or such shorter period of time specified by the Company, following such Covered
Termination, then in addition to any accrued but unpaid salary,

bonus, vacation and expense reimbursement payable in accordance with applicable law, the Company shall provide
Executive with the following:”

3. Other Changes. Except as set forth in this Amendment Number One, the Agreement remains unchanged and in full force and effect.
The Retention Agreement is amended as set forth below and except for this Amendment Number One, remains unchanged and in full
force and effect.

a. Section 1, Severance Agreement, now provides: “The Severance Agreement shall remain in full force and effect, except as

modified by Amendment Number One to the Severance Agreement, executed on December 1, 2021.”

b. Section 2, Annual Bonus. The second paragraph shall be modified with the addition of the following: “The Executive shall
earn and receive such portion of the 2021 Annual Bonus if the Company terminates the Executive’s employment without
cause before such portion is otherwise earned.”

c. Section 6, Full Agreement. The initial sentence shall be modified in its entirety by replacing it with the following: “This

Agreement, together with the Notice and the Severance Agreement referenced herein, as modified by Amendment Number
One executed on December 1, 2021, constitutes the entire agreement of the parties with respect to the subject matter hereof,
and supersedes all prior and contemporaneous discussions, negotiations, or understandings, written or oral, relating thereto.”
The second sentence in Section 6 remains unchanged.

4. Governing Law. The validity, interpretation, construction and performance of this Amendment Number One shall be governed by

the laws of the State of California.

5. Miscellaneous. This Amendment Number One may be signed by facsimile and in one or more counterparts, each of which shall be
deemed an original but all of which shall be deemed to constitute a single instrument. Signatures of the parties transmitted by
facsimile, PDF or other electronic file shall be deemed to be their original signatures for all purposes and the exchange of copies of
this agreement and of signature pages by facsimile transmission, PDF or other electronic file shall constitute effective execution and
delivery of this letter agreement as to the parties and may be used in lieu of the original agreement for all purposes.

IN WITNESS WHEREOF, each of the parties has executed this Amendment Number One, in the case of the Company, by its duly authorized
officer, as of the day and year set forth above.

ARDELYX, INC.

By: /s/ Michael Raab

Title: Chief Executive Officer

Date: December 1, 2021

EXECUTIVE

/s/ David P. Rosenbaum

David P. Rosenbaum

Date: December 1, 2021

2

Exhibit 10.21

RETENTION AGREEMENT

and ________________ (“Executive”), effective as of October 25, 2021 (“Effective Date”).

This Retention Agreement (“Agreement”) is made and entered into by and between Ardelyx, Inc. (“Company”)

A.

 The Company and the Board of Directors of the Company (“Board”) has determined that it is in the best

Recitals

interests of the Company and its stockholders to execute a second reduction in force in order to reduce operating costs and better
align the Company’s workforce with the needs of the business following the receipt of a complete response letter (“CRL”) from
the U.S. Food and Drug Administration (“FDA”) on July 28, 2021. 

B.

The Board has determined that it is in the best interests of the Company and the stockholders to put in
place arrangements designed to provide that the Company will have the continued dedication and commitment of Executive,
notwithstanding the reduction in force, and to provide Executive with an incentive to continue Executive’s employment and
further align Executive’s incentives to maximize the value of the Company for the benefit of its stockholders. 

C.

The Executive and the Company are parties to that certain ____________________________(“Severance

Agreement”). Capitalized terms not defined herein shall have the meaning assigned to them in the Severance Agreement.

The parties hereto agree as follows:

1

2

Severance Agreement. Except as specifically modified by the provisions of this Agreement, the Severance Agreement shall
remain in full force and effect.
2021 Annual Bonus.
The Compensation Committee of the Board previously set the Executive’s annual target bonus for fiscal year 2021 at an
amount equal to forty percent (40%) of the Executive’s base salary (“2021 Annual Bonus”). As an incentive to continue
Executive’s employment with the Company, subject to the terms of this Agreement, the Executive’s 2021 Annual Bonus shall
be earned and paid as follows: (a) fifty percent (50%) of the 2021 Annual Bonus shall be earned on the date in January 2022
when the Company pays annual bonuses to its employees, and (b) fifty percent (50%) of the 2021 Annual Bonus shall be
earned following the achievement of the 2021 Annual Bonus milestone described on Exhibit A hereto; provided, however,
that the second fifty percent (50%) of the 2021 Annual Bonus will not be earned earlier than April 1, 2022. 
The Executive shall not earn a portion of the 2021 Annual Bonus if the Executive voluntarily terminates his employment with
the Company for any reason or the Company terminates his employment for Cause prior to the date that such portion of the
2021 Annual Bonus is earned. 
Each portion of the 2021 Annual Bonus shall be paid in full, less applicable withholdings, as soon as practicable following
the date on which it is earned. 

3 Restricted Stock Unit

|

On October 8, 2021, the Company granted the Executive 250,000 restricted stock units (“RSUs”). The Executive has been or
will be provided with a Restricted Stock Unit Award Grant Notice (“Notice”) which sets forth the details of the RSUs and
provides the terms and conditions of the grant. Subject to the provisions of this Agreement and the Notice, the RSUs will vest
in full on the earliest of (a) June 1, 2022, (b) the closing of a Change in Control or (c) the date the Executive’s employment
with the Company is terminated by the Company without Cause , in each case, subject to the Executive remaining an
employee of the Company through such applicable vesting date.

4 Cash Bonus

The Executive shall earn a retention bonus in the aggregate amount of $250,000, subject to applicable tax withholding (“Cash
Bonus”) on the earliest of (a) the date of the achievement of the Cash Bonus milestone set forth on Exhibit A, (b) the closing
of a Change in Control or (c) the date the Executive’s employment with the Company is terminated by the Company without
Cause, subject to the Executive’s continued employment with the Company through such earliest date.
The Executive shall not earn the Cash Bonus if the Executive voluntarily terminates his employment with the Company or the
Company terminates the Executive’s employment for Cause prior to the date that the Cash Bonus is earned. 
The Cash Bonus shall be paid in full, less applicable withholdings, as soon as practicable following the date on which it is
earned. 

5 Nature of Agreement This Agreement is not a contract of employment for any specified term. Nothing contained in this

6

7

Agreement shall confer upon Executive any right to continue in the employ of the Company or interfere in any way with the
at-will nature of Executive’s employment with the Company (it being understood and agreed that (so long as it is done in
accordance with applicable law) the Company may terminate Executive’s employment at any time for any reason or for no
reason and that Executive may terminate his/her employment with the Company at any time for any reason or for no reason).
Full Agreement This Agreement, together with the Notice and the Severance Agreement referenced herein constitutes the
entire agreement of the parties with respect to the subject matter hereof, and supersedes all prior and contemporaneous
discussions, negotiations, or understandings, written or oral, relating thereto. This Agreement may not be amended or
modified except in a writing signed by both Executive and an authorized representative of the Company. 
Successors
Any successor to the Company (whether direct or indirect and whether by purchase, merger, consolidation, liquidation or
otherwise) to all or substantially all of the Company’s business and/or assets shall assume the obligations under this
Agreement and agree expressly to perform the obligations under this Agreement in the same manner and to the same extent as
the Company would be required to perform such obligations in the absence of a succession. For all purposes under this
Agreement, the term “Company” shall include any successor to the Company’s business and/or assets which executes and
delivers the assumption agreement described in the Severance Agreement or which becomes bound by the terms of this
Agreement by operation of law.

| ||

2

The terms of this Agreement and all rights of Executive hereunder shall inure to the benefit of, and be enforceable by,
Executive’s personal or legal representatives, executors, administrators, successors, heirs, distributees, devisees and legatees.

8 Choice of Law and Severability The validity, interpretation, construction and performance of this Agreement shall be
governed by the laws of the State of California. The invalidity or unenforceability of any provision or provisions of this
Agreement shall not affect the validity or enforceability of any other provision hereof, which shall remain in full force and
effect.

9 Date of Signature This Agreement shall be conveyed to Executive via DocuSign and in order to be effective, it must be

signed by Executive and delivered to the Company no later than November 15, 2021. Executive may elect to electronically
execute this Agreement using the DocuSign link provided, in which case this Agreement shall be automatically delivered to
Kelli Shaa and Mishu Nitulescu in Human Resources upon execution. Alternatively, Executive may elect to manually sign
this Agreement provided that such signature is delivered to Kelli Shaa in Human Resources no later than November 15,
2021.

Executive

Ardelyx, Inc.

________________________________
Signature

___________________________
Dated

By:____________________________

Title: Chief Executive Officer

Dated:_____________________

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3

Exhibit 10.22

RETENTION AGREEMENT

This Retention Agreement (“Agreement”) is made and entered into by and between Ardelyx, Inc. (“Company”)

and _______________ (“Executive”), effective as of October 25, 2021 (“Effective Date”).

Recitals

A.

 The Company and the Board of Directors of the Company (“Board”) has determined that it is in the best

interests of the Company and its stockholders to execute a second reduction in force in order to reduce operating costs and better
align the Company’s workforce with the needs of the business following the receipt of a complete response letter (“CRL”) from
the U.S. Food and Drug Administration (“FDA”) on July 28, 2021. 

B.

The Board has determined that it is in the best interests of the Company and the stockholders to put in
place arrangements designed to provide that the Company will have the continued dedication and commitment of Executive,
notwithstanding the reduction in force, and to provide Executive with an incentive to continue Executive’s employment and
further align Executive’s incentives to maximize the value of the Company for the benefit of its stockholders. 

C.

The Executive and the Company are parties to that certain __________________________________

(“Severance Agreement”). Capitalized terms not defined herein shall have the meaning assigned to them in the Severance
Agreement.

The parties hereto agree as follows:

1

2

Severance Agreement. Except as specifically modified by the provisions of this Agreement, the Severance Agreement shall
remain in full force and effect.
2021 Annual Bonus.
The Compensation Committee of the Board previously set the Executive’s annual target bonus for fiscal year 2021 at an
amount equal to forty percent (40%) of the Executive’s base salary (“2021 Annual Bonus”). As an incentive to continue
Executive’s employment with the Company, subject to the terms of this Agreement, the Executive’s 2021 Annual Bonus shall
be earned and paid as follows: (a) fifty percent (50%) of the 2021 Annual Bonus shall be earned on the date in January 2022
when the Company pays annual bonuses to its employees, and (b) fifty percent (50%) of the 2021 Annual Bonus shall be
earned following the achievement of the 2021 Annual Bonus milestone described on Exhibit A hereto; provided, however,
that the second fifty percent (50%) of the 2021 Annual Bonus will not be earned earlier than April 1, 2022. 
The Executive shall not earn a portion of the 2021 Annual Bonus if the Executive voluntarily terminates his employment with
the Company for any reason or the Company terminates his employment for Cause prior to the date that such portion of the
2021 Annual Bonus is earned. 
Each portion of the 2021 Annual Bonus shall be paid in full, less applicable withholdings, as soon as practicable following
the date on which it is earned. 

3 Restricted Stock Unit

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On October 8, 2021, the Company granted the Executive 150,000 restricted stock units (“RSUs”). The Executive has been or
will be provided with a Restricted Stock Unit Award Grant Notice (“Notice”) which sets forth the details of the RSUs and
provides the terms and conditions of the grant. Subject to the provisions of this Agreement and the Notice, the RSUs will vest
in full on the earliest of (a) June 1, 2022, (b) the closing of a Change in Control or (c) the date the Executive’s employment
with the Company is terminated by the Company without Cause , in each case, subject to the Executive remaining an
employee of the Company through such applicable vesting date.

4 Cash Bonus

The Executive shall earn a retention bonus in the aggregate amount of $150,000, subject to applicable tax withholding (“Cash
Bonus”) on the earliest of (a) the date of the achievement of the Cash Bonus milestone set forth on Exhibit A, (b) the closing
of a Change in Control or (c) the date the Executive’s employment with the Company is terminated by the Company without
Cause, subject to the Executive’s continued employment with the Company through such earliest date.
The Executive shall not earn the Cash Bonus if the Executive voluntarily terminates his employment with the Company or the
Company terminates the Executive’s employment for Cause prior to the date that the Cash Bonus is earned. 
The Cash Bonus shall be paid in full, less applicable withholdings, as soon as practicable following the date on which it is
earned. 

5 Nature of Agreement This Agreement is not a contract of employment for any specified term. Nothing contained in this

6

7

Agreement shall confer upon Executive any right to continue in the employ of the Company or interfere in any way with the
at-will nature of Executive’s employment with the Company (it being understood and agreed that (so long as it is done in
accordance with applicable law) the Company may terminate Executive’s employment at any time for any reason or for no
reason and that Executive may terminate his/her employment with the Company at any time for any reason or for no reason).
Full Agreement This Agreement, together with the Notice and the Severance Agreement referenced herein constitutes the
entire agreement of the parties with respect to the subject matter hereof, and supersedes all prior and contemporaneous
discussions, negotiations, or understandings, written or oral, relating thereto. This Agreement may not be amended or
modified except in a writing signed by both Executive and an authorized representative of the Company. 
Successors
Any successor to the Company (whether direct or indirect and whether by purchase, merger, consolidation, liquidation or
otherwise) to all or substantially all of the Company’s business and/or assets shall assume the obligations under this
Agreement and agree expressly to perform the obligations under this Agreement in the same manner and to the same extent as
the Company would be required to perform such obligations in the absence of a succession. For all purposes under this
Agreement, the term “Company” shall include any successor to the Company’s business and/or assets which executes and
delivers the assumption agreement described in the Severance Agreement or which becomes bound by the terms of this
Agreement by operation of law.

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2

The terms of this Agreement and all rights of Executive hereunder shall inure to the benefit of, and be enforceable by,
Executive’s personal or legal representatives, executors, administrators, successors, heirs, distributees, devisees and legatees.

8 Choice of Law and Severability The validity, interpretation, construction and performance of this Agreement shall be
governed by the laws of the State of California. The invalidity or unenforceability of any provision or provisions of this
Agreement shall not affect the validity or enforceability of any other provision hereof, which shall remain in full force and
effect.

9 Date of Signature This Agreement shall be conveyed to Executive via DocuSign and in order to be effective, it must be

signed by Executive and delivered to the Company no later than November 15, 2021. Executive may elect to electronically
execute this Agreement using the DocuSign link provided, in which case this Agreement shall be automatically delivered to
Kelli Shaa and Mishu Nitulescu in Human Resources upon execution. Alternatively, Executive may elect to manually sign
this Agreement provided that such signature is delivered to Kelli Shaa in Human Resources no later than November 15,
2021.

Executive

Ardelyx, Inc.

________________________________
Signature

___________________________
Dated

By:____________________________

Title: Chief Executive Officer

Dated:_____________________

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3

Exhibit 23.1

We consent to the incorporation by reference in the following Registration Statements:

Consent of Independent Registered Public Accounting Firm

1. Registration Statement on Form S-8 (No. 333-197408) pertaining to the 2008 Stock Incentive Plan, as amended, the 2014 Equity Incentive Award Plan

and the 2014 Employee Stock Purchase Plan of Ardelyx, Inc.

2. Registration Statements on Form S-8 (Nos. 333-202663 and 333-230156) pertaining to the 2014 Equity Incentive Award Plan and the 2014 Employee

Stock Purchase Plan of Ardelyx, Inc.

3. Registration Statements on Form S-3 (Nos. 333-205630, 333-213085 and 333-239764) of Ardelyx, Inc.

4. Registration Statements on Form S-8 (Nos. 333-210079, 333-216154, 333-223694 and 333-237057) pertaining to the 2014 Equity Incentive Award

Plan of Ardelyx, Inc.

5. Registration Statement on Form S-8 (No. 333-214538) pertaining to the 2016 Employment Commencement Incentive Plan of Ardelyx, Inc.

6. Registration Statement on Form S-8 (No. 333-254187) pertaining to the 2014 Equity Incentive Award Plan, the 2014 Employee Stock Purchase Plan

and the 2016 Employment Commencement Incentive Plan of Ardelyx, Inc.

of our reports dated February 28, 2022, with respect to the financial statements of Ardelyx, Inc. and the effectiveness of internal control over financial
reporting of Ardelyx, Inc. included in this Annual Report (Form 10-K) of Ardelyx, Inc. for the year ended December 31, 2021.

/s/ Ernst & Young LLP
Redwood City, California

February 28, 2022

CERTIFICATION

Exhibit 31.1

I, Michael Raab, certify that:

1.

I have reviewed this Annual Report on Form 10-K of Ardelyx, Inc.;

2. 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;

3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the

financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;

4. The registrant’s other certifying officer(s) and I are 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 reporting (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 information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those
entities, particularly during the period in which this report is being prepared;

Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our
supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for
external purposes in accordance with generally accepted accounting principles;

Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and

Disclosed in this report any change in the registrant’s internal control over financial reporting 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 reporting; and

5. The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the

registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):

(a)

(b)

All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; 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 reporting.

Date: February 28, 2022

By:

/s/ Michael Raab

Michael Raab
President, Chief Executive Officer and Director
(Principal Executive Officer)

Exhibit 31.2

I, Justin Renz, certify that:

1.

I have reviewed this Annual Report on Form 10-K of Ardelyx, Inc.;

CERTIFICATION

2. 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;

3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the

financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;

4. The registrant’s other certifying officer(s) and I are 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 reporting (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 information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those
entities, particularly during the period in which this report is being prepared;

Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our
supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for
external purposes in accordance with generally accepted accounting principles;

Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and

Disclosed in this report any change in the registrant’s internal control over financial reporting 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 reporting; and

5. The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the

registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):

(a)

(b)

All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; 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 reporting.

Date: February 28, 2022

By:

/s/ Justin Renz

Justin Renz
Chief Financial Officer
(Principal Financial Officer)

CERTIFICATION PURSUANT TO
18 U.S.C. SECTION 1350, AS ADOPTED PURSUANT TO SECTION 906
OF THE SARBANES-OXLEY ACT OF 2002

Exhibit 32.1

In connection with the Annual Report of Ardelyx, Inc. (the “Company”) on Form 10-K for the period ending December 31, 2020, as filed with the
Securities and Exchange Commission on the date hereof (the “Report”), Michael Raab, President and Chief Executive Officer of the Company, and Justin
Renz, Chief Financial Officer of the Company, respectively, do each hereby certify, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906
of the Sarbanes-Oxley Act of 2002, that:

(1) The Report fully complies with the requirements of section 13(a) or 15(d) of the Securities Exchange Act of 1934; and

(2) The information contained in the Report fairly presents, in all material respects, the financial condition and result of operations of the Company.

Date: February 28, 2022

Date: February 28, 2022

By:

By:

/s/ Michael Raab

Michael Raab
President, Chief Executive Officer and Director
(Principal Executive Officer)

/s/ Justin Renz

Justin Renz
Chief Financial Officer
(Principal Financial Officer)