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EXHIBIT J
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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2017
OR
☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
Commission File Number 001-36352
AKEBIA THERAPEUTICS, INC.
(Exact name of registrant as specified in its charter)
Delaware 20-8756903
(State or other jurisdiction of (I.R.S. Employer
incorporation or organization) Identification No.)
245 First Street, Suite 1100, Cambridge, MA 02142
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area code: (617) 871-2098
Securities registered pursuant to Section 12(b) of the Act: Common Stock, par value $0.00001 per share, traded on The NASDAQ Global Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☒ NO ☐
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒
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 ☒ NO ☐
Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted 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 and post such files). YES ☒ NO ☐
Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§ 229.405) is not contained herein, and will not be contained, to the best of registrant’s knowledge, in
definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☐
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 definitions of
“large accelerated filer”, “accelerated filer”, “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☒
Non-accelerated filer ☐ (Do not check if a smaller reporting company) Smaller reporting company ☐
Emerging growth company ☒
If an emerging growth company, indicated 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. ☒
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). YES ☐ NO ☒
The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant, based on the closing price of the registrant’s common stock on The NASDAQ Global
Market on June 30, 2017, was $576,393,274.
The number of shares of registrant’s common stock outstanding as of March 1, 2018 was 48,346,171.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the Proxy Statement for the registrant’s 2018 Annual Meeting of Stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K.
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NYSCEF DOC. NO. 60 TABLE OF CONTENTS RECEIVED NYSCEF: 01/18/2023
Page No.
PART I 3
Item 1. Business 3
Item 1A. Risk Factors 24
Item 1B. Unresolved Staff Comments 54
Item 2. Properties 54
Item 3. Legal Proceedings 54
Item 4. Mine Safety Disclosures 55
PART II 55
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 55
Item 6. Selected Financial Data 58
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 59
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 72
Item 8. Financial Statements and Supplementary Data 73
Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure 110
Item 9A. Controls and Procedures 110
Item 9B. Other Information 111
PART III 112
Item 10. Directors, Executive Officers and Corporate Governance 112
Item 11. Executive Compensation 112
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 112
Item 13. Certain Relationships and Related Transactions, and Director Independence 112
Item 14. Principal Accountant Fees and Services 112
PART IV 113
Item 15. Exhibits, Financial Statement Schedules 113
Item 16. Form 10-K Summary 115
SIGNATURES 116
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NYSCEF DOC. NO. 60 NOTE REGARDING FORWARD-LOOKING STATEMENTS RECEIVED NYSCEF: 01/18/2023
This Annual Report on Form 10-K contains forward-looking statements that are being made pursuant to the provisions of the U.S. Private Securities Litigation Reform Act of 1995
with the intention of obtaining the benefits of the “safe harbor” provisions of that Act. These forward-looking statements may be accompanied by words such as “anticipate,”
“believe,” “contemplate,” “continue,” “could,” “designed,” “estimate,” “expect,” “forecast,” “future,” “goal,” “intend,” “likely,” “may,” “plan,” “possible,” “potential,” “predict,”
“project,” “strategy,” “seek,” “should,” “target,” “will,” “would,” and other words and terms of similar meaning. These forward-looking statements include, but are not limited to,
statements about:
• the potential therapeutic applications of the HIF pathway;
• the potential of our pipeline and our research activities;
• the potential therapeutic benefits, safety profile, and effectiveness of our product candidates, including the potential for vadadustat to set a new standard of care in the
treatment of anemia due to chronic kidney disease
• the potential indications and market potential and acceptance of our product candidates;
• our competitive position, including estimates, developments and projections relating to our competitors and their products and product candidates, and our industry;
• our expectations, projections and estimates regarding our costs, revenues, capital requirements, need for additional capital, cash flows, financial performance,
profitability, tax obligations, liquidity, growth, contractual obligations, the period of time our cash resources and collaboration funding will fund our current operating
plan, internal control over financial reporting, disclosure controls and procedures;
• the timing of the availability and presentation of clinical trial data and results;
• our and our collaborators' strategy, plans and expectations with respect to the development, manufacturing, commercialization, launch, marketing and sale of our product
candidates, and the associated timing thereof;
• the designs of our studies, and the type of information and data expected from our studies;
• the timing of or likelihood of regulatory filings and approvals, including labeling or other restrictions;
• the targeted timing of enrollment of our clinical trials;
• the timing of initiation of our clinical trials and plans to conduct preclinical and clinical studies in the future;
• the timing and amounts of payments from our collaborators and licensees, and the anticipated arrangements and benefits under our collaboration and license
agreements;
• our intellectual property position, including obtaining and maintaining patents; and the timing, outcome and impact of administrative, regulatory, legal and other
proceedings relating to our patents and other proprietary and intellectual property rights;
• the impact of accounting standards and estimates;
• our facilities, lease commitments, and future availability of facilities;
• our employees, employee compensation, and employee relations; and
• the implementation of our business model and strategic plans for our business, product candidates and technology.
These forward-looking statements involve risks and uncertainties, including those that are described in Part I, Item 1A. Risk Factors included in this Annual Report and
elsewhere in this Annual Report, that could cause our actual results, financial condition, performance or achievements to be materially different from those indicated in these forward-
looking statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Forward-looking statements speak only as of the
date of this Annual Report on Form 10-K. Except as required by law, we assume no obligation to publicly update or revise these forward-looking statements for any reason.
This Annual Report on Form 10-K also contains estimates and other information concerning our industry and the markets for certain diseases, including data regarding the
estimated size of those markets, and the incidence and prevalence of certain medical conditions. Unless otherwise expressly stated, we obtained this industry, market and other data
from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and
similar sources.
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Item 1. Business
Overview
We are a biopharmaceutical company focused on developing and commercializing novel therapeutics for patients based on hypoxia-inducible factor, or HIF, biology, and building our
pipeline while leveraging our development and commercial expertise in renal disease. HIF is the primary regulator of the production of red blood cells, or RBCs, in the body, as well as
other important metabolic functions. Pharmacologic modulation of the HIF pathway may have broad therapeutic applications. Our lead product candidate, vadadustat, is an oral
therapy in Phase 3 development and has the potential to set a new standard of care in the treatment of anemia due to chronic kidney disease, or CKD. Our management team has
extensive experience in developing and commercializing drugs for the treatment of renal and metabolic disorders, as well as a deep understanding of HIF biology. This unique
combination of HIF and renal expertise is enabling us to advance a pipeline of HIF-based therapies to potentially address serious diseases.
HIF, a pathway involving hundreds of genes, is the same pathway used by the body to adapt to lower oxygen availability, or hypoxia, such as that experienced with a moderate increase
in altitude. At higher altitudes, the body responds to lower oxygen levels by increasing the availability of HIF, which coordinates the interdependent processes of iron utilization and
erythropoietin, or EPO, production to increase RBC production and, ultimately, improve oxygen delivery. The significance of the HIF pathway was recognized by the 2016 Albert
Lasker Basic Medical Research Award, which honored the three physician-scientists who discovered the HIF pathway and elucidated this primary oxygen sensing mechanism that is
essential for survival. HIF protein is constantly being produced under normal oxygen conditions, but is quickly degraded by prolyl hydroxylases, or PH. Under hypoxic conditions,
HIF-PHs are inhibited, allowing HIF to stimulate erythropoiesis. These findings have opened up new possibilities for developing therapeutics, such as HIF-PH inhibitors, which have
the potential to treat many diseases.
Our lead product candidate, vadadustat, is a HIF-PH inhibitor, or HIF-PHI, in Phase 3 development for the treatment of anemia due to CKD. Anemia is common in patients with CKD,
and its prevalence increases as CKD progresses. Anemia is a condition characterized by abnormally low levels of hemoglobin. Hemoglobin is contained within RBCs and carries
oxygen to other parts of the body. If there are too few RBCs or if hemoglobin levels are low, the cells in the body will not get enough oxygen. In patients with CKD, anemia results
from inadequate EPO levels, which negatively affect RBC production. In addition, iron, which is essential to RBC production, may be deficient in patients with CKD. Left untreated,
anemia significantly accelerates overall deterioration of patient health with increased morbidity and mortality. Based on third party prevalence data and company estimates,
approximately 37 million people in the United States have CKD and approximately 5.7 million of these individuals suffer from anemia. Anemia from CKD is currently treated by
injectable recombinant human erythropoiesis-stimulating agents, or injectable ESAs, such as EPOGEN® (epoetin alfa) and Aranesp® (darbepoetin alfa), or with iron supplementation
or RBC transfusion. Based on publicly available information on ESA sales and market data compiled by a third-party vendor, global sales of injectable ESAs for all uses were
estimated to be approximately $7.0 billion in 2016. The vast majority of these sales were for the treatment of anemia due to CKD.
When administered to a patient, injectable ESAs provide supra-physiological levels of exogenous erythropoietin to stimulate production of RBCs. While injectable ESAs can be
effective in raising hemoglobin levels, they have the potential to cause significant side effects, and need to be injected subcutaneously or intravenously. In particular, injectable ESAs
may lead to thrombosis, stroke, myocardial infarction and death. These safety concerns, which became evident starting in 2006, have led to a significant reduction in the use of
injectable ESAs. Today, anemia is either not treated or inadequately treated in the majority of non-dialysis dependent, or NDD, CKD patients. There is an unmet need for treatment
options that offer an improved safety profile and such agents would have significant market potential.
Vadadustat is designed to stimulate erythropoiesis and effectively treat renal anemia while avoiding the supra-physiologic EPO levels previously observed with injectable ESAs. In
addition, vadadustat, if approved, would provide patients with an oral treatment option, rather than an injection. For these reasons, we believe that vadadustat has the potential to set a
new standard of care for the treatment of anemia due to CKD.
Phase 1 and Phase 2 data led us to the design of our Phase 3 clinical program for vadadustat. The vadadustat Phase 3 program in NDD-CKD patients with anemia, called PRO2TECT,
and in dialysis dependent, or DD, CKD patients with anemia, called INNO2VATE, is designed to enroll up to approximately 6,900 patients evaluating once daily oral dosing of vadadustat
against an injectable ESA active comparator, darbepoetin alfa. The enrollment numbers and the completion of PRO2TECT and INNO2VATE will be driven by the accrual of major
adverse cardiovascular events, or MACE. In December 2015, the first patient was dosed in PRO2TECT, and the first patient was dosed in INNO2VATE in August 2016. As of
December 31, 2017, we expect the remaining external aggregate contract research organization, or CRO, costs of PRO2TECT and INNO2VATE to be in the range of $420.0 million to
$450.0 million. We anticipate reporting top-line clinical data for the PRO2TECT and INNO2VATE studies in 2019, subject to the accrual of MACE events. Subject to marketing
approvals, we plan to launch vadadustat for the treatment of anemia due to CKD in 2020.
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We revised the study designs of FO2RWARD and TRILO2GY, which we believe will provide additional characterization and differentiation of vadadustat and further strengthen our
commercial position if our product candidate is approved. The revised FO2RWARD study will include once-daily and three-times weekly dosing, data to inform ESA-switching
protocols, a larger sample size, and a broader dialysis population that is inclusive of hyporesponders, or patients with anemia due to CKD who are on dialysis and do not adequately
respond to injectable ESA. Hyporesponders represent approximately 10-15% of subjects with anemia due to DD-CKD, yet they account for 30-40% of total injectable ESA use. These
patients have demonstrated a persistently higher risk of mortality than non-hyporesponders, and represent a high unmet need. Given its differentiated mechanism of action, we believe
that vadadustat may provide a treatment option for these patients. The revised TRILO2GY study will include once-daily and three-times weekly dosing and an ESA control, a larger
sample size, and a design that can generate data to inform switching from Epogen®, Aranesp® and Mircera®.
If vadadustat is approved by the United States Food and Drug Administration, or FDA, we plan to establish our own commercial organization in the United States while leveraging our
collaboration with Otsuka Pharmaceutical Co. Ltd., or Otsuka, and its well-established commercial organization in the United States. We also granted Otsuka exclusive rights to
commercialize vadadustat in Europe, China and certain other markets, subject to marketing approvals. In Japan and certain other countries in Asia, we granted Mitsubishi Tanabe
Pharma Corporation, or MTPC, exclusive rights to commercialize vadadustat, subject to marketing approvals. In May 2017, we entered into an exclusive license agreement with Vifor
(International) Ltd., or Vifor Pharma, to sell vadadustat solely to Fresenius Kidney Care Group LLC, or FKC, dialysis clinics in the United States subject to approval by the FDA and
inclusion of vadadustat in a bundled reimbursement model. During the term of the license agreement, Vifor Pharma may not sell to FKC or its affiliates any HIF product that competes
with vadadustat in the United States.
In addition to vadadustat, we are developing a HIF-based portfolio of product candidates that target serious diseases of high unmet need. Our portfolio includes product candidates
developed internally as well as in-licensed product candidates, such as AKB-5169. In February 2017, we signed an exclusive agreement with Janssen Pharmaceutica NV, or Janssen, a
subsidiary of Johnson & Johnson, for access to an extensive library of well-characterized HIF pathway compounds with potential applications across multiple therapeutic areas. The
lead compound, AKB-5169, is a differentiated preclinical compound in development as an oral treatment for inflammatory bowel disease, or IBD. We intend to complete further
preclinical development of this compound, and we are targeting submitting an Investigational New Drug application, or IND, to the FDA in 2018.
Upcoming Milestones
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Anemia
NYSCEF Overview
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Anemia is a term used to describe a decrease in RBCs. RBCs contain a protein called hemoglobin that is responsible for moving oxygen throughout the body. As a result, anemia is
measured by the level of hemoglobin in the blood. Patients with CKD often have anemia because the kidneys do not make enough EPO, which stimulates the body to make RBCs.
Less EPO causes the body to make fewer RBCs and hemoglobin, decreasing the supply of oxygen throughout the body. Anemia is a serious medical condition that exists when
hemoglobin drops below 13 g/dL in men and 12 g/dL in women and, if left untreated, is associated with chronic fatigue, increased risk of progression of multiple diseases, and death.
Successful treatment of anemia significantly improves patients’ quality of life and is associated with decreased cardiovascular morbidity, less frequent hospitalizations and lower
mortality risk.
Chronic Kidney Disease
CKD, a common cause of anemia, is a condition in which the kidneys are progressively damaged to the point that they cannot properly filter the blood circulating in the body. This
damage causes waste products to build up in the patient’s blood leading to other health problems, including anemia, cardiovascular disease and bone disease. As illustrated in the table
below, CKD patients are categorized in one of five stages based on the degree of their loss of kidney function as measured by the glomerular filtration rate, or GFR, and the level of
protein in the urine, referred to as albuminuria.
As detailed in the table below, based on prevalence, CKD is estimated to affect approximately 37 million people in the United States. Additionally, the prevalence of anemia increases
with the severity of CKD from an estimated 20% in Stage 3 non-dialysis to an estimated 95% in Stage 5 dialysis.
Stages and Prevalence of Chronic Kidney Disease in the United States
Estimated Number of U.S. Patients
Stage Description GFR (mL/min/1.73m2)a U.S. Prevalence Ratesb, c (millions)d, e
Kidney damage with normal or increased
1 ≥90 4.6% 11.2
GFR
Kidney damage with mildly decreased
2 60-89 3.0% 7.3
GFR
3 Moderately decreased GFR 30-59 6.7% 16.4
4 Severely decreased GFR 15-29 0.4% 1.0
Kidney failure (includes non-dialysis,
5 <15 (or dialysis) 0.3% (calculated) 0.7
dialysis and transplant)
Sources:
a GFR categories defined in the August 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Anemia in Chronic Kidney Disease, p. vii.
b U.S. Prevalence Rates for Stages 1-4 based on averages of data from 2011-2012 and 2013-2014, CDC CKD Surveillance System, National Health and Nutrition Examination
Survey, or NHANES.
c U.S. Prevalence Rate for Stage 5 is based on a calculation using estimated number of U.S. patients with Stage 5 CKD from 2017 U.S. Renal Data System Annual Report, as
set forth in this table, and U.S. population data for people 20 years and older from www.census.gov.
d Estimated Number of U.S. Patients for Stages 1-4 based on the 2017 U.S. Prevalence rates, as set forth in this table, as applied by the Company to U.S. population data for
people 20 years and older from www.census.gov.
e Estimated Number of U.S. End-Stage Renal Disease Patients from 2017 U.S. Renal Data System Annual Report.
The prevalence and incidence of CKD is increasing in all segments of the United States population. Risk factors for the development of CKD include concomitant diseases such as
hypertension, diabetes mellitus and cardiovascular disease, lifestyle factors such as tobacco use and inactivity, family history, aging and prenatal factors such as maternal diabetes
mellitus, low birth weight and small-for-gestational-age status. According to an article in The Lancet published in May 2013, projected worldwide population changes suggest that the
potential number of cases of CKD, specifically end-stage, will increase disproportionately in countries such as Japan, China and India where the numbers of elderly people are
increasing. This effect will be enhanced further if the growth in the prevalence of hypertension and diabetes persists, along with the associated increased risk of stroke and
cardiovascular disease, and access to treatment does not improve.
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Current Treatments Leave a Substantial Unmet Need
Injectable ESAs are currently the standard of care for treating anemia in patients with CKD and must be administered intravenously or subcutaneously along with iron supplements. In
2006, data was published on the risks of injectable ESA use by these patients, forcing physicians to balance serious safety concerns against the efficacy of injectable ESAs. The well-
documented safety concerns associated with the use of injectable ESAs include increased cardiovascular risk and the potential for increased rate of tumor progression in patients with
cancer1.
As a result of the safety concerns related to injectable ESA use, patients live with lower hemoglobin levels, higher rates of RBC transfusions, and receive more intravenous iron, or IV
iron, to treat anemia due to CKD. IV iron and RBC transfusions also subject patients to safety risks. The risks of RBC transfusions include the development of antibodies to foreign
antigens, which may negatively impact candidacy for kidney transplantation, the potential transmission of blood-borne pathogens and iron overload with chronic transfusions. The
risks of IV iron use include hypersensitivity reactions, including fatal anaphylactic-type reactions.
The graph below, based on a post hoc analysis of the Correction of Hemoglobin and Outcomes in Renal Insufficiency, or CHOIR, study suggests that patients achieving higher
hemoglobin levels with lower injectable ESA doses had better outcomes than patients receiving higher injectable ESA doses despite lower achieved hemoglobin levels. Therefore,
higher injectable ESA doses, not the achieved hemoglobin level, appeared to be most strongly correlated with adverse outcomes.
1 Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease
who are receiving hemodialysis and epoetin. N Engl J Med 1998;339(9):584-590.
Pfeffer MA, Burdmann EA, Chen CY, Coopper ME, de Zeeuw D, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361(21):2019-2032.
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355(20):2085-2098.
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Vadadustat Has the Potential to Set a New Standard of Care
We believe that, based on the HIF-PHI mechanism of action and clinical data to date, vadadustat has the potential to set a new standard of care for the treatment of anemia due to CKD.
Below is a summary of the key clinical findings; further details are included under the “Vadadustat Clinical Development Overview” section below.
• Vadadustat stimulated endogenous EPO production. In two Phase 1 studies in normal healthy volunteers and one Phase 2 study in CKD patients, vadadustat increased
serum EPO levels in a dose-dependent manner. Pre-dose EPO levels returned to baseline levels prior to subsequent daily dose.
• Vadadustat significantly increased and maintained hemoglobin levels. Our Phase 2 studies in CKD subjects with anemia demonstrated that vadadustat significantly
increased and/or maintained hemoglobin levels.
• Vadadustat was dosed orally once daily and three-times weekly. Phase 2 studies have shown that vadadustat can be orally dosed once daily in NDD-CKD subjects over
20 weeks of dosing. In addition, a Phase 2 clinical study in DD-CKD subjects demonstrated that in subjects who remained on therapy, once daily or three-times
weekly oral dosing of vadadustat maintained stable hemoglobin levels in subjects converting from injectable ESA therapy over 16 weeks.
• Vadadustat resulted in favorable changes in iron parameters. In three Phase 2 clinical studies, treatment with vadadustat was associated with decreases in ferritin and
hepcidin and increases in total iron binding capacity. These changes are consistent with improved iron mobilization and utilization for erythropoiesis in NDD-CKD
and DD-CKD subjects.
For the above reasons, we believe that vadadustat has the potential to stimulate erythropoiesis while demonstrating a reduced risk of cardiovascular and thrombotic events compared to
injectable ESAs. These cardiovascular and thrombotic risks have been associated with supra-physiologic increases in EPO levels and excessive hemoglobin fluctuations and/or
excursions beyond the target range. The incidence of cardiovascular and thrombotic adverse events associated with vadadustat as compared with darbepoetin alfa, an injectable ESA, is
being assessed in the global Phase 3 program for vadadustat.
Market Potential
We believe there is significant market opportunity for an oral HIF-based product, such as vadadustat, to potentially treat dialysis and non-dialysis patients with anemia due to CKD,
some of whom are receiving injectable ESA therapy and many of whom are not due to the safety concerns and other barriers to treatment associated with injectable ESAs.
We estimate that approximately 400,000-450,000 U.S. dialysis patients are currently receiving some injectable ESA treatment for anemia due to CKD. According to the 2017 U.S.
Renal Data System, or USRDS, Annual Data Report, there are approximately 438,000 US patients on hemodialysis and 49,000 patients on peritoneal dialysis, with approximately 90%
of patients and 75% of patients receiving ESA therapy, respectively.
Data from the 2015 USRDS Annual Data Report indicate that the collective injectable ESA treatment rate in NDD-CKD patients decreased by approximately half from 2009 to 2013,
following the emergence of cardiovascular safety concerns associated with injectable ESAs and kidney disease guideline updates. This change in injectable ESA treatment rate
suggests there is potential to treat a large patient population with HIF-based products who are not receiving injectable ESAs today. Moreover, many patients are not treated with an
injectable ESA even though their hemoglobin concentration is below the ESA treatment initiation threshold suggested by the Kidney Disease Improving Global Outcomes, or KDIGO.
HIF-PH Inhibition: A Mechanism of Action That Is Designed to Mimic the Body’s Physiologic Response to Hypoxia
Vadadustat is designed to work by a mechanism of action that differs from injectable ESAs. This mechanism of action is referred to as HIF-PH inhibition. HIF is the primary regulator
of the production of RBCs and is responsible for orchestrating the body’s physiologic response to lower levels of oxygen, or hypoxia. In response to hypoxia, a coordinated adaptive
response occurs resulting in both an increase in RBC production, a normal biological process known as erythropoiesis, and enhancement of the delivery of iron to the bone marrow,
ensuring the incorporation of iron into hemoglobin to support erythropoiesis. HIFa is constitutively expressed in the cytoplasm but broken down immediately under normal oxygen
conditions by the HIF-PHa enzymes. Inhibition of these enzymes allows HIFa concentrations to build and translocate to the nucleus to initiate hypoxic gene transcription, where it
binds to the HIFß protein. When bound together, HIFa and HIFß stimulate erythropoiesis and iron transfer proteins. With continued stabilization of the HIFa protein either by staying
at higher altitude or by the administration of a HIF-PHI, the level of hemoglobin and RBCs will rise in order to increase the amount of oxygen circulating in the blood.
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Vadadustat Clinical Development Overview
The following 17 studies of vadadustat have evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic properties of vadadustat and supported further clinical
development:
• nine completed Phase 1 studies in normal healthy volunteers (CI‑0001, CI‑0002, CI‑0006, CI‑0008, CI‑0010, CI‑0012, CI‑0013, CI-0019, and CI-0020);
• one completed Phase 1 study in DD-CKD subjects with anemia (CI‑0009);
• five completed Phase 2 studies in NDD-CKD subjects with anemia (CI‑0003, CI‑0004, CI‑0005, CI‑0007, CI-0021); and
• two completed Phase 2 studies in DD-CKD subjects with anemia (CI‑0011, CI-0022).
The results from three of these studies are summarized below.
Vadadustat Clinical Development Summary
Findings from two clinical studies demonstrated that vadadustat stimulated endogenous EPO production while avoiding excessive increases, achieved the desired outcomes of raising
and maintaining hemoglobin, and increased iron mobilization to support erythropoiesis. Vadadustat’s safety profile has generally been consistent across Phase 1 and 2 studies
completed to date. The common adverse events, or AEs, and serious adverse events, or SAEs, for the respective studies are discussed below.
Phase 1 Study in Normal Healthy Volunteers (CI-0002)
We completed a Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending dose study to evaluate the safety, tolerability, pharmacodynamics response, and
pharmacokinetics of vadadustat administered for 10 days to healthy male volunteers. Dose responsive increases in reticulocytes, or immature RBCs, and hemoglobin levels were
demonstrated in the study. Mean serum EPO levels increased by 39%, 69%, and 86% over baseline, at 16 hours after dosing in the vadadustat 500 mg/day, 700 mg/day, and 900
mg/day dosing groups, respectively, and returned to baseline by 24 hours after dosing. The incidence of AEs was generally similar between the combined vadadustat dosing groups,
which was 76.5%, and the placebo group, which was 78%. Gastrointestinal AEs occurred in 26.5% of subjects in the vadadustat groups and in no subjects on placebo, of which mild to
moderate diarrhea was the most frequent at 16.7%, with evidence of a dose-related effect. No SAEs or deaths were reported in this study.
Phase 2b Study in Non-Dialysis CKD Subjects (CI-0007)
We completed a multi-center Phase 2b study of vadadustat in non-dialysis subjects with anemia due to CKD. This double-blind, randomized, placebo-controlled study evaluated the
efficacy and safety of vadadustat over 20 weeks of dosing in 210 subjects (138 vadadustat and 72 placebo) with CKD stages 1 to 5. Subjects were enrolled into one of three groups: (1)
injectable ESA naïve with hemoglobin ≤10.5 g/dL, (2) previously treated with injectable ESA with hemoglobin ≤10.5 g/dL, or (3) actively treated with injectable ESA with hemoglobin
≥9.5 and ≤12.0 g/dL, and were randomized at a rate of 2 to 1 to once daily vadadustat or placebo. The primary endpoint was the percentage of subjects with either a mean hemoglobin
of ≥11.0 g/dL or an increase in hemoglobin by ≥1.2 g/dL from baseline. A protocol-defined dose adjustment algorithm was used to achieve the primary endpoint and to minimize
variations of hemoglobin from baseline, known as hemoglobin excursions, of ≥13 g/dL.
The average age of subjects was 66 years; approximately 75% of subjects had diabetes mellitus; and the mean estimated GFR was 25 mL/min/1.73m2. 54.9% of vadadustat treated
subjects compared to 10.3% of placebo treated subjects met the primary endpoint (p=0.0001). Only 4.3% of subjects in the vadadustat group had any hemoglobin excursion
≥13.0 g/dL. Between Groups 1 and 2 (the two correction cohorts; ESA-naïve and ESA previously treated), mean Hb increased significantly in the vadadustat group from pre-dose
average to end-of-study average (Week 19/20). In Group 3 (conversion cohorts; ESA actively treated), placebo treated subjects experienced a decline in the mean hemoglobin within
the first 2 weeks, whereas subjects randomized to vadadustat maintained a stable hemoglobin throughout the study.
Increases in hemoglobin in the vadadustat group were preceded by an increase in reticulocytes and accompanied by an increase in total iron binding capacity and a decrease in serum
hepcidin and ferritin. There was no difference between the vadadustat and placebo groups in vascular endothelial growth factor, or VEGF, levels during the study.
A similar percentage of subjects experienced an AE in the vadadustat and placebo treatment groups (vadadustat 74.6% vs. placebo 73.6%); however, the frequency of certain AEs -
diarrhea, nausea, hypertension and hyperkalemia - was greater in the vadadustat arm compared to placebo. In the vadadustat arm, a higher number of subjects reported SAEs of acute
and chronic renal failure compared to
8
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placebo (9.4% vs. 2.8%, respectively); however, none were considered drug-related by the investigator. The percentage of subjects who had an SAE resulting in dialysis initiation, an
objective measure of the severity of renal disease, was comparable between vadadustat and placebo groups (8.0% versus 9.7%, respectively) and the number of subjects who
discontinued from the study due to AEs of worsening CKD requiring dialysis was also comparable between the vadadustat (4.3%) and placebo (5.6%) groups. There were three deaths
in vadadustat-treated subjects of which two were considered to be unrelated to vadadustat and one was considered by the investigator to be possibly related because no autopsy was
performed to assess relatedness. There were no deaths in the placebo group.
In summary, vadadustat achieved the desired outcomes of raising and maintaining hemoglobin and increasing iron mobilization, while minimizing hemoglobin excursions ≥13 g/dL.
Pergola et al published the results of this study in Kidney International 2016.
Phase 2 Study in Dialysis-Dependent CKD Subjects (CI-0011)
We completed a multi-center, open-label, 16-week study to assess the hemoglobin response, safety, and tolerability of vadadustat in DD-CKD subjects. The study enrolled 94
hemodialysis subjects with baseline hemoglobin levels of 9-12 g/dL, who were maintained on injectable ESAs prior to study entry. Subjects were converted from injectable ESA to
vadadustat, and assigned to one of three dose cohorts: 300 mg once daily; 450 mg once daily; or 450 mg three-times weekly. For each dose cohort, the average hemoglobin level at
study entry was compared to the average hemoglobin level at weeks 7 and 8, and to the average hemoglobin level at weeks 15 and 16. To evaluate hemoglobin response to each of the
dose regimens, during the first eight weeks of this study, subjects were to remain on the prescribed starting dose, or decreased if necessary to control hemoglobin in the target range.
Beginning at week 8, the dose of vadadustat could be increased or decreased to maintain hemoglobin levels as needed. Intravenous iron use was allowed.
The underlying demographics and profiles of these CKD subjects were well-balanced across the three cohorts, and reflective of the United States DD-CKD population as reported in
the literature. Average age was 58 years, with an average time on dialysis of 4.6 years. The most common cause of end-stage renal disease was diabetes mellitus and/or hypertension.
Baseline hemoglobin levels were similar at 10.4-10.6 g/dL in all three cohorts and the serum ferritin levels indicated that the subjects were iron replete at study entry and throughout
the study.
For subjects in all three dosing cohorts (converted from ESA) who completed the study, the primary endpoint of maintaining stable mean hemoglobin levels over 16 weeks was
achieved. The study supports both daily and three-times weekly vadadustat dosing regimens as viable options. Consistent with previous studies, all three starting dose regimens
suggested an improvement in iron mobilization, as reflected by increases in total iron binding capacity and serum iron, and decreases in serum ferritin and hepcidin levels. Only one
subject in the 300 mg once daily cohort had a single hemoglobin excursion to 13.1 g/dL.
Adverse events were balanced across the three cohorts. There were no discernible trends in the frequency of AEs or SAEs by dose cohort. The most frequently reported AEs were
nausea and diarrhea with no apparent dose relationship. The majority of AEs were mild or moderate in severity. SAEs were reported in 13 subjects, or 13.8%; no SAEs were reported
as related to vadadustat and no deaths occurred during the study. Reported events appear to be consistent in frequency and severity with previous clinical experience and co-
morbidities described in medical literature in subjects with CKD. The results of this study were reported at the American Society of Nephrology meeting in November 2015 and the
National Kidney Foundation Spring Clinical Meeting in April 2016.
Phase 3 Global Program
We are conducting two global Phase 3 studies to support an indication for the treatment of anemia in NDD-CKD patients and two global Phase 3 studies to support an indication for
the t
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FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 EXHIBIT J FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-K (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2017 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 Commission File Number 001-36352 AKEBIA THERAPEUTICS, INC. (Exact name of registrant as specified in its charter) Delaware 20-8756903 (State or other jurisdiction of (I.R.S. Employer incorporation or organization) Identification No.) 245 First Street, Suite 1100, Cambridge, MA 02142 (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: (617) 871-2098 Securities registered pursuant to Section 12(b) of the Act: Common Stock, par value $0.00001 per share, traded on The NASDAQ Global Market Securities registered pursuant to Section 12(g) of the Act: None Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☒ NO ☐ Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒ 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 ☒ NO ☐ Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted 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 and post such files). YES ☒ NO ☐ Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§ 229.405) is not contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☐ 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 definitions of “large accelerated filer”, “accelerated filer”, “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act. Large accelerated filer ☐ Accelerated filer ☒ Non-accelerated filer ☐ (Do not check if a smaller reporting company) Smaller reporting company ☐ Emerging growth company ☒ If an emerging growth company, indicated 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. ☒ Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). YES ☐ NO ☒ The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant, based on the closing price of the registrant’s common stock on The NASDAQ Global Market on June 30, 2017, was $576,393,274. The number of shares of registrant’s common stock outstanding as of March 1, 2018 was 48,346,171. DOCUMENTS INCORPORATED BY REFERENCE Portions of the Proxy Statement for the registrant’s 2018 Annual Meeting of Stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K. FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 TABLE OF CONTENTS RECEIVED NYSCEF: 01/18/2023 Page No. PART I 3 Item 1. Business 3 Item 1A. Risk Factors 24 Item 1B. Unresolved Staff Comments 54 Item 2. Properties 54 Item 3. Legal Proceedings 54 Item 4. Mine Safety Disclosures 55 PART II 55 Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 55 Item 6. Selected Financial Data 58 Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 59 Item 7A. Quantitative and Qualitative Disclosures About Market Risk 72 Item 8. Financial Statements and Supplementary Data 73 Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure 110 Item 9A. Controls and Procedures 110 Item 9B. Other Information 111 PART III 112 Item 10. Directors, Executive Officers and Corporate Governance 112 Item 11. Executive Compensation 112 Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 112 Item 13. Certain Relationships and Related Transactions, and Director Independence 112 Item 14. Principal Accountant Fees and Services 112 PART IV 113 Item 15. Exhibits, Financial Statement Schedules 113 Item 16. Form 10-K Summary 115 SIGNATURES 116 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 NOTE REGARDING FORWARD-LOOKING STATEMENTS RECEIVED NYSCEF: 01/18/2023 This Annual Report on Form 10-K contains forward-looking statements that are being made pursuant to the provisions of the U.S. Private Securities Litigation Reform Act of 1995 with the intention of obtaining the benefits of the “safe harbor” provisions of that Act. These forward-looking statements may be accompanied by words such as “anticipate,” “believe,” “contemplate,” “continue,” “could,” “designed,” “estimate,” “expect,” “forecast,” “future,” “goal,” “intend,” “likely,” “may,” “plan,” “possible,” “potential,” “predict,” “project,” “strategy,” “seek,” “should,” “target,” “will,” “would,” and other words and terms of similar meaning. These forward-looking statements include, but are not limited to, statements about: • the potential therapeutic applications of the HIF pathway; • the potential of our pipeline and our research activities; • the potential therapeutic benefits, safety profile, and effectiveness of our product candidates, including the potential for vadadustat to set a new standard of care in the treatment of anemia due to chronic kidney disease • the potential indications and market potential and acceptance of our product candidates; • our competitive position, including estimates, developments and projections relating to our competitors and their products and product candidates, and our industry; • our expectations, projections and estimates regarding our costs, revenues, capital requirements, need for additional capital, cash flows, financial performance, profitability, tax obligations, liquidity, growth, contractual obligations, the period of time our cash resources and collaboration funding will fund our current operating plan, internal control over financial reporting, disclosure controls and procedures; • the timing of the availability and presentation of clinical trial data and results; • our and our collaborators' strategy, plans and expectations with respect to the development, manufacturing, commercialization, launch, marketing and sale of our product candidates, and the associated timing thereof; • the designs of our studies, and the type of information and data expected from our studies; • the timing of or likelihood of regulatory filings and approvals, including labeling or other restrictions; • the targeted timing of enrollment of our clinical trials; • the timing of initiation of our clinical trials and plans to conduct preclinical and clinical studies in the future; • the timing and amounts of payments from our collaborators and licensees, and the anticipated arrangements and benefits under our collaboration and license agreements; • our intellectual property position, including obtaining and maintaining patents; and the timing, outcome and impact of administrative, regulatory, legal and other proceedings relating to our patents and other proprietary and intellectual property rights; • the impact of accounting standards and estimates; • our facilities, lease commitments, and future availability of facilities; • our employees, employee compensation, and employee relations; and • the implementation of our business model and strategic plans for our business, product candidates and technology. These forward-looking statements involve risks and uncertainties, including those that are described in Part I, Item 1A. Risk Factors included in this Annual Report and elsewhere in this Annual Report, that could cause our actual results, financial condition, performance or achievements to be materially different from those indicated in these forward- looking statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Forward-looking statements speak only as of the date of this Annual Report on Form 10-K. Except as required by law, we assume no obligation to publicly update or revise these forward-looking statements for any reason. This Annual Report on Form 10-K also contains estimates and other information concerning our industry and the markets for certain diseases, including data regarding the estimated size of those markets, and the incidence and prevalence of certain medical conditions. Unless otherwise expressly stated, we obtained this industry, market and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources. 2 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 PART I RECEIVED NYSCEF: 01/18/2023 Item 1. Business Overview We are a biopharmaceutical company focused on developing and commercializing novel therapeutics for patients based on hypoxia-inducible factor, or HIF, biology, and building our pipeline while leveraging our development and commercial expertise in renal disease. HIF is the primary regulator of the production of red blood cells, or RBCs, in the body, as well as other important metabolic functions. Pharmacologic modulation of the HIF pathway may have broad therapeutic applications. Our lead product candidate, vadadustat, is an oral therapy in Phase 3 development and has the potential to set a new standard of care in the treatment of anemia due to chronic kidney disease, or CKD. Our management team has extensive experience in developing and commercializing drugs for the treatment of renal and metabolic disorders, as well as a deep understanding of HIF biology. This unique combination of HIF and renal expertise is enabling us to advance a pipeline of HIF-based therapies to potentially address serious diseases. HIF, a pathway involving hundreds of genes, is the same pathway used by the body to adapt to lower oxygen availability, or hypoxia, such as that experienced with a moderate increase in altitude. At higher altitudes, the body responds to lower oxygen levels by increasing the availability of HIF, which coordinates the interdependent processes of iron utilization and erythropoietin, or EPO, production to increase RBC production and, ultimately, improve oxygen delivery. The significance of the HIF pathway was recognized by the 2016 Albert Lasker Basic Medical Research Award, which honored the three physician-scientists who discovered the HIF pathway and elucidated this primary oxygen sensing mechanism that is essential for survival. HIF protein is constantly being produced under normal oxygen conditions, but is quickly degraded by prolyl hydroxylases, or PH. Under hypoxic conditions, HIF-PHs are inhibited, allowing HIF to stimulate erythropoiesis. These findings have opened up new possibilities for developing therapeutics, such as HIF-PH inhibitors, which have the potential to treat many diseases. Our lead product candidate, vadadustat, is a HIF-PH inhibitor, or HIF-PHI, in Phase 3 development for the treatment of anemia due to CKD. Anemia is common in patients with CKD, and its prevalence increases as CKD progresses. Anemia is a condition characterized by abnormally low levels of hemoglobin. Hemoglobin is contained within RBCs and carries oxygen to other parts of the body. If there are too few RBCs or if hemoglobin levels are low, the cells in the body will not get enough oxygen. In patients with CKD, anemia results from inadequate EPO levels, which negatively affect RBC production. In addition, iron, which is essential to RBC production, may be deficient in patients with CKD. Left untreated, anemia significantly accelerates overall deterioration of patient health with increased morbidity and mortality. Based on third party prevalence data and company estimates, approximately 37 million people in the United States have CKD and approximately 5.7 million of these individuals suffer from anemia. Anemia from CKD is currently treated by injectable recombinant human erythropoiesis-stimulating agents, or injectable ESAs, such as EPOGEN® (epoetin alfa) and Aranesp® (darbepoetin alfa), or with iron supplementation or RBC transfusion. Based on publicly available information on ESA sales and market data compiled by a third-party vendor, global sales of injectable ESAs for all uses were estimated to be approximately $7.0 billion in 2016. The vast majority of these sales were for the treatment of anemia due to CKD. When administered to a patient, injectable ESAs provide supra-physiological levels of exogenous erythropoietin to stimulate production of RBCs. While injectable ESAs can be effective in raising hemoglobin levels, they have the potential to cause significant side effects, and need to be injected subcutaneously or intravenously. In particular, injectable ESAs may lead to thrombosis, stroke, myocardial infarction and death. These safety concerns, which became evident starting in 2006, have led to a significant reduction in the use of injectable ESAs. Today, anemia is either not treated or inadequately treated in the majority of non-dialysis dependent, or NDD, CKD patients. There is an unmet need for treatment options that offer an improved safety profile and such agents would have significant market potential. Vadadustat is designed to stimulate erythropoiesis and effectively treat renal anemia while avoiding the supra-physiologic EPO levels previously observed with injectable ESAs. In addition, vadadustat, if approved, would provide patients with an oral treatment option, rather than an injection. For these reasons, we believe that vadadustat has the potential to set a new standard of care for the treatment of anemia due to CKD. Phase 1 and Phase 2 data led us to the design of our Phase 3 clinical program for vadadustat. The vadadustat Phase 3 program in NDD-CKD patients with anemia, called PRO2TECT, and in dialysis dependent, or DD, CKD patients with anemia, called INNO2VATE, is designed to enroll up to approximately 6,900 patients evaluating once daily oral dosing of vadadustat against an injectable ESA active comparator, darbepoetin alfa. The enrollment numbers and the completion of PRO2TECT and INNO2VATE will be driven by the accrual of major adverse cardiovascular events, or MACE. In December 2015, the first patient was dosed in PRO2TECT, and the first patient was dosed in INNO2VATE in August 2016. As of December 31, 2017, we expect the remaining external aggregate contract research organization, or CRO, costs of PRO2TECT and INNO2VATE to be in the range of $420.0 million to $450.0 million. We anticipate reporting top-line clinical data for the PRO2TECT and INNO2VATE studies in 2019, subject to the accrual of MACE events. Subject to marketing approvals, we plan to launch vadadustat for the treatment of anemia due to CKD in 2020. 3 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 We revised the study designs of FO2RWARD and TRILO2GY, which we believe will provide additional characterization and differentiation of vadadustat and further strengthen our commercial position if our product candidate is approved. The revised FO2RWARD study will include once-daily and three-times weekly dosing, data to inform ESA-switching protocols, a larger sample size, and a broader dialysis population that is inclusive of hyporesponders, or patients with anemia due to CKD who are on dialysis and do not adequately respond to injectable ESA. Hyporesponders represent approximately 10-15% of subjects with anemia due to DD-CKD, yet they account for 30-40% of total injectable ESA use. These patients have demonstrated a persistently higher risk of mortality than non-hyporesponders, and represent a high unmet need. Given its differentiated mechanism of action, we believe that vadadustat may provide a treatment option for these patients. The revised TRILO2GY study will include once-daily and three-times weekly dosing and an ESA control, a larger sample size, and a design that can generate data to inform switching from Epogen®, Aranesp® and Mircera®. If vadadustat is approved by the United States Food and Drug Administration, or FDA, we plan to establish our own commercial organization in the United States while leveraging our collaboration with Otsuka Pharmaceutical Co. Ltd., or Otsuka, and its well-established commercial organization in the United States. We also granted Otsuka exclusive rights to commercialize vadadustat in Europe, China and certain other markets, subject to marketing approvals. In Japan and certain other countries in Asia, we granted Mitsubishi Tanabe Pharma Corporation, or MTPC, exclusive rights to commercialize vadadustat, subject to marketing approvals. In May 2017, we entered into an exclusive license agreement with Vifor (International) Ltd., or Vifor Pharma, to sell vadadustat solely to Fresenius Kidney Care Group LLC, or FKC, dialysis clinics in the United States subject to approval by the FDA and inclusion of vadadustat in a bundled reimbursement model. During the term of the license agreement, Vifor Pharma may not sell to FKC or its affiliates any HIF product that competes with vadadustat in the United States. In addition to vadadustat, we are developing a HIF-based portfolio of product candidates that target serious diseases of high unmet need. Our portfolio includes product candidates developed internally as well as in-licensed product candidates, such as AKB-5169. In February 2017, we signed an exclusive agreement with Janssen Pharmaceutica NV, or Janssen, a subsidiary of Johnson & Johnson, for access to an extensive library of well-characterized HIF pathway compounds with potential applications across multiple therapeutic areas. The lead compound, AKB-5169, is a differentiated preclinical compound in development as an oral treatment for inflammatory bowel disease, or IBD. We intend to complete further preclinical development of this compound, and we are targeting submitting an Investigational New Drug application, or IND, to the FDA in 2018. Upcoming Milestones 4 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 Anemia NYSCEF Overview DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 Anemia is a term used to describe a decrease in RBCs. RBCs contain a protein called hemoglobin that is responsible for moving oxygen throughout the body. As a result, anemia is measured by the level of hemoglobin in the blood. Patients with CKD often have anemia because the kidneys do not make enough EPO, which stimulates the body to make RBCs. Less EPO causes the body to make fewer RBCs and hemoglobin, decreasing the supply of oxygen throughout the body. Anemia is a serious medical condition that exists when hemoglobin drops below 13 g/dL in men and 12 g/dL in women and, if left untreated, is associated with chronic fatigue, increased risk of progression of multiple diseases, and death. Successful treatment of anemia significantly improves patients’ quality of life and is associated with decreased cardiovascular morbidity, less frequent hospitalizations and lower mortality risk. Chronic Kidney Disease CKD, a common cause of anemia, is a condition in which the kidneys are progressively damaged to the point that they cannot properly filter the blood circulating in the body. This damage causes waste products to build up in the patient’s blood leading to other health problems, including anemia, cardiovascular disease and bone disease. As illustrated in the table below, CKD patients are categorized in one of five stages based on the degree of their loss of kidney function as measured by the glomerular filtration rate, or GFR, and the level of protein in the urine, referred to as albuminuria. As detailed in the table below, based on prevalence, CKD is estimated to affect approximately 37 million people in the United States. Additionally, the prevalence of anemia increases with the severity of CKD from an estimated 20% in Stage 3 non-dialysis to an estimated 95% in Stage 5 dialysis. Stages and Prevalence of Chronic Kidney Disease in the United States Estimated Number of U.S. Patients Stage Description GFR (mL/min/1.73m2)a U.S. Prevalence Ratesb, c (millions)d, e Kidney damage with normal or increased 1 ≥90 4.6% 11.2 GFR Kidney damage with mildly decreased 2 60-89 3.0% 7.3 GFR 3 Moderately decreased GFR 30-59 6.7% 16.4 4 Severely decreased GFR 15-29 0.4% 1.0 Kidney failure (includes non-dialysis, 5 <15 (or dialysis) 0.3% (calculated) 0.7 dialysis and transplant) Sources: a GFR categories defined in the August 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Anemia in Chronic Kidney Disease, p. vii. b U.S. Prevalence Rates for Stages 1-4 based on averages of data from 2011-2012 and 2013-2014, CDC CKD Surveillance System, National Health and Nutrition Examination Survey, or NHANES. c U.S. Prevalence Rate for Stage 5 is based on a calculation using estimated number of U.S. patients with Stage 5 CKD from 2017 U.S. Renal Data System Annual Report, as set forth in this table, and U.S. population data for people 20 years and older from www.census.gov. d Estimated Number of U.S. Patients for Stages 1-4 based on the 2017 U.S. Prevalence rates, as set forth in this table, as applied by the Company to U.S. population data for people 20 years and older from www.census.gov. e Estimated Number of U.S. End-Stage Renal Disease Patients from 2017 U.S. Renal Data System Annual Report. The prevalence and incidence of CKD is increasing in all segments of the United States population. Risk factors for the development of CKD include concomitant diseases such as hypertension, diabetes mellitus and cardiovascular disease, lifestyle factors such as tobacco use and inactivity, family history, aging and prenatal factors such as maternal diabetes mellitus, low birth weight and small-for-gestational-age status. According to an article in The Lancet published in May 2013, projected worldwide population changes suggest that the potential number of cases of CKD, specifically end-stage, will increase disproportionately in countries such as Japan, China and India where the numbers of elderly people are increasing. This effect will be enhanced further if the growth in the prevalence of hypertension and diabetes persists, along with the associated increased risk of stroke and cardiovascular disease, and access to treatment does not improve. 5 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 Current Treatments Leave a Substantial Unmet Need Injectable ESAs are currently the standard of care for treating anemia in patients with CKD and must be administered intravenously or subcutaneously along with iron supplements. In 2006, data was published on the risks of injectable ESA use by these patients, forcing physicians to balance serious safety concerns against the efficacy of injectable ESAs. The well- documented safety concerns associated with the use of injectable ESAs include increased cardiovascular risk and the potential for increased rate of tumor progression in patients with cancer1. As a result of the safety concerns related to injectable ESA use, patients live with lower hemoglobin levels, higher rates of RBC transfusions, and receive more intravenous iron, or IV iron, to treat anemia due to CKD. IV iron and RBC transfusions also subject patients to safety risks. The risks of RBC transfusions include the development of antibodies to foreign antigens, which may negatively impact candidacy for kidney transplantation, the potential transmission of blood-borne pathogens and iron overload with chronic transfusions. The risks of IV iron use include hypersensitivity reactions, including fatal anaphylactic-type reactions. The graph below, based on a post hoc analysis of the Correction of Hemoglobin and Outcomes in Renal Insufficiency, or CHOIR, study suggests that patients achieving higher hemoglobin levels with lower injectable ESA doses had better outcomes than patients receiving higher injectable ESA doses despite lower achieved hemoglobin levels. Therefore, higher injectable ESA doses, not the achieved hemoglobin level, appeared to be most strongly correlated with adverse outcomes. 1 Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339(9):584-590. Pfeffer MA, Burdmann EA, Chen CY, Coopper ME, de Zeeuw D, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361(21):2019-2032. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355(20):2085-2098. 6 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 Vadadustat Has the Potential to Set a New Standard of Care We believe that, based on the HIF-PHI mechanism of action and clinical data to date, vadadustat has the potential to set a new standard of care for the treatment of anemia due to CKD. Below is a summary of the key clinical findings; further details are included under the “Vadadustat Clinical Development Overview” section below. • Vadadustat stimulated endogenous EPO production. In two Phase 1 studies in normal healthy volunteers and one Phase 2 study in CKD patients, vadadustat increased serum EPO levels in a dose-dependent manner. Pre-dose EPO levels returned to baseline levels prior to subsequent daily dose. • Vadadustat significantly increased and maintained hemoglobin levels. Our Phase 2 studies in CKD subjects with anemia demonstrated that vadadustat significantly increased and/or maintained hemoglobin levels. • Vadadustat was dosed orally once daily and three-times weekly. Phase 2 studies have shown that vadadustat can be orally dosed once daily in NDD-CKD subjects over 20 weeks of dosing. In addition, a Phase 2 clinical study in DD-CKD subjects demonstrated that in subjects who remained on therapy, once daily or three-times weekly oral dosing of vadadustat maintained stable hemoglobin levels in subjects converting from injectable ESA therapy over 16 weeks. • Vadadustat resulted in favorable changes in iron parameters. In three Phase 2 clinical studies, treatment with vadadustat was associated with decreases in ferritin and hepcidin and increases in total iron binding capacity. These changes are consistent with improved iron mobilization and utilization for erythropoiesis in NDD-CKD and DD-CKD subjects. For the above reasons, we believe that vadadustat has the potential to stimulate erythropoiesis while demonstrating a reduced risk of cardiovascular and thrombotic events compared to injectable ESAs. These cardiovascular and thrombotic risks have been associated with supra-physiologic increases in EPO levels and excessive hemoglobin fluctuations and/or excursions beyond the target range. The incidence of cardiovascular and thrombotic adverse events associated with vadadustat as compared with darbepoetin alfa, an injectable ESA, is being assessed in the global Phase 3 program for vadadustat. Market Potential We believe there is significant market opportunity for an oral HIF-based product, such as vadadustat, to potentially treat dialysis and non-dialysis patients with anemia due to CKD, some of whom are receiving injectable ESA therapy and many of whom are not due to the safety concerns and other barriers to treatment associated with injectable ESAs. We estimate that approximately 400,000-450,000 U.S. dialysis patients are currently receiving some injectable ESA treatment for anemia due to CKD. According to the 2017 U.S. Renal Data System, or USRDS, Annual Data Report, there are approximately 438,000 US patients on hemodialysis and 49,000 patients on peritoneal dialysis, with approximately 90% of patients and 75% of patients receiving ESA therapy, respectively. Data from the 2015 USRDS Annual Data Report indicate that the collective injectable ESA treatment rate in NDD-CKD patients decreased by approximately half from 2009 to 2013, following the emergence of cardiovascular safety concerns associated with injectable ESAs and kidney disease guideline updates. This change in injectable ESA treatment rate suggests there is potential to treat a large patient population with HIF-based products who are not receiving injectable ESAs today. Moreover, many patients are not treated with an injectable ESA even though their hemoglobin concentration is below the ESA treatment initiation threshold suggested by the Kidney Disease Improving Global Outcomes, or KDIGO. HIF-PH Inhibition: A Mechanism of Action That Is Designed to Mimic the Body’s Physiologic Response to Hypoxia Vadadustat is designed to work by a mechanism of action that differs from injectable ESAs. This mechanism of action is referred to as HIF-PH inhibition. HIF is the primary regulator of the production of RBCs and is responsible for orchestrating the body’s physiologic response to lower levels of oxygen, or hypoxia. In response to hypoxia, a coordinated adaptive response occurs resulting in both an increase in RBC production, a normal biological process known as erythropoiesis, and enhancement of the delivery of iron to the bone marrow, ensuring the incorporation of iron into hemoglobin to support erythropoiesis. HIFa is constitutively expressed in the cytoplasm but broken down immediately under normal oxygen conditions by the HIF-PHa enzymes. Inhibition of these enzymes allows HIFa concentrations to build and translocate to the nucleus to initiate hypoxic gene transcription, where it binds to the HIFß protein. When bound together, HIFa and HIFß stimulate erythropoiesis and iron transfer proteins. With continued stabilization of the HIFa protein either by staying at higher altitude or by the administration of a HIF-PHI, the level of hemoglobin and RBCs will rise in order to increase the amount of oxygen circulating in the blood. 7 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 Vadadustat Clinical Development Overview The following 17 studies of vadadustat have evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic properties of vadadustat and supported further clinical development: • nine completed Phase 1 studies in normal healthy volunteers (CI‑0001, CI‑0002, CI‑0006, CI‑0008, CI‑0010, CI‑0012, CI‑0013, CI-0019, and CI-0020); • one completed Phase 1 study in DD-CKD subjects with anemia (CI‑0009); • five completed Phase 2 studies in NDD-CKD subjects with anemia (CI‑0003, CI‑0004, CI‑0005, CI‑0007, CI-0021); and • two completed Phase 2 studies in DD-CKD subjects with anemia (CI‑0011, CI-0022). The results from three of these studies are summarized below. Vadadustat Clinical Development Summary Findings from two clinical studies demonstrated that vadadustat stimulated endogenous EPO production while avoiding excessive increases, achieved the desired outcomes of raising and maintaining hemoglobin, and increased iron mobilization to support erythropoiesis. Vadadustat’s safety profile has generally been consistent across Phase 1 and 2 studies completed to date. The common adverse events, or AEs, and serious adverse events, or SAEs, for the respective studies are discussed below. Phase 1 Study in Normal Healthy Volunteers (CI-0002) We completed a Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending dose study to evaluate the safety, tolerability, pharmacodynamics response, and pharmacokinetics of vadadustat administered for 10 days to healthy male volunteers. Dose responsive increases in reticulocytes, or immature RBCs, and hemoglobin levels were demonstrated in the study. Mean serum EPO levels increased by 39%, 69%, and 86% over baseline, at 16 hours after dosing in the vadadustat 500 mg/day, 700 mg/day, and 900 mg/day dosing groups, respectively, and returned to baseline by 24 hours after dosing. The incidence of AEs was generally similar between the combined vadadustat dosing groups, which was 76.5%, and the placebo group, which was 78%. Gastrointestinal AEs occurred in 26.5% of subjects in the vadadustat groups and in no subjects on placebo, of which mild to moderate diarrhea was the most frequent at 16.7%, with evidence of a dose-related effect. No SAEs or deaths were reported in this study. Phase 2b Study in Non-Dialysis CKD Subjects (CI-0007) We completed a multi-center Phase 2b study of vadadustat in non-dialysis subjects with anemia due to CKD. This double-blind, randomized, placebo-controlled study evaluated the efficacy and safety of vadadustat over 20 weeks of dosing in 210 subjects (138 vadadustat and 72 placebo) with CKD stages 1 to 5. Subjects were enrolled into one of three groups: (1) injectable ESA naïve with hemoglobin ≤10.5 g/dL, (2) previously treated with injectable ESA with hemoglobin ≤10.5 g/dL, or (3) actively treated with injectable ESA with hemoglobin ≥9.5 and ≤12.0 g/dL, and were randomized at a rate of 2 to 1 to once daily vadadustat or placebo. The primary endpoint was the percentage of subjects with either a mean hemoglobin of ≥11.0 g/dL or an increase in hemoglobin by ≥1.2 g/dL from baseline. A protocol-defined dose adjustment algorithm was used to achieve the primary endpoint and to minimize variations of hemoglobin from baseline, known as hemoglobin excursions, of ≥13 g/dL. The average age of subjects was 66 years; approximately 75% of subjects had diabetes mellitus; and the mean estimated GFR was 25 mL/min/1.73m2. 54.9% of vadadustat treated subjects compared to 10.3% of placebo treated subjects met the primary endpoint (p=0.0001). Only 4.3% of subjects in the vadadustat group had any hemoglobin excursion ≥13.0 g/dL. Between Groups 1 and 2 (the two correction cohorts; ESA-naïve and ESA previously treated), mean Hb increased significantly in the vadadustat group from pre-dose average to end-of-study average (Week 19/20). In Group 3 (conversion cohorts; ESA actively treated), placebo treated subjects experienced a decline in the mean hemoglobin within the first 2 weeks, whereas subjects randomized to vadadustat maintained a stable hemoglobin throughout the study. Increases in hemoglobin in the vadadustat group were preceded by an increase in reticulocytes and accompanied by an increase in total iron binding capacity and a decrease in serum hepcidin and ferritin. There was no difference between the vadadustat and placebo groups in vascular endothelial growth factor, or VEGF, levels during the study. A similar percentage of subjects experienced an AE in the vadadustat and placebo treatment groups (vadadustat 74.6% vs. placebo 73.6%); however, the frequency of certain AEs - diarrhea, nausea, hypertension and hyperkalemia - was greater in the vadadustat arm compared to placebo. In the vadadustat arm, a higher number of subjects reported SAEs of acute and chronic renal failure compared to 8 FILED: NEW YORK COUNTY CLERK 01/18/2023 08:22 PM INDEX NO. 654373/2021 NYSCEF DOC. NO. 60 RECEIVED NYSCEF: 01/18/2023 placebo (9.4% vs. 2.8%, respectively); however, none were considered drug-related by the investigator. The percentage of subjects who had an SAE resulting in dialysis initiation, an objective measure of the severity of renal disease, was comparable between vadadustat and placebo groups (8.0% versus 9.7%, respectively) and the number of subjects who discontinued from the study due to AEs of worsening CKD requiring dialysis was also comparable between the vadadustat (4.3%) and placebo (5.6%) groups. There were three deaths in vadadustat-treated subjects of which two were considered to be unrelated to vadadustat and one was considered by the investigator to be possibly related because no autopsy was performed to assess relatedness. There were no deaths in the placebo group. In summary, vadadustat achieved the desired outcomes of raising and maintaining hemoglobin and increasing iron mobilization, while minimizing hemoglobin excursions ≥13 g/dL. Pergola et al published the results of this study in Kidney International 2016. Phase 2 Study in Dialysis-Dependent CKD Subjects (CI-0011) We completed a multi-center, open-label, 16-week study to assess the hemoglobin response, safety, and tolerability of vadadustat in DD-CKD subjects. The study enrolled 94 hemodialysis subjects with baseline hemoglobin levels of 9-12 g/dL, who were maintained on injectable ESAs prior to study entry. Subjects were converted from injectable ESA to vadadustat, and assigned to one of three dose cohorts: 300 mg once daily; 450 mg once daily; or 450 mg three-times weekly. For each dose cohort, the average hemoglobin level at study entry was compared to the average hemoglobin level at weeks 7 and 8, and to the average hemoglobin level at weeks 15 and 16. To evaluate hemoglobin response to each of the dose regimens, during the first eight weeks of this study, subjects were to remain on the prescribed starting dose, or decreased if necessary to control hemoglobin in the target range. Beginning at week 8, the dose of vadadustat could be increased or decreased to maintain hemoglobin levels as needed. Intravenous iron use was allowed. The underlying demographics and profiles of these CKD subjects were well-balanced across the three cohorts, and reflective of the United States DD-CKD population as reported in the literature. Average age was 58 years, with an average time on dialysis of 4.6 years. The most common cause of end-stage renal disease was diabetes mellitus and/or hypertension. Baseline hemoglobin levels were similar at 10.4-10.6 g/dL in all three cohorts and the serum ferritin levels indicated that the subjects were iron replete at study entry and throughout the study. For subjects in all three dosing cohorts (converted from ESA) who completed the study, the primary endpoint of maintaining stable mean hemoglobin levels over 16 weeks was achieved. The study supports both daily and three-times weekly vadadustat dosing regimens as viable options. Consistent with previous studies, all three starting dose regimens suggested an improvement in iron mobilization, as reflected by increases in total iron binding capacity and serum iron, and decreases in serum ferritin and hepcidin levels. Only one subject in the 300 mg once daily cohort had a single hemoglobin excursion to 13.1 g/dL. Adverse events were balanced across the three cohorts. There were no discernible trends in the frequency of AEs or SAEs by dose cohort. The most frequently reported AEs were nausea and diarrhea with no apparent dose relationship. The majority of AEs were mild or moderate in severity. SAEs were reported in 13 subjects, or 13.8%; no SAEs were reported as related to vadadustat and no deaths occurred during the study. Reported events appear to be consistent in frequency and severity with previous clinical experience and co- morbidities described in medical literature in subjects with CKD. The results of this study were reported at the American Society of Nephrology meeting in November 2015 and the National Kidney Foundation Spring Clinical Meeting in April 2016. Phase 3 Global Program We are conducting two global Phase 3 studies to support an indication for the treatment of anemia in NDD-CKD patients and two global Phase 3 studies to support an indication for the t