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 PRO
2
TECT, and in dialysis dependent, or DD, CKD patients with anemia, called INNO
2
VATE, 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
PRO
2
TECT and INNO
2
VATE will be driven by the accrual of major adverse cardiovascular events, or MACE. In December 2015, the first patient
was dosed in PRO
2
TECT, and the first patient was dosed in INNO
2
VATE in August 2016. As of December 31, 2017, we expect the remaining
external aggregate contract research organization, or CRO, costs of PRO
2
TECT and INNO
2
VATE to be in the range of $420.0 million to $450.0
million. We anticipate reporting top-line clinical data for the PRO
2
TECT and INNO
2
VATE 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.
We revised the study
designs of FO
2
RWARD and TRILO
2
GY, 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 FO
2
RWARD 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 TRILO
2
GY 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.