Axis Shield : Rationale and Design of the PRO2TECT Global Phase 3 Studies of Vadadustat for the Treatment of Anemia in Patients with Non-Dialysis-Dependent Chronic Kidney Disease

Rationale and Design of the PRO2TECT Global Phase 3 Studies of

Vadadustat for the Treatment of Anemia in Patients With SUN-266 Non-Dialysis-Dependent Chronic Kidney Disease

Pablo E. Pergola;1 Bruce S. Spinowitz;2 Matthew R. Weir;3 James Tumlin;4 Rajiv Agarwal;5 Masaomi Nangaku;6

Qing Zuraw;7 Emil deGoma;7 Amit Sharma;7 Bradley J. Maroni;7 Geoffrey A. Block8

1Renal Associates PA, San Antonio, TX, USA; 2New York Presbyterian Queens, Flushing, NY, USA; 3University of Maryland School of Medicine, Baltimore, MD, USA; 4Southeast Renal Research Institute, Chattanooga, TN, USA;

5Indiana University School of Medicine, Indianapolis, IN, USA; 6The University of Tokyo Graduate School of Medicine, Tokyo, Japan; 7Akebia Therapeutics, Inc., Cambridge, MA, USA; 8Denver Nephrology Research, Denver, CO, USA

Background

• Anemia is a common complication of chronic kidney disease (CKD), with an estimated prevalence exceeding 50% in patients with CKD stage 4 or 5.1
• The presence of anemia is associated with worse prognosis in CKD, including a higher risk of cardiovascular disease, hospitalization, and mortality.2,3
• The current mainstay of treatment of CKD-associated anemia are erythropoiesis-stimulating agents (ESAs) and oral and intravenous iron.4,5
• Several clinical studies in patients with CKD reported that the use of ESAs, although effective in treating anemia, was associated with worse cardiovascular outcomes.6-8
• Despite the decline in ESA use following these trial results,9 patients with
  CKD and anemia continue to suffer from a substantial burden of cardiovascular morbidity and mortality.10 Thus, there is an unmet need for alternative therapies that present an improvement on the existing standard of care for CKD-associated anemia.

Vadadustat, a Hypoxia-Inducible Factor

Prolyl-Hydroxylase Domain (HIF-PHD) Inhibitor

• Vadadustat is an orally bioavailable, HIF-PHD inhibitor under clinical develop- ment for the treatment of anemia in patients with dialysis-dependent and non- dialysis-dependent CKD (DD-CKD and NDD-CKD, respectively; Figure 1).
• Because it mimics the body's natural adaptive response to hypoxia,11 HIF-PHD inhibition by vadadustat is being studied to determine if it raises and maintains hemoglobin (Hb) levels in the target range.

Vadadustat, a Hypoxia-Inducible Factor

Prolyl-Hydroxylase Domain (HIF-PHD) Inhibitor (cont.)

Figure 1: Mechanism of Action of Vadadustat

EPO, erythropoietin; Hb, hemoglobin; HIF, hypoxia-inducible factor; HIF-PHD, HIF prolyl-hydroxylase domain; RBC, red blood cell

Design of PRO2TECT: Vadadustat Global Phase 3 NDD-CKD Program

• PRO2TECT comprises 2 global, randomized, open-label,active-controlled, noninferiority, Phase 3 studies to evaluate the efficacy and safety of oral vadadustat for the correction of anemia (PRO2TECT-CORRECTION) or maintenance treatment of anemia (PRO2TECT-CONVERSION) in patients with NDD-CKD (Tables 1 and 2).

Table 1: Key Eligibility Criteria

Table 2: Key Efficacy and Safety Endpoints

• Following the screening period, eligible patients are randomized to vadadustat or darbepoetin alfa and enter 4 sequential study periods (Figure 2). Study drug is titrated to achieve target Hb levels (US: 10-11 g/dL; Ex-US:10-12 g/dL).

Figure 2: Study Design (PRO2TECT-CORRECTION and PRO2TECT-CONVERSION)

Summary

PRO2TECT-CORRECTION and PRO2TECT-CONVERSION are ongoing global Phase 3 studies evaluating the efficacy and safety of vadadustat in patients with anemia secondary to NDD-CKD.

References

1. Stauffer ME & Fan T. PLoS One. 2014;9:e84943. 2) Nangaku M & Eckardt KU. Semin Nephrol. 2006;26:261-268.

1. Portoles J, et al. BMC Nephrol. 2013;14:2. 4) Koulouridis I, et al. Am J Kidney Dis. 2013;61:44-56.

1. Macdougall IC, et al. Kidney Int. 2016;89:28-39.6) Besarab A, et al. N Engl J Med. 1998;339:584-590.

1. Singh AK, et al. N Engl J Med. 2006;355:2085-2098.8) Pfeffer MA, et al. N Engl J Med. 2009;361:2019-2032.

1. Thamer M, et al. Am J Kidney Dis. 2014;64:706-713.10) McCullough PA, et al. Am J Nephrol. 2013;37:549-558.

1. Maxwell PH & Eckardt KU. Nat Rev Nephrol. 2016;12:157-168.

Acknowledgments

The study was funded by Akebia Therapeutics, Inc. Editorial assistance was provided by AlphaBioCom, LLC, King of Prussia, and funded by Akebia Therapeutics, Inc. Authors thank Prof. Christian Rosenberger for improvising Figure 1.

*Cardiovascular safety endpoints are adjudicated by a central clinical endpoint committee blinded to treatment allocation

Contact Dr. Pergola at [e-mail] with any questions

Presented at the ISN World Congress of Nephrology 2017, Mexico City, Mexico, April 21−25, 2017