The INNO2VATE Phase 3 Program of Vadadustat for Treatment of Anemia in Dialysis-Dependent CKD: Rationale and Study Design

173	THE INNO2VATE PHASE 3 PROGRAM OF VADADUSTAT FOR TREATMENT OF ANEMIA IN DIALYSIS-DEPENDENT CKD: RATIONALE AND STUDY DESIGN
	Wolfgang C. Winkelmayer1, Geoffrey A. Block2, Glenn M. Chertow3, Steven Fishbane4, Yasuhiro Komatsu5, Peter A. McCullough6, Pablo E. Pergola7, Christian Rosenberger8, Don E. Williamson9, Jerry Yee10,
	Allan J. Collins11, Zeeshan Khawaja12, Amit Sharma12, Qing Zuraw12, Bradley J. Maroni12
	1Baylor College of Medicine, Houston, TX; 2Denver Nephrology Research, Denver, CO; 3Stanford University, Palo Alto, CA; 4Hofstra Northwell Health, Hempstead, NY; 5St. Luke's International Hospital, Tokyo, Japan; 6Baylor University Medical Center, Dallas, TX; 7Renal Associates PA, San Antonio, TX;
	8Charité University, Berlin, Germany; 9Nephrology Associates, PC, Augusta, GA; 10Henry Ford Hospital, Detroit, MI; 11Chronic Disease Research Group, Minneapolis, MN; 12Akebia Therapeutics, Inc., Cambridge, MA

Background		Design of INNO2VATE: Vadadustat Global Phase 3 DD-CKD Program
• Anemia is a common complication of chronic kidney disease (CKD), with	Table 1: Key Eligibility Criteria	Figure 2. Study Design (INNO2VATE-CORRECTION and INNO2VATE-CONVERSION)
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.

DD-CKD,dialysis-dependent chronic kidney disease. Hb, hemoglobin.

Figure 1. Mechanism of Action of Vadadustat		•	INNO2VATE comprises 2 global, randomized, open-label,active-controlled,	References
	Table 2. Key Efficacy and Safety Endpoints	noninferiority, Phase 3 studies to evaluate the efficacy and safety of oral	1.	Stauffer ME & Fan T. PLoS One. 2014;9:e84943.
			vadadustat for the correction of anemia (INNO2VATE-CORRECTION) or	2.	Nangaku M & Eckardt KU. Semin Nephrol. 2006;26:261-268.
			maintenance treatment of anemia (INNO2VATE-CONVERSION) in	3.	Portoles J, et al. BMC Nephrol. 2013;14:2.
			4.	Koulouridis I, et al. Am J Kidney Dis. 2013;61:44-56.
			patients with DD-CKD (Tables 1 and 2).	5.	Macdougall IC, et al. Kidney Int. 2016;89:28-39.
		• Following the screening period, eligible patients are randomized to	6.	Besarab A, et al. N Engl J Med. 1998;339:584-590.
			vadadustat or darbepoetin alfa and enter 4 sequential study periods	7.	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.
			(Figure 2). Study drug is titrated to achieve target Hb levels
			9.	Thamer M, et al. Am J Kidney Dis. 2014;64:706-713.
			(US: 10-11 g/dL; Ex-US:10-12 g/dL).	10.	McCullough PA, et al. Am J Nephrol. 2013;37:549-558.
					11.	Maxwell PH & Eckardt KU. Nat Rev Nephrol. 2016;12:157-168.
			Summary	Acknowledgments
					The study was funded by Akebia Therapeutics, Inc. Editorial assistance was provided by
		INNO2VATE-CORRECTION and INNO2VATE-CONVERSION are ongoing
		AlphaBioCom, LLC, King of Prussia, PA, and funded by Akebia Therapeutics, Inc.
		global Phase 3 studies evaluating the efficacy and safety of vadadustat in

patients with anemia secondary to DD-CKD.

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

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

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

Presented at the National Kidney Foundation 2017 Spring Clinical Meetings, Orlando, FL, April 18−22, 2017