Positive Top-Line Results from Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients on Dialysis

CAMBRIDGE, Mass., May 5, 2020 /PRNewswire/ — Akebia Therapeutics, Inc. (Nasdaq: AKBA), a biopharmaceutical company with the purpose to better the lives of people impacted by kidney disease, today announced positive top-line results from INNO2VATE, the first of its two global Phase 3 cardiovascular outcomes programs. The two INNO2VATE studies evaluated the efficacy and safety of vadadustat, Akebia’s investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), versus darbepoetin alfa for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.

Vadadustat achieved the primary and key secondary efficacy endpoint in each of the two INNO2VATE studies, demonstrating non-inferiority to darbepoetin alfa as measured by a mean change in hemoglobin (Hb) between baseline and the primary evaluation period (weeks 24 to 36) and secondary evaluation period (weeks 40 to 52). Vadadustat also achieved the primary safety endpoint of the INNO2VATE program, defined as non-inferiority of vadadustat versus darbepoetin alfa in time to first occurrence of major adverse cardiovascular events (MACE), which is the composite of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke across both INNO2VATE studies. Each analysis was measured against non-inferiority (NI) margins agreed upon with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

“The INNO2VATE study results are very compelling,” stated Glenn Chertow, M.D., M.P.H., Professor of Medicine, Chief, Division of Nephrology at Stanford University, and Co-Chair of the independent Executive Steering Committee for INNO2VATE. “The greatest strength of the INNO2VATE data is the consistency across both efficacy and all MACE components. The nephrology community has been eagerly awaiting straightforward, high-quality data evaluating the treatment of anemia due to CKD with a novel HIF-PHI. Based on these two randomized trials comparing vadadustat to the active darbepoetin control, I am confident that vadadustat has the potential to be a safe and effective option for the treatment of anemia due to CKD in adult patients requiring dialysis, upon approval.”

John P. Butler, President and Chief Executive Officer of Akebia Therapeutics stated, “We are thrilled to be sharing positive top-line data from INNO2VATE, the first of our two global Phase 3 programs studying vadadustat to treat anemia due to CKD. It is extremely rewarding to see this program yield clear, consistent, straightforward results. We believe our data uniquely positions vadadustat as a potential new oral standard of care for treating all populations of dialysis patients, including both incident and prevalent dialysis patients, with anemia due to CKD, subject to approval.”

“We look forward to sharing these compelling data with regulators, as well as with physicians, dialysis providers and payers. We are more confident than ever that the clinical success we’ve demonstrated with INNO2VATE supports vadadustat’s potential for regulatory and commercial success, upon approval.” Butler continued, “The team is already at work on vadadustat’s New Drug Application (NDA), which we expect to file as quickly as possible following the top-line data readout of PRO2TECT, our global Phase 3 program studying vadadustat in adult patients not on dialysis with anemia due to CKD, which we expect in mid-2020, as planned. We believe that the INNO2VATE data will be highly informative for physicians, patients, dialysis providers and payers, as they make important decisions about patient care, once vadadustat is approved.”

Global Phase 3 INNO2VATE Program
Akebia’s global INNO2VATEprogram is a cardiovascular outcomes program that includes two separate Phase 3 studies (Correction/Conversion and Conversion), which collectively enrolled 3,923 adult patients on dialysis with anemia due to CKD. Both INNO2VATE studies are global, multicenter, open label (sponsor blinded), active-controlled (darbepoetin alfa – an injectable erythropoiesis stimulating agent (ESA)), non-inferiority studies. In both studies, patients were randomized 1:1 to receive either vadadustat or darbepoetin alfa. Vadadustat was initiated at a starting oral dose of 300 mg once daily and adjusted over time in increments of 150 mg within the range of 150 to 600 mg daily using a dose adjustment algorithm, while darbepoetin alfa was dosed per the US package insert (USPI) or summary of product characteristics (SmPCs) in appropriate geographies.

The INNO2VATE Correction/Conversion study evaluated 369 incident dialysis patients (181 and 188 patients randomized to vadadustat and darbepoetin alfa, respectively) who initiated chronic dialysis (either peritoneal dialysis (PD) or hemodialysis (HD)) for end-stage renal disease (ESRD) ≤ 16 weeks prior to screening and had limited exposure to recombinant erythropoiesis stimulating agents (rESAs). The INNO2VATE Conversion study evaluated 3,554 dialysis patients (1,777 and 1,777 patients randomized to vadadustat and darbepoetin alfa, respectively) currently receiving rESA who were converted to either vadadustat or darbepoetin alfa.

In both INNO2VATE studies, the primary efficacy endpoint was the mean change in Hb between baseline and the primary evaluation period (weeks 24-36). NI was achieved if the lower bound of the 95% confidence interval for the between-group difference of the mean Hb change did not fall below the pre-specified NI margin (-0.75 g/dL). The INNO2VATE program’s primary safety endpoint, MACE, was independently and blindly assessed by the Brigham and Women’s Hospital’s Clinical Endpoint Center (BWH CEC) in Boston, MA, with a comparison of vadadustat to darbepoetin alfa. MACE is defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke. To assess MACE, a combined analysis of time to first MACE event from the two INNO2VATE studies was performed. NI was achieved if the upper bound of the 95% confidence interval for the hazard ratio of vadadustat to darbepoetin alfa did not exceed the pre-specified NI margin of 1.25.

Primary and Key Secondary Efficacy Endpoint Results
Vadadustat achieved each of the INNO2VATE studies’ primary efficacy endpoints of mean change in Hb between baseline and the primary evaluation period (mean Hb from weeks 24 to 36) compared to darbepoetin alfa, in adult patients on dialysis, demonstrating non-inferiority to darbepoetin alfa based on using a non-inferiority margin of -0.75 g/dL prospectively agreed to with FDA and EMA.

In INNO2VATE’s Correction/Conversion study of incident dialysis patients (n=369):

  • Primary Efficacy Endpoint Result: Vadadustat was non-inferior to darbepoetin alfa. The least square mean difference in Hb was -0.31 g/dL (95% CI: -0.53, -0.10), achieving the pre-specified non-inferiority criterion of -0.75 g/dL. The mean (SD) Hb level at week 24 to week 36 was 10.36 (1.13) g/dL for vadadustat-treated patients compared to 10.61 (0.94) g/dL for darbepoetin alfa-treated patients.
  • Key Secondary Efficacy Endpoint Result: Vadadustat sustained the target Hb efficacy response at weeks 40 to 52 achieving non-inferiority compared to darbepoetin alfa. The least square mean difference in Hb was -0.07 g/dL (95% CI: -0.34, 0.19). The mean (SD) Hb level at week 40 to week 52 was 10.51 (1.19) g/dL for vadadustat treated-patients compared to 10.55 (1.14) g/dL for darbepoetin alfa-treated patients.

In INNO2VATE’s Conversion study of dialysis patients (n=3,554):

  • Primary Efficacy Endpoint Result: Vadadustat was non-inferior to darbepoetin alfa. The least square mean difference in Hb was -0.17 g/dL (95% CI: -0.23, -0.10), achieving the pre-specified non-inferiority criterion of -0.75 g/dL. The mean (SD) Hb level at week 24 to week 36 was 10.36 (1.01) g/dL for vadadustat-treated patients compared to 10.53 (0.96) g/dL for darbepoetin alfa-treated patients.
  • Key Secondary Efficacy Endpoint Result: Vadadustat sustained efficacy in the Conversion study demonstrating non-inferiority to darbepoetin with a least square mean difference in Hb of -0.18 g/dL (95% CI: -0.25, -0.12). The mean (SD) Hb level at week 40 to week 52 was 10.40 (1.04) g/dL in the vadadustat-treated patients compared to 10.58 (0.98) g/dL for darbepoetin treated patients.

Primary Safety Major Adverse Cardiovascular Events (MACE) Endpoint Result
Vadadustat achieved the INNO2VATE program’s primary safety endpoint of non-inferiority for MACE. In the primary analysis of time to first MACE event, vadadustat demonstrated non-inferiority to darbepoetin alfa using a non-inferiority margin of 1.25 prospectively agreed to by FDA and a non-inferiority margin of 1.3 prospectively agreed to by EMA.

The INNO2VATE program (Correction/Conversion and Conversion studies) of dialysis patients (n=3,902):

  • Vadadustat was non-inferior to darbepoetin alfa. The upper bound of the 95% confidence interval (CI) of the Hazard Ratio (HR) was below the pre-specified non-inferiority margin of 1.25 for primary MACE analysis. (HR 0.96, 95% CI: 0.83, 1.11.) MACE is defined as the composite endpoint of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke.

The incidence of treatment emergent adverse events during the Correction/Conversion study in vadadustat treated patients was 83.8% and 85.5% in darbepoetin alfa treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa treated patients were hypertension (16.2%/ 12.9%) and diarrhea (10.1%/ 9.7%). Serious treatment emergent adverse events were lower in vadadustat treated patients at 49.7% compared to 56.5% for darbepoetin alfa treated patients. The incidence of treatment emergent adverse events during the Conversion study in the vadadustat treated patients was 88.3%, and 89.3% in darbepoetin alfa treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa treated patients were diarrhea (13.0%/ 10.1%), pneumonia (11.0%/ 9.7%), hypertension (10.6%/ 13.8%), and hyperkalemia (9.0%/ 10.8%). Serious treatment emergent adverse events were slightly lower for vadadustat treated patients at 55.0% and 58.3% for darbepoetin alfa-treated patients.

“With nearly 4,000 patients participating in INNO2VATE and a total exposure of just over 2,200 patient-years with vadadustat, INNO2VATE has been a tremendous undertaking. We would like to extend our sincere thanks to everyone involved in this study including the patients, physicians, investigators and site coordinators,” said Steven K. Burke, M.D., Senior Vice President, Research & Development and Chief Medical Officer of Akebia. “We believe vadadustat has the potential to play a key role in the treatment of anemia due to CKD, and we are another step closer to realizing that vision. We are very pleased with these clear and consistent findings and are excited to share the full data set, together with the data from our PRO2TECT studies, later this year at a medical conference and in a peer-reviewed journal.”

Upon successful completion of the Phase 3 program, which includes the PRO2TECT studies of vadadustat for the treatment of anemia due to CKD in adult patients not on dialysis that the Company expects to read out mid-2020, Akebia plans to submit to FDA an NDA for vadadustat for the treatment of anemia due to CKD in adult dialysis-dependent and non-dialysis dependent patients. In close coordination with its collaborator, Otsuka Pharmaceutical Co. Ltd., the Company also plans to submit a Marketing Authorization Application (MAA) to EMA. Akebia and Otsuka are collaborating on the development and commercialization of vadadustat in the US, Europe, China, Russia, Canada, Australia, the Middle East, and certain other territories. A Japanese New Drug Application (JNDA) for vadadustat was submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) in July 2019 by Mitsubishi Tanabe Pharma Corporation (MTPC), Akebia’s development and commercialization collaboration partner in Japan for vadadustat.

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