Benzinga | Oct 23, 2020 11:16AM EDT

Akebia Therapeutics Reports Results From PRO2TECT Phase 3 Program Of Vadaustat For Treatment Of Anemia: Data Shows No Clinically Meaningful Increase In Risk Of MACE

Akebia Therapeutics, Inc. (NASDAQ:AKBA), today announced the presentation of clinical data from its PRO2TECT global Phase 3 program that 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 not on dialysis, at American Society of Nephrology Kidney Week 2020 Reimagined (ASN Kidney Week). As previously announced, vadadustat achieved the primary and key secondary efficacy endpoints in each of the two studies in the program, but did not meet the primary safety endpoint. Newly presented pre-specified regional analyses of the PRO2TECT program show vadadustat demonstrated no clinically meaningful increase in cardiovascular risk compared to darbepoetin alfa in analyses of MACE, expanded MACE and all-cause mortality in U.S. patients treated to a target hemoglobin (Hb) range of 10 to 11 g/dL, consistent with U.S. treatment guidelines.

"The PRO2TECT results show that orally administered vadadustat achieved both primary and secondary efficacy endpoints in patients not on dialysis with anemia associated with CKD. The newly presented analyses showed that there were regional differences with respect to MACE, expanded MACE and all-cause mortality, consistent with well-known, differing regional hemoglobin treatment target guidelines," said 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 PRO2TECT and INNO2VATE. "The analyses also confirm there was no increased cardiovascular risk associated with vadadustat across the U.S. patients treated to a target hemoglobin range of 10 to 11 g/dL."

The PRO2TECT data are being presented today during a late-breaking oral presentation, titled "Global Phase 3 Clinical Trials of Vadadustat vs Darbepoetin Alfa for Treatment of Anemia in Patients with Non-Dialysis-Dependent Chronic Kidney Disease" (Abstract FR-OR54) at ASN Kidney Week. Akebia's vadadustat development program also includes INNO2VATE, the global Phase 3 program for the treatment of anemia due to CKD in adult patients on dialysis. Results from this program were presented at ASN Kidney Week in an oral presentation on October 22, 2020.

Highlights of the PRO2TECT ASN Kidney Week Presentation:

Efficacy:

* As previously reported, vadadustat achieved the primary and key secondary efficacy endpoints in each of the two PRO2TECT studies, which demonstrated non-inferiority of vadadustat to darbepoetin alfa as measured by a mean change in Hb between baseline and the primary evaluation period (weeks 24 to 36) and secondary evaluation period (weeks 40 to 52). Non-inferiority was achieved as 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 non-inferiority margin (-0.75 g/dL).

Safety:

* As previously reported, vadadustat did not meet the primary safety endpoint of the PRO2TECT 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 (MI), or non-fatal stroke across both PRO2TECT studies.

* The analysis of the primary safety endpoint used a Cox regression model that was pre-specified to be adjusted for certain variables, including age dichotomized >65 and ?65 years.

* In order to optimize the Cox model used to analyze the primary safety endpoint and increase its statistical power in regional subsets, age was rescaled from dichotomous to a continuous variable.

* In the optimized Cox model, the hazard ratios (HR) were attenuated and the confidence intervals (CI) were narrowed.

* The PRO2TECT study analysis plan was prospectively designed to analyze the effect of regional differences, most notably, well-known differences in Hb treatment targets. Within the study, U.S. patients were treated to a target Hb range of 10 to 11 g/dL and non-U.S. patients were treated to a target Hb range of 10 to 12 g/dL.

* In a pre-specified regional analysis using age as a dichotomous variable, vadadustat was not associated with a clinically meaningful increase in cardiovascular risk compared to darbepoetin alfa in U.S. patients treated to a target Hb range of 10 to 11 g/dL, with a MACE HR of 1.06 (0.87, 1.29). This was confirmed using age as a continuous variable as shown below.

* The incidence of treatment emergent adverse events during the ESA-untreated patients (Correction) study in the vadadustat-treated patients was 90.9%, and 91.6% in darbepoetin alfa-treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa-treated patients were end-stage renal disease (34.7%/ 35.2%), hypertension (17.7%/ 22.1.%), hyperkalemia (12.3.%/ 15.6%), urinary tract infection (12.9%/ 12.0%), diarrhea (13.9%/ 10.0%), peripheral oedema (12.5%/ 10.5%), fall (9.6%/ 10%) and nausea (10%/ 8.2%). Serious treatment emergent adverse events were 65.3% for vadadustat-treated patients and 64.5% for darbepoetin alfa-treated patients. The incidence of treatment emergent adverse events during the ESA-treated patients (Conversion) study in vadadustat treated patients was 89.1% and 87.7% in darbepoetin alfa-treated patients. During the study, the most common treatment emergent adverse events reported in vadadustat/darbepoetin alfa-treated patients were end-stage renal disease (27.5%/ 28.4%), hypertension (14.4%/ 14.8%), urinary tract infection (12.2%/ 14.5%), diarrhea (13.8.%/ 8.8.%), peripheral oedema (9.9%/ 10.1%) and pneumonia (10.0%/ 9.7%). Serious treatment emergent adverse events were 58.5% for vadadustat-treated patients and 56.6% for darbepoetin alfa-treated patients.

"The newly presented pre-specified analyses of PRO2TECT showed that vadadustat had no clinically meaningful increase in cardiovascular risk in U.S. patients not on dialysis treated to a target hemoglobin range of 10 to 11 g/dL, consistent with U.S. treatment guidelines. Upon submission of our NDA for vadadustat, we expect that the potential approval of vadadustat as a treatment for patients not on dialysis will be a review issue for the FDA, and we continue to believe that these important analyses, together with the totality of data from our Phase 3 program, will inform that review," said John P. Butler, President and CEO of Akebia Therapeutics. "We remain confident that vadadustat has a straightforward path to potential approval for the treatment of patients on dialysis, globally."

Akebia plans to submit to the U.S. Food and Drug Administration (FDA) a New Drug Application (NDA) for vadadustat for the treatment of anemia due to CKD in adult dialysis-dependent and non-dialysis dependent patients as early as possible in 2021. In addition, Akebia and its collaborator, Otsuka Pharmaceutical Co. Ltd., are working together to further analyze these study results to support a Marketing Authorization Application (MAA) for submission to the European Medicines Agency (EMA) next year.

Investor Briefing Webcast

Akebia management will host an investor briefing webcast with Dr. Glenn Chertow on October 23, 2020 at 4:10 p.m. ET to review highlights of the global Phase 3 vadadustat data presentations from ASN Kidney Week. To access Akebia's investor briefing webcast and the accompanying slides please log into the Investors section of the Company's website at https://ir.akebia.com and proceed to the events and presentations page at https://ir.akebia.com/events-and-presentations. Please connect to the Company's website at least 10 minutes prior to the online event to ensure adequate time for any software download that may be required to view the webcast. After the webcast concludes, a replay of the event will be available at that same location until October 29, 2020