Vadadustat safe and effective treatment for anemia in CKD: PRO2TECT studies
USA: Vadadustat achieved the primary and key secondary efficacy endpoint in each of the two PRO2TECT studies -- that evaluated the safety and efficacy of Akebia's vadadustat versus darbepeotin alfa for the treatment of anemia due to chronic kidney disease (CKD) in adult patients not on dialysis. In simpler words, Vadadustat was found to be safe and effective for the treatment of anemia due to CKD.
The Company's vadadustat development program also includes two other global Phase 3 studies (INNO2VATE) for the treatment of anemia due to CKD in adult patients on dialysis.
Vadadustat demonstrated non-inferiority (NI) 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 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, and non-fatal stroke across both PRO2TECT studies.
Akebia's global PRO2TECT program is a cardiovascular outcomes program that includes two separate Phase 3 studies (Correction and Conversion), which collectively enrolled 3,476 adult patients not on dialysis with anemia due to CKD. Both PRO2TECT studies are global, multicenter, open-label, 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 U.S. package insert (USPI) or summary of product characteristics (SmPCs) in appropriate geographies.
The PRO2TECT Correction study evaluated 1,751 patients with anemia due to CKD without recent ESA use (879 and 872 patients randomized to vadadustat and darbepoetin alfa, respectively). The PRO2TECT Conversion study evaluated 1,725 patients with anemia due to CKD on an active ESA treatment (862 and 863 patients randomized to vadadustat and darbepoetin alfa, respectively).
In both PRO2TECT studies, the primary efficacy endpoint was the mean change in Hb between baseline and the primary evaluation period (weeks 24-36). Non-inferiority was achieved if the lower bound of the 95% confidence interval (CI) for the between-group difference of the mean Hb change did not fall below the pre-specified NI margin (-0.75 g/dL).
The PRO2TECT 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, and non-fatal stroke. To assess MACE, a combined analysis of time to first MACE event from the two PRO2TECT 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.
Key findings of the PRO2TECT's Correction study (n=1,751)
- Vadadustat was non-inferior to darbepoetin alfa.
- The least square mean difference in Hb was 0.05 g/dL, achieving the pre-specified NI criterion of -0.75 g/dL.
- The mean (SD) Hb level at week 24 to week 36 was 10.39 (0.99) g/dL for vadadustat-treated patients compared to 10.35 (1.03) g/dL for darbepoetin alfa-treated patients.
- 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 0.04 g/dL. The mean (SD) Hb level at week 40 to week 52 was 10.48 (1.05) g/dL for vadadustat-treated patients compared to 10.45 (1.01) g/dL for darbepoetin alfa-treated patients.
Key findings of the PRO2TECT's Conversion study (n=1,725)
- Vadadustat was non-inferior to darbepoetin alfa.
- The least square mean difference in Hb was -0.01 g/dL., achieving the pre-specified NI criterion of -0.75 g/dL.
- The mean (SD) Hb level at week 24 to week 36 was 10.77 (0.98) g/dL for vadadustat-treated patients compared to 10.77 (0.99) g/dL for darbepoetin alfa-treated patients.
- Vadadustat sustained efficacy in the Conversion study demonstrating non-inferiority to darbepoetin with a least square mean difference in Hb of 0.00 g/dL.
- The mean (SD) Hb level at week 40 to week 52 was 10.80 (1.04) g/dL in the vadadustat-treated patients compared to 10.79 (1.05) g/dL for darbepoetin alpha-treated patients.
"The results of Akebia's global Phase 3 program continue to underscore the potential of vadadustat as a once-daily oral standard of care for patients living with anemia due to CKD, upon approval," stated Steven K. Burke, M.D., Senior Vice President, Research & Development and Chief Medical Officer of Akebia Therapeutics.
