Vadadustat has met its primary and secondary efficacy endpoints for the treatment of anemia due to nondialysis chronic kidney disease (CKD), but not its safety endpoint of time to first occurrence of major adverse cardiovascular events (MACE), according to topline results announced by Akebia Therapeutics, which makes vadadustat.

In the 2 phase 3 PRO2TECT randomized trials, investigators evaluated the efficacy and safety of vadadustat, an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), compared with the erythropoiesis stimulating agent (ESA) darbepoetin alfa. In a correction study involving 1751 patients, vadadustat proved noninferior to darbepoetin with a least square mean difference in hemoglobin (Hb) of 0.05g/dL (the prespecified noninferiority criterion was -0.75g/dL). At weeks 24 to 36, mean Hb was 10.39 vs 10.35g/dL for the vadadustat and darbepoetin group, respectively. Vadadustat also sustained target Hb at weeks 40 to 52. The HIF-PHI appeared noninferior to darbepoetin with a least square mean difference in Hb of 0.04g/dL. Mean Hb at 40 to 52 weeks was 10.48 vs 10.45g/dL for the vadadustat and darbepoetin group, respectively.

Investigators found similar results in a conversion study involving 1725 patients. Vadadustat appeared to have similar efficacy to darbepoetin alfa with a least square mean difference in Hb of -0.01 g/dL. Mean Hb at 24 to 36 weeks was 10.77 vs 10.77g/dL, respectively. Vadadustat sustained this effect with a least square mean difference in Hb of 0g/dL. Mean Hb at 40 to 52 weeks was 10.80 vs 10.79g/dL, respectively.

The HIF-PHI failed to demonstrate noninferiority with respect to the primary safety endpoint of time to first MACE, including all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke. In combined data, vadadustat was associated with a 17% increased risk with the upper bound of the 95% confidence interval of the hazard ratio (95% CI: 1.01, 1.36) exceeding the prespecified noninferiority margin of 1.25.

This safety finding contrasts with results from the INNO2VATE trials announced in May. In those trials, vadadustat fared similarly to darbepoetin in time to first occurrence of MACE among dialysis patients (HR 0.96; 95% CI: 0.83, 1.11). With respect to efficacy, the HIF-PHI appeared acceptably similar to the ESA among dialysis patients.

“We remain confident that we have a path toward potential approval for vadadustat in dialysis supported by positive top-line results for efficacy and safety from INNO2VATE,” John P. Butler, president and chief executive officer of Akebia Therapeutics, stated in a company press release. “PRO2TECT delivered positive top-line efficacy results; however, the MACE result presents challenges to achieving our goal of bringing vadadustat to patients in the non-dialysis market. While achieving the MACE endpoint would have made our path here more straightforward, as it is in dialysis, we still believe we have a path toward approval for vadadustat in non-dialysis.”

Akebia Therapeutics plans to submit a new drug application for vadadustat for treating both patients with dialysis and nondialysis CKD in 2021. “We believe the cardiovascular safety of vadadustat is supported by the totality of the data from our global Phase 3 program, including additional analyses on cardiovascular outcomes observed within key geographic regions and across certain patient sub-populations within PRO2TECT,” Butler stated.

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In the PRO2TECT trials, treatment-emergent adverse events (AEs) occurred in 90.9% vs 91.6% of the vadadustat and darbepoetin group, respectively, in the correction study and 89.1% vs 87.7%, respectively, in the conversion study.

In the correction study, the most common treatment-emergent AEs, respectively, were end-stage kidney disease (ESKD, 34.7% vs 35.2%), hypertension (17.7% vs 22.1.%), hyperkalemia (12.3.% vs 15.6%), urinary tract infection (12.9% vs 12.0%), diarrhea (13.9% vs 10.0%), peripheral edema (12.5% vs 10.5%), fall (9.6% vs 10%), and nausea (10.0% vs 8.2%). Serious treatment-emergent AEs occurred in 65.3% vs 64.5%, respectively.

In the conversion study, the most common treatment-emergent AEs were ESKD (27.5% vs 28.4%), hypertension (14.4% vs 14.8%), urinary tract infection (12.2% vs 14.5%), diarrhea (13.8.% vs 8.8.%), peripheral edema (9.9% vs 10.1%), and pneumonia (10.0% vs 9.7%), respectively. Serious treatment-emergent AEs occurred in 58.5% of vadadustat-treated patients and 56.6% of darbepoetin-treated patients.

The PRO2TECT and INNO2VATE clinical trials were supported by Akebia Therapeutics. Please see the original references for a full list of authors’ disclosures.

References

Akebia Therapeutics announces top-line results from its PRO2TECT global phase 3 program of vadadustat for treatment of anemia due to chronic kidney disease in adult patients not on dialysis [press release]. Cambridge, MA: Akebia Therapeutics; September 3, 2020.

Akebia’s Inno2vate top-line data and first quarter 2020 financial results. Akebia Therapeutics. https://ir.akebia.com/static-files/35b56c39-c78a-4024-a5f4-63afad960c65 Accessed on September 8, 2020.

This article originally appeared on Renal and Urology News