Phase 3 data published on anemia drug vadadustat
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Phase 3 trial results of the anemia drug vadadustat for patients with kidney disease show the drug is efficacious but acknowledge safety issues when used in the non-dialysis patient population.
“ ... [W]e found that, among patients with (non-dialysis dependent chronic kidney disease) NDD-CKD, vadadustat [Akebia Therapeutics Inc.] was noninferior to darbepoetin alfa with regard to hematologic efficacy but did not meet the prespecified noninferiority criterion for cardiovascular safety, which was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke,” Glenn M. Chertow, MD, MPH, professor of medicine at Stanford University School of Medicine and lead author of one of two manuscripts, and colleagues wrote. Chertow is also co-chair of the independent executive steering committee for the phase 3 program.
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia due to chronic kidney disease. Akebia has used results from the company’s INNO2VATE and its PRO2TECT trial for the new drug application, which was submitted to the FDA earlier this year for the two indications.
Trial
For the INNO2VATE trial, two randomized studies were conducted to evaluate the safety and efficacy of vadadustat compared with darbepoetin alfa. The test group included patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD).
The primary safety end point was the first occurrence of a major adverse cardiovascular event (MACE). A key secondary safety end point was the first occurrence of a MACE, plus hospitalization for either heart failure or a thromboembolic event.
“The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively,” Kai-Uwe Eckardt, MD, from the department of nephrology and medical intensive care, Charité–Universitätsmedizin Berlin, and colleagues wrote.
In the pooled analysis, investigators found a first MACE occurred in 18.2% of patients in the vadadustat group and in 19.3% of patients in the darbepoetin alfa group.
“The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively,” the authors reported.
“Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations,” they wrote.
Major adverse cardiovascular event
Akebia officials reported last September that data from its two PRO2TECT studies for patients not on dialysis showed vadadustat had noninferiority vs. darbepoetin alfa in time to first occurrence of MACE.
“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,” John P. Butler, president and CEO of Akebia Therapeutics Inc., said in a press release at the time.
In the PRO2TECT trial, researchers randomized 3,476 patients to those with untreated anemia (n = 1,751) and 1,725 patients who were being treated with darbepoetin alfa.
“We conducted all the analyses related to MACE safety end points using the safety population (all patients who received at least one dose of the trial drug), pooled across the two trials; therefore, 1,739 patients were included in the vadadustat group and 1,732 in the darbepoetin alfa group,” Chertow and colleagues wrote. “ ... A first MACE occurred in 382 of 1,739 patients (22%) in the vadadustat group and in 344 of 1,732 patients (19.9%) in the darbepoetin alfa group.”
They added, “With regard to the components of MACE, death from any cause occurred in 319 patients (18.3%) in the vadadustat group and in 307 (17.7%) in the darbepoetin alfa group; nonfatal myocardial infarction in 67 (3.9%) and 48 (2.8%), respectively; and nonfatal stroke in 34 (2%) and 28 (1.6%), respectively.”
The authors noted the higher rate of MACE in the non-dialysis group was not seen among patients in the INNO2VATE trial and could have a link to hemoglobin levels.
References:
Chertow GM, et al. N Engl J Med 2021;doi:10.1056/NEJMoa2035938.
Eckardt KU, et al. N Engl J Med 2021;doi:10.1056/NEJMoa2025956.
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