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The investigational hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor vadadustat was noninferior to the erythropoiesis-stimulating agent darbepoetin alfa for treating anemia in chronic kidney disease (CKD) patients, a pair of phase III trials found.

In the first trial -- of non-dialysis-dependent CKD -- treatment with vadadustat met the pre-specified noninferiority endpoint for hematologic efficacy compared with darbepoetin alfa, reported Glenn Chertow, MD, MPH, of Stanford University School of Medicine in California, and colleagues.

Looking only at ESA-untreated patients, there was an average between-group hemoglobin concentration difference of 0.05 g/dL (95% CI -0.04 to 0.15) maintained from weeks 24 to 36 with vadadustat or darbepoetin alfa treatment.

Similarly, there was a mean hemoglobin concentration between-group difference of -0.01 g/dL (95% CI -0.09 to 0.07) among ESA-treated patients, meeting the prespecified noninferiority margin of -0.75 g/dL.

Heart health suffered in the vadadustat arm, however, with a pooled analysis of the ESA-treated and untreated patients demonstrating a 17% higher risk of a first major cardiovascular event (MACE), defined as death from any cause, nonfatal MI, or nonfatal stroke (HR 1.17, 95% CI 1.01-1.36).

Overall, 22% of those on vadadustat (382 of 1,739) and 19.9% of those on darbepoetin alfa (344 of 1,732) experienced their first MACE during the trial. Individual components of the MACE endpoint were numerically higher for the non-dialysis patients treated with vadadustat.

Despite this, adverse events were similar between the two groups, including the cumulative incidences of pulmonary hypertension and cancer.

This trial randomized patients in a 1:1 fashion. Patients randomized to oral vadadustat were started on 300 mg once daily, titrated up to a maximum dose of 600 mg daily. Darbepoetin alfa was given either subcutaneously or intravenously. Iron supplementation was also encouraged, so that a ferritin concentration of at least 100 ng/mL or a transferrin saturation of at least 20% would be maintained.

In the second trial -- of dialysis-dependent CKD -- vadadustat was again noninferior to darbepoetin alfa in regards to efficacy of hemoglobin concentration maintenance.

Looking just at patients with incident dialysis-dependent CKD, the mean between-group differences in the change in hemoglobin concentrations were -0.31 g/dL (95% CI -0.53 to -0.10) at weeks 24 to 36 and -0.07 g/dL (95% CI -0.34 to 0.19) at weeks 40 to 52, reported Kai-Uwe Eckardt, MD, of the Charité-Universitätsmedizin Berlin in Germany, and colleagues.

For patients with prevalent dialysis-dependent CKD, the investigators saw average between-group differences in hemoglobin concentration change of -0.17 g/dL (95% CI -0.23 to -0.10) at weeks 24 to 36 and -0.18 g/dL (95% CI -0.25 to -0.12) at weeks 40 to 52.

Interestingly, a pooled analysis of all dialysis-dependent CKD patients in INNO₂VATE didn't indicate the same heart safety signal that was seen in PRO₂TECT.

Instead, there wasn't any significant risk difference in first MACE occurrence between dialysis patients on vadadustat and darbepoetin alfa (18.2% vs 19.3%; HR 0.96, 95% CI 0.83-1.11).

This trial randomized a total of 3,923 patients in a 1:1 fashion, 369 of whom had incident dialysis-dependent CKD and 3,554 of whom had prevalent dialysis-dependent CKD.

Both trials were published in the New England Journal of Medicine and were presented at the American Society of Nephrology's virtual Kidney Week 2020.

"The discovery of HIF prolyl hydroxylase inhibitors has reinvigorated the field of research involving anemia associated with kidney disease," noted Adeera Levin, MD, of the University of British Columbia in Vancouver, Canada, in an .

"Current treatment targets are underpinned by avoidance of harm when ESAs are used in high-risk populations; whether the same targets apply to HIF prolyl hydroxylase inhibitors is open to debate," Levin wrote, adding that these two trials "may stimulate discussion regarding the appropriateness of a noninferiority trial design to answer questions about comparative drug safety."

Levin continued, pointing out that although these trials confirm the efficacy of vadadustat in regards to increasing hemoglobin concentrations in both dialysis and non-dialysis dependent patients, the jury is still out when it comes to heart safety.

"The issues raised in these trials should motivate us to answer critical questions regarding goals of therapy, risks, and benefits, with trials specifically designed to do so," she suggested.

Drug developer Akebia Therapeutics submitted a to the FDA in March seeking approval of vadadustat.