Another CKD-Related Anemia Drug Goes Under the Microscope of FDA Advisors

An FDA advisory panel will weigh in on whether the safety signals of daprodustat in chronic kidney disease (CKD)-related anemia are too risky to recommend the oral agent for approval.

On Wednesday, the FDA's Cardiovascular and Renal Drugs Advisory Committee will review the evidence and vote on whether the investigational agent's benefits for CKD-related anemia in patients both on or off dialysis outweigh its risks, which range from gastric erosions or hemorrhage to acute kidney injury and heart failure.

There's no question there is an unmet need for these patients. Standard treatment options consist of iron, red blood cell transfusions, and erythropoiesis-stimulating agents (ESAs). But ESAs carry boxed warnings for increased mortality and serious cardiovascular and thromboembolic events like stroke and myocardial infarction.

According to FDA briefing documents released ahead of the meeting, about 8% of patients with stage 4 CKD and 13% of those with stage 5 CKD are treated with an ESA, as are 12% to 17% of patients with pre-end-stage renal disease.

Daprodustat is a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) from developer GSK, and was tested for non-inferiority against intravenous or subcutaneous ESAs in the phase III ASCEND clinical program. These agents work by inhibiting the oxygen pathway, stimulating endogenous erythropoietin production and thus raising hemoglobin levels. While several HIF-PHI drugs have been developed, none have received approval from the FDA. Roxadustat was the first agent in this class to be sent to the FDA for review, but was ultimately turned down by this same advisory panel in July 2021 due to concerns about thrombotic risk.

"The efficacy of daprodustat to raise hemoglobin is not in question," the FDA wrote in its briefing documents.

In the ASCEND program, participants with CKD undergoing hemodialysis or peritoneal dialysis had a mean change in hemoglobin level of 0.28±0.02 g/dL from baseline to weeks 28 through 52 with daprodustat -- showing a 0.18 g/dL improvement compared with ESA treatment. As for patients with CKD not on dialysis, the average change in hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g/dL in the daprodustat group and 0.66±0.02 g/dL in the darbepoetin alfa group.

"Daprodustat is the first agent within the HIF-PHI class to demonstrate clear and consistent efficacy in achieving and maintaining hemoglobin levels," Ajay Singh, MBBS, MBA, of Brigham and Women's Hospital in Boston and ASCEND clinical program chair, previously told MedPage Today.

Safety of daprodustat is slated to be the main point of discussion among panel members, with questions from the agency geared toward cardiovascular harm, gastric erosions and hemorrhage, and acute kidney injury.

With regard to major adverse cardiovascular events (MACE), the agency said daprodustat did not "unacceptably increase the risk" in the dialysis-dependent population. But FDA noted that some analyses found elevated hazard ratios for MACE in the non-dialysis population, including cardiovascular mortality, myocardial infarction, stroke, thromboembolic disease, and vascular access thrombosis.

"Because ESAs such as darbepoetin alfa already carry some of these risks, a further increase in these risks beyond that seen with the ESAs is concerning," FDA staff noted.

In subanalyses of the non-dialysis trial involving U.S. patients, significantly higher risks with daprodustat were seen for cardiovascular mortality (HR 1.86, 95% CI 1.10-3.12), hospitalization for heart failure (HR 1.65, 95% CI 1.09-2.50), and thromboembolic events (HR 2.03, 95% CI 1.06-3.87) as well.

"The elevated risks in the U.S. subgroup across multiple cardiovascular endpoints is noteworthy because daprodustat would be used in the U.S. if FDA approved," the agency noted.

A higher number of serious gastric/esophageal erosions with the drug was similarly isolated to the non-dialysis-dependent group (HR 1.63, 95% CI 1.17-2.27), and "the risk appears to accumulate constantly over time," the FDA noted, adding that most of these events were "overt gastrointestinal bleeding," with more than half requiring transfusions.

FDA staff also warned of a possible increased risk for serious acute kidney injury in the non-dialysis population (relative risk 1.47, 95% CI 1.07-2.00), but added that this risk was attenuated when considering all acute kidney injury adverse events regardless of severity.

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