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A group of FDA advisors recommended approval of daprodustat for treating chronic kidney disease (CKD)-related anemia, but only for the subset of patients on dialysis, determining that the same risk-benefit profile did not exist for those not dependant on the kidney replacement therapy.

By a 13-3 vote on Wednesday, the decided that any safety signals that emerged in clinical testing versus erythropoiesis stimulating agents (ESAs) were generally muted in the dialysis population and were largely overshadowed by the benefits of having this new oral anemia treatment, especially for home dialysis patients.

"In this patient population, efficacy was met," said Christopher O'Connor, MD, of Inova Heart and Vascular Institute in Falls Church, Virginia, who voted to recommend approval in the dialysis group. "I felt that the safety signals in the cardiovascular space appeared more favorable than the ESA" -- a therapy with risks that include serious cardiovascular and thromboembolic events like stroke and myocardial infarction.

When looking at individual cardiovascular safety endpoints, he noted that while not statistically significant, six of seven favored daprodustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) drug.

"This could afford a potential advantage over ESAs," said O'Connor.

After also voting in favor for this population, Kevin Abbott, MD, MPH, of the National Institutes of Health in Bethesda, Maryland, said this anemia therapeutic could be particularly beneficial as an alternative for patients who are ESA-resistant.

There's a group of dialysis patients, "hemodialysis patients particularly, who are on truly astronomical doses of ESAs to maintain their hemoglobin levels, and it's a significant problem for them," he said.

As the only available anemia treatment options currently include iron, red blood cell transfusions, and ESAs, many members of the committee pointed out how helpful an oral treatment option would be as home dialysis starts to be encouraged more and more.

In the non-dialysis CKD population, the panel voted 11-5 against recommending approval of daprodustat, largely over concerns that the potential risks did not outweigh the convenience of an oral treatment option.

"While I don't think that we feel confident that it has increased risk, I do think that the data we reviewed today leaves us feeling very uncertain about increased risk," said C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles, who voted against recommending approval in the non-dialysis population.

Certain risks that emerged in the ASCEND clinical program for daprodustat appeared solely in non-dialysis patients treated in the U.S.

Subanalyses showed higher risk for thromboembolic events (HR 2.03, 95% CI 1.06-3.87) and cardiovascular mortality (HR 1.86, 95% CI 1.10-3.12) among the U.S. patients. There were also safety signals for serious gastric/esophageal erosions and acute kidney injury exclusive to this non-dialysis population.

But the heart failure-related hospitalization risk in the U.S. patients (HR 1.65, 95% CI 1.09-2.50) was the outcome that seemed to weigh most heavily on panelists.

Most committee members who voted against recommending approval in the non-dialysis population called for additional data. A few suggested another trial would be helpful -- one that looked exclusively at the U.S. populations with an expanded major adverse cardiovascular event (MACE) endpoint including heart failure and patient-reported outcomes.

If approved, daprodustat would be the first HIF-PHI to get the agency's blessing. Roxadustat, another HIF-PHI, was last year for CKD-related anemia after the same committee voted against the drug due to concerns about thrombotic risks.

A main topic of discussion on Wednesday was whether these safety signals could be due to a class effect. Merz, along with a few other panel members, suggested a meta-analysis be conducted in order to confirm if these safety signals are apparent in the HIF-PHI class, or if they disappear entirely with greater statistical power.

Having voted in favor of the drug for both populations, Patrick Nachman, MD, of the University of Minnesota in Minneapolis, highlighted that the majority of non-dialysis CKD patients aren't treated at all for their anemia.

"Having an oral drug would increase access to care and decrease the burden on patients who are left untreated right now," he said.

Another panelist, Ravi Thadhani, MD, MPH, of Massachusetts General Brigham in Boston, encouraged daprodustat's developer GSK and the FDA to work together to figure out ways to identify a lower-risk non-dialysis population, develop risk-mitigation strategies, and then revisit the vote.

Although the FDA is not required to follow its advisory committee recommendations, the agency typically does.

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