An advisory committee to the US Food and Drug Administration (FDA) has overwhelmingly rejected the approval application for roxadustat, a novel, oral agent for the treatment of anemia secondary to chronic kidney disease (CKD).
The committee voted 1 in favor and 13 against this indication in non-dialysis-dependent patients with CKD, and 2 in favor and 12 against for patients receiving dialysis.
Safety concerns drove both negative votes. In four pivotal trials that included a total of nearly 4900 patients with non-dialysis-dependent CKD and in four trials that enrolled more than 4700 patients with dialysis-dependent CKD, results of analyses presented by FDA staffers showed worrisome signals of increases among roxadustat-treated patients in all-cause death, major adverse coronary events, thrombotic events, thrombosis in vascular access sites among patients receiving dialysis, infections, and seizures compared with control patients.
The agency acknowledged that roxadustat is effective in comparison with placebo or darbepoetin alfa for non-dialysis-dependent patients and in comparison with either epoetin alfa or darbepoetin alfa for dialysis-dependent patients.
Efficacy Looked Fine, but What About Safety?
“The FDA believes the Applicant has provided substantial evidence of efficacy,” said Saleh Ayache, MD, from the FDA’s staff.
The major question the agency asked the Cardiovascular and Renal Drugs Advisory Committee to address was whether the safety profile showed that this efficacy came without undue risk. The committee members collectively replied no.
“There is an unmet need” for more options for treating CKD-associated anemia, summed up committee chair Julia B. Lewis, MD, “but there are concerns over adverse safety, especially all-cause death.”
In a move aimed at blunting the increased thrombotic risk for patients who have achieved higher hemoglobin levels, staff from the drug’s developer, Fibrogen, proposed that if approved, roxadustat’s labeling should specify a lower dose than that used in the pivotal trials and a reduced hemoglobin target of 10.0–11.0 g/mL, rather than the 10.5–12.0 g/mL target used in the pivotal trials.
Most committee members panned this proposal.
“Modeling Can’t Replace a Clinical Trial”
“Modeling can’t replace a clinical trial for safety,” observed Lewis, a nephrologist at Vanderbilt University Medical Center, Nashville, Tennessee, who is one of several panel members who said that the company’s proposal required testing in a new study before it could be accepted as a viable safety solution.
The sole committee member who twice voted in favor of approval, Susan T. Crowley, MD, a nephrologist at Yale University School of Medicine, New Haven, Connecticut, said that she was swayed by the unmet need to improve convenience for patients undergoing treatment for anemia, as well as the fact that the drug would enable a smoother transition for patients who are not yet receiving dialysis as they did begin dialysis.
Several other panel members, including the patient and the consumer representatives, agreed that these are potential advantages of roxadustat, which would be the first oral agent for this indication, but they also found the safety concerns too compelling to ignore.
Another flaw cited in the data was the low enrollment of Black persons, who constituted 8% of the nondialysis-dependent patients and 15% of those receiving dialysis in the trials ― numbers substantially below the prevalence rates among Black patients in real-world US practice.
“Underrepresentation of Blacks is unfortunate and of concern,” Lewis said.
Several panel members suggested that the best chance for getting roxadustat approved for patients with CKD might be to target dialysis-dependent patients who have demonstrated an inadequate response to erythropoietin-stimulating agents. These patients, known as hyporesponders, constitute roughly 10% of all dialysis-dependent patients.
Roxadustat is an orally administered, reversible inhibitor of hypoxia inducible factor (HIF)-prolyl hydroxylases (PH). Inhibition of HIF-PH stabilizes and increases levels of HIFs, which in turn increases endogenous erythropoietin, thereby increasing erythropoiesis. HIFs are transcription factors that mediate responses to hypoxia, such as occurs among people who live at high altitudes with low oxygen levels.
Roxadustat received approval for treating CKD-associated anemia in China in 2018 and in Japan in 2020, and it was given a positive opinion by a European Medicines Agency panel at the end of June; approval is normally granted within 60 days.
Questions regarding safety, in particular, cardiovascular safety, have been raised with another HIF-PH inhibitor in development, vadadustat (Akebia Therapeutics), in trials published in The New England Journal of Medicine earlier this year.
Lewis has received personal fees from Sanofi. Crowley has disclosed no relevant financial relationships.
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler.
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