FDA Committee Recommends Against Roxadustat Approval for CKD Patients

The FDA Cardiovascular and Renal Drugs Advisory Committee cited concerns over an increase in thrombotic events.

The US Food and Drug Administration’s (FDA) Cardiovascular and Renal Drugs Advisory Committee has recommended against the approval of roxadustat for the treatment of anemia in adult patients with chronic kidney disease (CKD) patients citing concerns over an increased risk for thrombotic events and other major cardiovascular adverse events.

The committee voted 13-1 against the approval of the treatment being developed by a partnership of FibroGen and AstraZeneca for chronic kidney disease patients not on dialysis (NDD) and 12-2 against the approval for patients on dialysis (DD).

The Drug

Roxadustat is an oral, small molecule, hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. The treatment represents the first HIF-PH inhibitor accepted by the FDA for review to treat anemia of CKD.

Anemia is a common early complication of chronic kidney disease, affecting approximately 20% of CKD patients. Roxadustat works by increasing endogenous production of erythropoietin, improved iron absorption and mobilization, and down regulation of hepcidin.

Currently, erythropoiesis stimulating agents (ESA), including epoetin alfa and darbepoetin alfa, are generally to treat anemia in CKD patients. However, this class of medications increase red blood cell mass through the same mechanism as endogenous erythropoietin.

Efficacy and Safety

In briefing documents released prior to the meeting, the FDA said the treatment’s efficacy does warrant approval based on 6 adequate and well-controlled trials involving both dialysis and non-dialysis patients.

“As is the case with ESAs, roxadustat is titrated to achieve a target Hb level, and roxadustat’s efficacy is not in question,” the agency said. “All studies in both the NDD and DD patient populations demonstrated efficacy.”

However, the main issue is over the safety of the treatment.

One of the major concerns is both Roxadustat and ESAs could increase the risk of thrombotic events in this patient population.

“The ESAs are known to increase the risk of thrombotic events, and they are listed as adverse drug reactions in their labeling,” the FDA said. “Roxadustat also shows an obvious signal for serious thrombotic events, with an estimated risk difference (vs. placebo) of 1.1 events per 100 P-Y and a relative risk of 1.45.”

Lack of Diversity in Trials

Another concern raised by multiple members of the committee was a lack of diversity in the clinical trials for roxadustat, particularly for African-American patients.

The treatment is currently approved in China, Japan, and Chile for the treatment of anemia of chronic kidney disease in adult patients on dialysis and not on dialysis.