FDA Advisory Committee Votes Against Roxadustat Approval Amid Safety Concerns

By | Shibei

On July 15, the U.S. FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted against approving the marketing application for roxadustat, an oral HIF-PH inhibitor developed by FibroGen/AstraZeneca, for the treatment of anemia in patients with chronic kidney disease (CKD). Specifically, the voting results were 12:2 against approval for dialysis-dependent CKD patients and 13:1 against for non-dialysis-dependent CKD patients. The committee’s vote was based on data from a global Phase III clinical program involving over 8,000 patients.

Roxadustat is an oral, first-in-class small-molecule hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that promotes erythropoiesis by increasing endogenous erythropoietin production, improving iron absorption and mobilization, and downregulating hepcidin. This discovery was awarded the 2019 Nobel Prize in Physiology or Medicine. Roxadustat has the potential to transform the treatment of anemia in chronic kidney disease (CKD).

The expert committee voted against approving roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis, primarily due to concerns regarding the overall safety profile. Additionally, they expressed skepticism toward partner AstraZeneca’s proposal to conduct a post-marketing study to further evaluate the cardiac safety of the drug.

The only person to vote in favor was Dr. Susan Crowley of the Veterans Health Administration, who stated that under a potential risk-mitigation plan, it is fair for patients and providers to share decision-making responsibility.

For CKD patients on dialysis, the expert committee voted against approval by a margin of 2 to 12. During the voting process, Dr. Ravi Thadhani from Mass General Brigham switched his vote to yes, stating that some patients could benefit from this treatment and expressing confidence that AstraZeneca and FibroGen are carefully addressing the safety concerns.

During the meeting, members of the FDA Cardiovascular and Renal Drugs Advisory Committee discussed the safety and efficacy of the drug in dialysis and non-dialysis patients, as well as the enrollment criteria for the clinical study program, a potential post-marketing study, and other related matters.

Most of the discussion focused on the safety of use in healthcare institutions and the application materials submitted by the company. Finally, the experts recommended that the company provide additional safety data prior to market approval.

At a public hearing prior to the vote, patients and physicians urged the experts to support the drug's market approval, citing the challenges associated with current therapies and the advantages of oral medications.

Dr. Alice Wei, a nephrologist in New York City, stated that many patients lack access to standard treatment for anemia of chronic kidney disease, underscoring an urgent need for alternative options. She noted that roxadustat, an oral medication, is "more accessible" to patients in need.

The outcome of this vote by the FDA Advisory Committee has significantly increased the uncertainty surrounding the FDA's approval of this drug. While the FDA retains the authority to make approval decisions independently of the committee, it typically adheres to the committee's recommendations. However, the FDA's prior approval of Biogen's Alzheimer's therapy despite the committee's opposition has altered this precedent.

For roxadustat, the FDA's initial PDUFA date was December 2020, but the agency later extended its review to March 2021. In March of this year, the FDA announced it would convene an Advisory Committee meeting, which further delayed the process.

After experiencing consecutive delays, the partners faced another setback in April when FibroGen admitted to altering the criteria used to analyze the cardiac safety data for roxadustat in order to make the results more favorable.

Industry observers initially regarded the drug as a blockbuster, believing it could capture market share from the standard therapy, recombinant human erythropoietin, and additionally gain market share among non-dialysis patients.

Roxadustat has been approved in China, Japan, Chile, and South Korea for the treatment of chronic renal anemia in non-dialysis-dependent (NDD) and dialysis-dependent (DD) adult patients. It has also received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

Astellas and FibroGen are jointly responsible for the development and commercialization of roxadustat in Japan, Europe, Turkey, Russia, the Commonwealth of Independent States (CIS), the Middle East, and South Africa. AstraZeneca and FibroGen are jointly responsible for the development and commercialization in the United States, China, other markets in the Americas, Australia/New Zealand, and Southeast Asia.