FDA Rejects Disc Medicine's Bitopertin Despite Fast-Track Review Under New Voucher Program

Disc Medicine said on Tuesday it will pursue a traditional U.S. approval pathway for its rare disease drug after the Food and Drug Administration declined to approve the treatment under a new fast-track review program. The FDA on Friday rejected bitopertin, a therapy developed to treat the rare blood disorder erythropoietic protoporphyria, which makes patients extremely sensitive to sunlight.

The drug was previously reviewed under the FDA's national priority voucher program, which fast-tracks the process to one to two months from the typical 10-12 months. In October, the FDA named bitopertin as one of the first nine drugs selected for a Commissioner's National Priority Review Voucher (CNPV) pilot program. It's the first experimental drug to go through the new program to fast-track drug reviews. The agency previously approved a generic antibiotic through the new drug review program in December.

Erythropoietic protoporphyria is a blood disorder caused by deficiency of an enzyme needed to produce heme, the iron-containing molecule that's part of hemoglobin in red blood cells. The disease leads to buildup of protoporphyrin IX (PPIX). High levels of this compound are associated with skin that's hypersensitive to light. Patients experience tingling, itching, even burning sensation from sunlight and some forms of artificial light. The Disc drug, an oral small molecule formulated as a once-daily pill, is intended to reduce PPIX levels. Disc licensed bitopertin from Roche in 2021.

The FDA, in its letter rejecting bitopertin, cited "uncertainties" about the correlation between the blood-based biomarker used as the efficacy goal in Disc's clinical trials and clinical benefit for patients. The agency's complete response letter states that Disc needed to not only show evidence of effect according to the surrogate endpoint, but also that this surrogate measure, including the magnitude of change, is reasonably likely to predict clinical benefit. The FDA agreed Disc's clinical data showed superiority compared to placebo. But the letter also said there are uncertainties about the patient benefit resulting from the surrogate measure. The percent change in PPIX was a "relatively modest" 40% reduction from baseline to day 121 for the highest dose, and it's unknown whether that magnitude of change will lead to clinical benefit.

"This lack of correlation between the changes in PPIX and clinical outcomes measured leaves significant uncertainty that bitopertin will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling," the FDA said in the letter.

The FDA added that data from another clinical trial are needed to show efficacy to support regulatory approval. Disc's September FDA submission was based on the results of a placebo-controlled Phase 2 study and an open-label clinical trial, each evaluating a high and low dose of bitopertin. The main goal was measuring the percent change in blood levels of PPIX as the surrogate endpoint. According to the FDA's guidance to Disc, reducing PPIX could serve as a surrogate clinical trial endpoint to support accelerated approval, the company said in regulatory filings.

A Phase 3 study that was intended to be the confirmatory study is ongoing. A confirmatory study was already underway when Disc last fall submitted an application seeking accelerated FDA approval. Disc said Friday that it expects to complete enrollment in March. According to the company, the agency indicated the results from this study could provide evidence to support traditional approval. The company said it expects late-stage data in fourth-quarter this year. Completing the study and resubmitting an application could lead to a regulatory decision in mid-2027, Disc said.

The rejection sent Disc shares down 31% to $49 in afternoon trading on Friday. The agency posted the rejection letter on its website Friday afternoon.

Documents reviewed previously indicated that the agency has concerns about whether the secondary goal of pain-free time in the sun was a statistically solid measure of efficacy, or if other data could justify approval. Expedited consideration, the FDA has said, does not ensure approval.

The rejection is the latest example of the growing uncertainty at the nation's top drug regulator. It's the latest medical product that's been delayed or rejected by the agency based on questions about development plans that were allowed by previous administrations.