Disc Medicine’s effort to introduce a new therapy for a rare blood disorder with few treatment options has been derailed with the FDA turning down the application and asking for more data from another clinical trial.
The company is positioned to gather those data for its drug, bitopertin. A confirmatory study was already underway when Disc last fall submitted an application seeking accelerated FDA approval. But completing that study and resubmitting an application could push another regulatory decision well into next year — an unexpected delay for one of the first medicines selected for a pilot FDA program intended to shorten review times and bring critical products to patients more quickly.
Bitopertin was developed as a treatment for erythropoietic protoporphyria, 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.
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. 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. 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. While standard review takes 10 to 12 months, vouchers are supposed to shorten reviews to one or two months.
The agency’s complete response letter (CRL) sent Friday 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. A Phase 3 study that was intended to be the confirmatory study is ongoing. 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. Completing the study and resubmitting an application could lead to a regulatory decision in mid-2027, Disc said.
In a Saturday research note, Leerink Partners analyst Thomas Smith said the FDA rejection is a surprise given the regulator’s prior indication that PPIX reduction is sufficient to support accelerated approval and the award of a CNPV to speed up that review. Leerink continues to believe in bitopertin’s clinical profile and sees a straightforward path to a resubmission, as long as the Phase 3 data readout is positive. But Smith also acknowledged reports of challenges for the Disc drug.
Reuters last month identified bitopertin as one of two drugs in the pilot FDA program whose reviews have been delayed. Documents reviewed by Reuters 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. In December, Stat News reported that Center for Biologics Evaluation and Research Director Vinay Prasad “became personally involved and expressed skepticism about the drug’s efficacy.” The bitopertin rejection is the second surprising FDA decision in recent days. Last week, the FDA refused to even review a Moderna messenger RNA flu vaccine. That FDA letter was signed by Prasad, who reportedly made the decision over objections of FDA staff.
“While Dr. Prasad’s level of involvement in this CRL remains unclear, we believe that this CRL issuance reinforces investors’ growing concerns regarding the consistency and predictability of the FDA review process — particularly via the CNPV pilot program, as this was the first completed review for an innovative therapeutic vis this program with a controversial negative outcome,” Smith wrote.
Disc has scheduled an investor call for Tuesday, 8 am Eastern time, to discuss the FDA’s bitopertin decision.
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