Disc Medicine’s effort to introduce a new therapy for a rare blood disorder with few treatment options has been derailed by the FDA. rejecting the application and request more data from another clinical trial.
The company is able to collect that data for its drug, bitopertin. A confirmatory study was already underway when Disc submitted an application for accelerated FDA approval last fall. 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 drugs selected for an FDA pilot program aimed at shortening review times and bringing critical products to patients more quickly.
Bitopertin was developed as a treatment for erythropoietic protoporphyria, a blood disorder caused by a deficiency of an enzyme necessary to produce heme, the iron-containing molecule that is part of hemoglobin in red blood cells. The disease leads to the accumulation of protoporphyrin IX (PPIX). High levels of this compound are associated with skin hypersensitive to light. Patients experience tingling, itching and even burning sensations due to sunlight and some forms of artificial light. The drug Disc, a small oral molecule formulated as a pill taken once a day, aims to reduce PPIX levels. Bitopertin licensed from Roche disc in 2021.
Under the FDA guidance for Disc, PPIX reduction could serve as a surrogate clinical trial endpoint to support accelerated approval, the company said in regulatory filings. Disc’s submission to the FDA in September was based on results from a placebo-controlled Phase 2 study and an open-label clinical trial, each of which evaluated a high and low dose of bitopertin. The primary objective was to measure the percentage change in PPIX blood levels as a surrogate endpoint. In October, the FDA named bitopertin as one of the first nine drugs selected for the Commissioner’s National Priority Review Voucher (CNPV) pilot program. While the standard review takes 10 to 12 months, vouchers are supposed to shorten reviews to one to two months.
the agency complete response letter (CRL) sent on Friday states that Disc not only had to show evidence of effect based on the surrogate endpoint, but also that this surrogate measure, including the magnitude of change, has a reasonable probability of predicting clinical benefit. The FDA agreed that Disc’s clinical data showed superiority compared to placebo. But the letter also said there are uncertainties about the patient benefit resulting from the substitute measure. The percentage change in PPIX was a “relatively modest” 40% reduction from baseline to day 121 for the highest dose, and it is unknown whether that magnitude of change will lead to clinical benefit.
“This lack of correlation between changes in PPIX and measured clinical outcomes leaves significant uncertainty about whether bitopertin will have the effect it is intended or represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling,” the FDA said in the letter.
The FDA added that data from another clinical trial is needed to demonstrate efficacy and support regulatory approval. A phase 3 study that was intended to be a confirmatory study is ongoing. Disc said Friday that it hopes to complete enrollment in March. According to the company, the agency indicated that the results of this study could provide evidence to support traditional approval. Completing the study and resubmitting an application could result in a regulatory decision by mid-2027, Disc said.
In a research note on Saturday, Leerink Partners analyst Thomas Smith said the FDA’s rejection is a surprise given the regulator’s previous indication that the PPIX reduction is sufficient to support accelerated approval and the granting of a CNPV to expedite that review. Leerink continues to believe in the clinical profile of bitopertin and sees an easy path to reintroducing it, provided the Phase 3 data readout is positive. But Smith also acknowledged reports about the challenges facing the drug Disc.
Reuters last month bitopertin identified as one of two drugs in the FDA pilot program whose reviews have been delayed. Documents reviewed by Reuters indicated that the agency was concerned about whether the secondary goal of spending pain-free time in the sun was a statistically sound measure of effectiveness, or whether other data could justify approval. In December, Statistical news reported That director of the Center for Biologics Evaluation and Research, Vinay Prasad, “became personally involved and expressed skepticism about the drug’s effectiveness.” The rejection of bitopertin is the second surprising decision by the FDA in recent days. Last week, the FDA refused to even review a messenger RNA flu vaccine from Moderna. That FDA letter was signed by Prasad, who supposedly made the decision. despite objections from FDA staff. The FDA redacted the name of the person who signed the letter sent to Disc.
“While Dr. Prasad’s level of involvement in this CRL remains unclear, we believe this CRL issuance reinforces growing investor concerns regarding the consistency and predictability of the FDA review process, particularly through the CNPV pilot program, as this was the first full review of an innovative therapeutic against this program with a controversial negative outcome,” Smith wrote.
The disk has programmed a investor call for Tuesday at 8 a.m. ET to discuss the FDA’s decision on bitopertin.
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