Disk Medicine rare disease drug rejected by FDA for faster regulatory review
Disc Medicine's attempt to launch a new treatment for a rare blood disorder with few treatment options has been derailed when the FDA rejected the application and requested more data from another clinical trial.
The company aims to collect this data for its drug Bitopertin. When Disc submitted an application seeking accelerated approval from the FDA last fall, a confirmatory study was already underway. But completing the study and resubmitting the application could push another regulatory decision into next year — an unexpected delay for one of the first drugs under an FDA pilot program designed to shorten review times and get a critical product to patients faster.
Bitopertin was developed to treat erythropoietic protoporphyria, a blood disorder caused by a lack of the enzyme needed to produce heme, an iron-containing molecule that is part of the hemoglobin in red blood cells. The disease causes a buildup of protoporphyrin IX (PPIX). High levels of this compound have been linked to photosensitive skin. Patients experience stinging, itching, and even burning from sunlight and certain artificial lights. The Disc drug is an oral, once-daily, small molecule drug designed to lower PPIX levels. Disc licensed bitopertin from Roche in 2021.
The company said in a regulatory filing that PPIX reduction could be used as a surrogate clinical trial endpoint to support accelerated approval under FDA guidance for Disc. Disc's September submission to the FDA was based on results from a placebo-controlled Phase 2 study and an open-label clinical trial, each of which evaluated high and low doses of bitopertin. The primary objective is to measure the percent change in PPIX blood levels as a surrogate endpoint. In October, the FDA named pyridine as one of the first nine drugs selected for the Commissioner's National Priority Review Voucher (CNPV) pilot program. While a standard audit takes 10 to 12 months, vouchers should reduce that time to one or two months.
The agency's complete response letter (CRL) sent on Friday noted that the Disc not only needs to show evidence of effect based on a surrogate endpoint, but also that this surrogate measure, including the magnitude of the change, is reasonably likely to predict clinical benefit. The FDA agrees that Disc's clinical data show superiority compared to placebo. But the letter also said there was uncertainty about the benefits to patients of alternative measures. For the highest dose, the percentage change in PPIX from baseline to day 121 was a “relatively modest” 40% reduction, and it is unclear whether this magnitude of change would result in clinical benefit.
“The lack of correlation between changes in PPIX and measured clinical outcomes creates substantial uncertainty as to whether butadione will produce its claimed or indicated effects under the conditions of use specified, recommended, or implied in its proposed labeling,” the FDA said in the letter.
The FDA added that data from another clinical trial are needed to demonstrate efficacy to support regulatory approval. A Phase 3 study, intended as a confirmatory study, is ongoing. Disc said on Friday it expected to complete registration in March. The agency said the study's results could provide evidence to support traditional approval, according to the company. Disc said completing the study and resubmitting the application could lead to a regulatory decision by mid-2027.
Leerink Partners analyst Thomas Smith said in a research note on Saturday that the FDA's rejection was surprising because the regulator had indicated beforehand that the reduction in PPIX was sufficient to support accelerated approval and granted CNPV to expedite review. Leerink remains convinced of bitopertin's clinical profile and believes it can be resubmitted directly as long as the Phase 3 data readout is positive. But Smith also acknowledged reports of challenges facing Disc's drug.
Reuters last month identified Bitopertin as one of two drugs in an FDA pilot program whose review has been delayed. Documents reviewed by Reuters showed the agency was concerned about whether the secondary goal of pain-free time in the sun was a statistically reliable measure of efficacy or whether other data could justify approval. In December, Stat News reported that Vinay Prasad, director of the Center for Biologics Evaluation and Research, was “personally involved and expressed doubts about the drug's efficacy.” The rejection of Bitadine was the FDA's second surprising decision in recent days. Last week, the FDA even declined to review Moderna's messenger RNA flu vaccine. The FDA letter was signed by Prasad, who reportedly made the decision over the objections of FDA staff.
“While the extent of Dr. Prasad's involvement in the CRL remains unclear, we believe the release of this CRL adds to growing investor concerns about the consistency and predictability of the FDA's review process, particularly through the CNPV pilot program, as this is the first complete review of an innovative therapy for this program with controversial negative results,” Smith wrote.
Disc has scheduled an investor call for Tuesday at 8 a.m. ET to discuss the FDA's decision on bitopertin.
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