FDA rejects Disc's rare disease drug despite commissioner's voucher

 The FDA has rejected a rare blood disease candidate from Disc Medicine, a compound that had been granted expedited review through a newly launched priority voucher program. 

While the agency agreed that Disc’s bitopertin had hit the primary endpoint in an adequate, well-controlled trial, the regulator took issue with the trial’s use of a surrogate endpoint in place of clinical outcomes, according to the rejection letter (PDF). 

The phase 2 trial that formed the bulk of Disc’s approval application enrolled 75 patients with erythropoietic protoporphyria (EPP), a rare genetic disease where molecules called protoporphyrins build up in red blood cells, causing pain when exposed to the sun. The condition can also lead to liver disease. 

In this randomized, placebo-controlled trial as well as another open-label study that also formed part of the submission, Disc used a drop in levels of protoporphyrin IX (PPIX) as the primary endpoint. The FDA agreed that both trials achieved their goals but called the 40% change in PPIX seen in the randomized trial’s high-dose arm “relatively modest.” 

“Whether that magnitude of change in whole blood metal-free PPIX is reasonably likely to predict clinical benefit is unknown,” the agency said in its letter. What’s more, both trials showed no evidence that lowered PPIX levels correlated with an improved tolerance of the sun, “despite the strong mechanistic and biological plausibility” of a connection. 

Massachusetts-based Disc believes it can address the FDA’s concerns with its ongoing phase 3 Apollo trial, the company said in a Feb. 13 release, which is set to enroll about 150 patients and is using sun exposure outcomes as primary endpoints. Top-line data from the study are expected in the fourth quarter of this year, Disc said. 

“While our efforts at utilizing expedited pathways to get bitopertin to patients quickly have not come to fruition, we are continuing to pursue all avenues in support of FDA approval,” John Quisel, Ph.D., Disc’s president and CEO, said in the release. The rejection “will delay the potential approval of bitopertin, but we have confidence in the ongoing APOLLO trial, for which we are seeing incredible enthusiasm from the EPP community.” 

In October, Disc was one of the first nine recipients of a Commissioner’s National Priority Voucher (CNPV), an opaque program promising speedy reviews for “companies aligned with U.S. national priorities,” FDA Commissioner Marty Makary, M.D., said in the program’s June unveiling. 

Aside from a generic antibiotic approved in December, Disc’s bitopertin is the first investigational drug to be reviewed through the CNPV pathway. 

The CNPV program has attracted intense scrutiny due to its lack of transparency and concerns about possible corruption and rushed reviews. 

The rebuff is the latest of a series of FDA rejections, particularly in rare diseases, a pattern that has increasingly been the subject of industry ire. Just this week, the agency refused to approve Regenxbio’s Hunter syndrome gene therapy based on concerns about several trial design features, considerations that are typically addressed much earlier. 

“This is a systemic problem that we saw at the FDA last year and continue to see,” Biohaven CEO Vlad Coric, M.D., told Fierce earlier this week, citing his company’s own complete response letter received at the end of last year for its spinocerebellar ataxia therapy. Though Biohaven had discussed with the FDA in 2024 about using real-world evidence in a submission, the agency in 2025 cited “issues that can be inherent to real-world evidence and external control studies” in its rejection letter. 

That being said, the agency came under new leadership in 2025, with President Donald Trump-appointed Marty Makary, M.D., taking the helm.  

Makary’s FDA has since been scrutinized for decisions that go back on prior guidance or keep potentially beneficial treatments from patients who have no other options.  

All this has created a more tenuous regulatory environment, particularly for drugmakers in certain disease areas or specialties. For vaccine developers, the FDA’s refusal-to-file (RTF) letter delivered to Moderna this week—despite the success of a phase 3 trial—is forcing players to rethink their strategy. 

The RTF decision reflects “how sharp the departure has been between the prior administration and this administration,” Mani Foroohar, M.D., an analyst with Leerink Partners, told Fierce. 

“I think companies have found the pivot jarring, having developed drugs and clinical trials based on prior feedback,” Foroohar said. “It feels like a bait and switch.” 

https://www.fiercebiotech.com/biotech/fda-rejects-discs-rare-disease-drug-despite-commissioners-voucher