The U.S. Food and Drug Administration has declined to approve Disc Medicine’s investigational therapy bitopertin for erythropoietic protoporphyria (EPP), despite the drug having received expedited consideration through the agency’s Commissioner’s National Priority Voucher (CNPV) program. The decision was communicated in a complete response letter made public by the company.
In its review, the FDA acknowledged that Disc’s mid-stage study met its primary objective in an adequate and well-controlled trial. However, regulators objected to the company’s reliance on a surrogate biomarker endpoint rather than direct clinical outcomes.
The application was largely supported by a Phase 2 randomized, placebo-controlled study involving 75 patients with EPP, a rare inherited condition marked by the accumulation of protoporphyrins in red blood cells. Exposure to sunlight in affected individuals can result in severe pain, and the disease may also cause liver complications.
Across the randomized study and a supporting open-label trial, Disc measured changes in whole-blood metal-free protoporphyrin IX (PPIX) as the primary endpoint. While the FDA agreed that both trials achieved their stated goals, it characterized the approximately 40% reduction in PPIX observed in the high-dose arm of the randomized trial as “relatively modest.” The agency further stated in its letter, “Whether that magnitude of change in whole blood metal-free PPIX is reasonably likely to predict clinical benefit is unknown.”
Regulators also indicated that reductions in PPIX levels did not demonstrate a clear relationship with improvements in patients’ tolerance to sunlight, despite what the agency described as strong mechanistic plausibility. The FDA concluded that the data submitted did not sufficiently establish that the biomarker effect would translate into meaningful clinical benefit.
Disc, headquartered in Massachusetts, said it intends to address these concerns through its ongoing Phase 3 APOLLO trial. The study is designed to enroll approximately 150 patients with EPP or X-linked protoporphyria and will evaluate clinical endpoints, including the average monthly duration patients can spend in sunlight without experiencing phototoxic pain.
Topline results are expected in the fourth quarter of this year. The company stated it plans to seek a meeting with the FDA to confirm that the Phase 3 design will support a future resubmission.
Bitopertin functions by inhibiting glycine transporter 1, a protein involved in hemoglobin production. EPP arises from a genetic mutation that leads to the toxic accumulation of protoporphyrin in the bone marrow, blood plasma, and red blood cells when individuals are exposed to sunlight or certain artificial light sources.
In October 2025, bitopertin was among the first nine therapies granted a CNPV, a program introduced to provide accelerated review, typically one to two months, for companies aligned with U.S. national priorities. Aside from a generic antibiotic approved in December, bitopertin was the first investigational therapy reviewed under this pathway. The program has drawn scrutiny due to concerns regarding transparency and the potential for expedited timelines to affect review consistency.
The rejection comes amid broader debate over recent regulatory decisions in rare diseases and other therapeutic areas. Industry observers have pointed to instances in which trial design elements or evidentiary standards have been reassessed during review. In this case, the FDA determined that additional well-controlled data using clinical endpoints would be required before reconsidering approval of bitopertin.
FDA Rejects Bitopertin for EPP After Priority Voucher Review
The U.S. Food and Drug Administration (FDA) has rejected bitopertin, an investigational drug from Disc Medicine, intended to treat erythropoietic protoporphyria (EPP), a rare genetic blood disorder marked by extreme sensitivity to sunlight and painful reactions. This rejection comes after the drug was reviewed under the FDA’s Commissioner’s National Priority Voucher program, which aims to expedite review timelines for priority therapies.
Although the FDA acknowledged that bitopertin met its primary surrogate endpoint of significantly lowering whole-blood protoporphyrin IX (PPIX) in earlier Phase 2 trials, the agency concluded that the change did not reliably predict meaningful clinical benefit, such as improved tolerance to sunlight exposure. Because of this, the regulator issued a Complete Response Letter (CRL) to Disc Medicine, effectively declining accelerated approval for bitopertin at this time.
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