FDA Issues Complete Response Letter for Disc Medicine's Bitopertin in EPP

Disc Medicine has received a complete response letter from the FDA concerning its new drug application for bitopertin for erythropoietic protoporphyria (EPP). The submission sought accelerated approval and was part of the FDA Commissioner's National Priority Voucher pilot programme.

Bitopertin is an oral GlyT1 inhibitor designed to treat EPP, a form of inherited metabolic disorder caused by an enzyme deficiency that leads to a buildup of protoporphyrin in cells and results in severe skin pain, burning, and itching on exposure to light.

The FDA acknowledged that the AURORA and BEACON studies demonstrated that bitopertin significantly reduces whole blood metal-free protoporphyrin IX (PPIX). The accelerated approval process required evidence of impact on a surrogate endpoint, the percentage change in whole blood metal-free PPIX, and whether this change is likely to predict clinical benefit.

However, the agency concluded there was no demonstrated association between per cent change in PPIX and sunlight exposure-based endpoints, as measured in these studies, despite the biological plausibility of PPIX as a biomarker in protoporphyria. According to Disc, the FDA is not convinced about PPIX data because there is a lack of a strong correlation between the percentage reduction of the biomarker and clinical endpoints, including light tolerance and the rate of phototoxic reactions.

The agency indicated that results from the ongoing phase 3 APOLLO trial could support traditional approval. Disc expects issues raised by the FDA can be addressed through data from the APOLLO study, with topline data anticipated in the fourth quarter of 2026.

In January, a blinded sample size re-estimation for APOLLO was performed and did not necessitate any adjustments. Enrolment is expected to be completed next month, ahead of schedule.

Upon completion of APOLLO, Disc plans to respond to the complete response letter and anticipates receiving a revised decision by mid-2027. On the plus side, if APOLLO does deliver a positive result, Disc reckons it will be able to go directly for a full, rather than conditional, approval.

The company intends to seek a Type A meeting with the FDA. The decision dashes Disc's hopes of approval and launch "in early 2026."

The chief executive stated: "We are committed to delivering bitopertin to patients, knowing how critical this potentially disease-modifying therapy is to the EPP community. While our efforts at utilising 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. The CRL 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."

Bitopertin was among the first programmes to be awarded the Commissioner's national priority voucher programme. The CNPV programme was launched earlier this year and is designed to bring important new therapies to patients more quickly and plug gaps in the domestic supply of essential medicines, with FDA reviews in two months or less. However, questions have been raised about its legality and vulnerability to political influence. The first medicine to be approved under the scheme was a US-manufactured version of the widely used antibiotic Augmentin XR (amoxicillin-clavulanate potassium).

In January 2025, Disc raised $225.5 million via an upsized public offering to support its pipeline, which included bitopertin.