Disc hints at NDA for rare skin disorder drug

Disc Medicine has announced that the US Food and Drug Administration (FDA) has agreed on the regulatory pathway for its experimental drug bitopertin to treat erythropoietic protoporphyria (EPP), a rare skin condition. This decision follows an end of Phase II meeting where the FDA expressed support for an accelerated approval application based on existing clinical data, with the forthcoming Phase III trial to serve as a confirmatory study. The agency has approved Disc's proposed trial design and endpoints, including the use of protoporphyrin IX (PPIX) reduction as a surrogate marker.

The potential approval of bitopertin is contingent upon its ability to enable pain-free sunlight exposure for patients with EPP and X-linked protoporphyria (XLP). EPP is a genetic disorder marked by the accumulation of a phototoxic heme precursor in red blood cells, leading to severe burn injuries on the skin after minimal exposure to visible light. Specifically, individuals with EPP can suffer severe burns after just ten minutes of light exposure.

In the Phase II trial, bitopertin demonstrated promising results. Administered in once-daily doses of 20mg and 60mg over a period of 24 weeks in 22 patients, the drug was well tolerated, with no serious adverse events reported. Patients also had the option to continue in an open-label extension of the trial for an additional 24 weeks.

Disc Medicine aims to initiate the Phase III APOLLO trial by mid-2025. The primary endpoint of the trial, which the FDA has agreed upon, will measure the average monthly time patients can spend in sunlight without experiencing pain during the final month of a six-month treatment period. Additionally, the FDA has approved a 60mg dose of bitopertin and a six-month trial duration. Secondary outcome measures will include PPIX levels, phototoxic reactions, cumulative pain-free sunlight exposure, and patient global impression of change.

The APOLLO study will involve patients aged 12 and older with either EPP or XLP and will follow a randomized, double-blind, placebo-controlled design. Disc Medicine plans to finalize details with the FDA and provide an update on the New Drug Application (NDA) timeline in the first quarter of 2025.

The ethical challenges of conducting EPP trials were highlighted at the Outsourcing in Clinical Trials (OCT) DACH 2024 conference in Zurich, Switzerland. A patient with EPP raised concerns about the potential for phototoxic burns among participants randomized to control groups and the risk of bias in patient selection, as those more severely affected by the condition may be reluctant to participate.

In the announcement, Disc’s CEO John Quisel expressed enthusiasm about the possibility of filing for accelerated approval based on existing data and the use of PPIX reduction as a surrogate endpoint.

Currently, there is only one approved treatment for EPP: Scenesse (afamelanotide), developed by Clinuvel Pharmaceuticals, an Australia-based biotech company. Scenesse works by increasing skin pigmentation and has anti-inflammatory properties, thereby offering protection against light-induced skin damage. Results from a pivotal trial (NCT01605136) indicated that patients treated with Scenesse could spend, on average, an additional 20 minutes in sunlight daily without experiencing pain, compared to those who received a placebo.