Disc Medicine (IRON) Status update summary

Regulatory update and FDA response

• FDA issued a Complete Response Letter (CRL) for bitopertin, citing the need for additional data from the ongoing Phase 3 APOLLO study before considering approval, with the main objection focused on the sufficiency of PPIX as a surrogate biomarker and a request to see APOLLO outcomes.

• The CRL was made publicly available, reflecting a new level of transparency.

• No CMC or other non-efficacy issues were raised in the CRL; all other NDA modules are considered aligned or complete.

• FDA requires additional evidence demonstrating clinical efficacy, specifically linking PPIX reduction to clinical benefit, and requested a standard safety update with new APOLLO data.

Clinical trial progress and next steps

• APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled study with approximately 150 patients, focusing on average monthly pain-free sunlight exposure and PPIX change as co-primary endpoints.

• APOLLO enrollment is expected to close in March 2026, with topline data anticipated in Q4 2026 and a potential FDA decision by mid-2027.

• The trial design and endpoints are robust, well-powered, and aligned with the FDA through multiple meetings.

• No changes to the APOLLO trial are planned; confidence remains high in its ability to demonstrate clinical benefit.

• A Type A meeting will be requested to confirm alignment on data package and resubmission approach.

Data highlights and regulatory standards

• Previous trials (AURORA and BEACON) showed significant PPIX reduction but did not establish a clear association between PPIX change and sunlight exposure endpoints.

• AURORA data demonstrated a 49% reduction in whole blood PPIX and 63% reduction in plasma PPIX, with improvements in clinical metrics, though not all were statistically significant.

• APOLLO’s co-primary endpoints require statistical significance (p<0.05) for both PPIX reduction and pain-free sunlight exposure.

• No minimum threshold for light tolerance improvement was specified by the FDA.

• The FDA did not find the evidence sufficient for accelerated approval, reflecting a more stringent regulatory environment.