Disc Medicine to Seek Traditional FDA Approval for Bitopertin After EPP CRL; APOLLO Data Due Q4

Key Points

• Disc received a Complete Response Letter (CRL) after the FDA said bitopertin clearly reduces PPIX but raised uncertainty that those reductions are “reasonably likely” to predict clinical benefit, so the company will pursue a traditional approval pathway rather than accelerated approval.
• The Phase III APOLLO trial — a randomized, double‑blind study with co‑primary endpoints of PPIX reduction and sunlight tolerance — is expected to be fully enrolled by March with top‑line data due in Q480% power, and plans to resubmit by year‑end with a potential FDA decision around mid‑2027.
• Disc reiterated other near‑term readouts (Phase II updates for DISC‑0974 and DISC‑3405 and Phase 1b sickle cell data in H2) and is maintaining its cash runway guidance into 2029.

Disc Medicine NASDAQ: IRON executives said the company plans to pursue a traditional FDA approval for bitopertin in erythropoietic protoporphyria (EPP) after receiving a Complete Response Letter (CRL) that blocked its accelerated approval application.

FDA CRL centers on clinical benefit linkage

Chief Executive Officer John Quisel said the FDA acknowledged there was “sufficient evidence” that bitopertin significantly lowers protoporphyrin IX (PPIX, referred to on the call as PP9), but the agency raised uncertainty about whether those reductions are “reasonably likely to predict a clinical benefit,” which is a key requirement for accelerated approval.

Quisel said the company was disappointed by the outcome, but described the issue as “readily addressable” with results from the ongoing Phase III APOLLO trial. He added that the full CRL was publicly available via the FDA and Disc’s Form 8-K and called the transparency notable.

How AURORA data factored into the review

Management pointed to results from the Phase II AURORA study, which Quisel said were central to the regulatory review and have been published in the Journal of the American Academy of Dermatology. He highlighted that the trial met its primary endpoint of PPIX reduction with a high degree of statistical significance and showed evidence of improvement across endpoints intended to measure clinical benefit, including placebo-corrected time in light and phototoxic events.

Quisel said phototoxic event data in the 60 mg dose group were particularly notable, describing a “complete elimination” of attacks during the second half of the study and a temporal relationship between PPIX reductions and improvements in clinical endpoints. However, he emphasized AURORA was powered for biomarker reduction, and some clinically meaningful endpoints were statistically significant while others were not, which he suggested may have contributed to debate around whether the accelerated approval standard was met.

During Q&A, Quisel said the company only has the CRL language to interpret the basis for the decision, but it “does appear” FDA may have been looking for a statistically significant relationship between PPIX and one of the clinical endpoints.

APOLLO trial timeline and design

The company positioned APOLLO as the next major milestone and the pathway to what Quisel called “inarguable evidence” of bitopertin’s safety and efficacy in EPP. He said enrollment demand has been “very high” and the trial is expected to be fully enrolled in March, several months earlier than anticipated. Disc expects top-line data in Q4 of this year.

APOLLO is a randomized, double-blind Phase III trial with two co-primary endpoints: PPIX reduction and improvement in sunlight tolerance. Quisel said Disc reviewed and aligned the design with FDA in an end-of-Phase II meeting and Type C meetings in 2024, and reiterated on the call that he sees “absolutely no evidence” the FDA has changed its view on APOLLO’s design.

In response to analyst questions, the company said both co-primary endpoints are independent and both need to meet a p-value of 0.05. Executives also said no minimum threshold for light tolerance improvement has been identified by FDA.

Powering, data capture, and sample size recalculation

Disc said APOLLO includes more rigorous baseline light tolerance assessments during screening, along with stratification by geography, to minimize confounding factors. The company also reported completing a blinded sample size recalculation based on time-in-sunlight diary data from the first 50 completers. Management said the variability assumptions used for powering the study have held, and there was no need to increase the sample size.

Executives did not disclose specific powering inputs or effect size assumptions, but said the trial has greater than 80% power across a range of variability and effect-size scenarios.

Regulatory and corporate next steps

Quisel said Disc plans to request a Type A meeting with the FDA to review its approach for resubmission and response to the CRL, largely to ensure alignment on the eventual data package and analyses to be submitted after APOLLO reads out. He said the company typically waits for meeting minutes before publicly communicating outcomes, which he noted can take about 30 days.

After APOLLO top-line data in Q4, Disc expects to resubmit its application by the end of the year. Quisel said a typical CRL response carries a six-month FDA review goal, which would place a potential decision around mid-2027 on a traditional approval basis.

On manufacturing and other application components, management said the CRL did not raise CMC or other issues, which the company interpreted as those review elements being satisfactory. Quisel noted there are still “trailing” commercial supply activities underway that may later be amended into the filing.

Beyond bitopertin, Disc reiterated anticipated updates across other programs, including additional Phase II data for DISC-0974 in myelofibrosis in the second half of the year and initial Phase II data for DISC-3405 in polycythemia vera, as well as Phase 1b sickle cell disease data targeted for the second half. Quisel also said the company is maintaining its cash runway guidance into 2029.

About Disc Medicine NASDAQ: IRON

Disc Medicine, Inc NASDAQ: IRON is a clinical-stage biotechnology company focused on discovering and developing precision medicines that restore normal cellular function in severe genetic and acquired diseases. The company employs a chemistry-driven approach to identify small molecules that selectively modulate RNA-binding proteins or splicing regulatory pathways. By leveraging proprietary screening and medicinal chemistry platforms, Disc Medicine aims to address diseases with high unmet medical needs and limited treatment options.

The company's pipeline is anchored by lead programs targeting neuromuscular and hematological disorders.

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