Disc Medicine’s Study in EPP Meets Primary Endpoint, but Misses Secondary

Rare Daily Staff

Disc Medicine’s shares dropped 45 percent after it reported topline results from the phase 2 AURORA light sensitivity study of bitopertin in patients with erythropoietic protoporphyria showed it met the primary endpoint but failed to reach statistical significance in a key secondary endpoint due to strong placebo performance.

The company said treatment with bitopertin resulted in dose-dependent, statistically significant reductions in protoporphyrin IX (PPIX), the primary endpoint, and significant improvements in the rate of phototoxic reactions with pain and the Patient Global Impression of Change (PGIC). On the key secondary endpoint of cumulative time in sunlight on days without pain, bitopertin patients had a positive response consistent with previous studies, but the endpoint did not meet statistical significance due to strong placebo performance.

“This study has confirmed that bitopertin significantly reduces the toxic metabolite, PPIX, in patients with EPP, and we have shown that bitopertin-treated patients experience improvements in the clinically meaningful outcomes of Patient Global Impression of Change and the number and rate of phototoxic reactions with pain, with the 60 mg dose reaching statistical significance compared to placebo,” said John Quisel, president and CEO of Disc Medicine. “Despite the strong performance of bitopertin on the key secondary endpoint of cumulative time in light, consistent with results seen in BEACON, statistical significance was not met due to an outsized placebo response. Given that, we will need to conduct an analysis of our final data set and work with investigators, regulators, and patient advocacy groups to define the optimal registrational endpoints moving forward.”

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare, debilitating and potentially life-threatening diseases caused by mutations that affect heme biosynthesis, resulting in the accumulation of a toxic, photoactive intermediate called protoporphyrin IX (PPIX). This causes severe reactions when patients are exposed to sunlight, characterized by excruciating pain, edema, burning sensations and potential blistering and disfigurement. PPIX also accumulates in the hepatobiliary system and can result in complications including gallstones, cholestasis, and liver damage in 20 to 30 percent of patients and in extreme cases liver failure. Current standard of care involves extreme measures to avoid sunlight, including restricting outdoor activities to nighttime, use of protective clothing and opaque shields, and pain management. There is currently no cure for EPP and only one FDA-approved therapy, a surgically implanted synthetic hormone designed to stimulate melanin production.

Bitopertin is an investigational, clinical-stage, orally-administered inhibitor of glycine transporter 1 (GlyT1) that is designed to modulate heme biosynthesis. GlyT1 is a membrane transporter expressed on developing red blood cells and is required to supply sufficient glycine for heme biosynthesis and support erythropoiesis. Disc is planning to develop bitopertin as a potential treatment for a range of hematologic diseases including erythropoietic porphyrias, where it has potential to be the first disease-modifying therapy. There are currently two ongoing phase 2 clinical trials of bitopertin in patients with EPP that have fully enrolled and have had key data readouts: the open-label trial called BEACON and a randomized, double-blind placebo-controlled trial called AURORA. Disc obtained global rights to bitopertin under a license agreement from Roche in May 2021.

The AURORA study is a randomized, double-blind, placebo-controlled phase 2 study that enrolled 75 adult subjects with EPP. Subjects were randomized 1:1:1 to receive 20 mg of bitopertin, 60 mg of bitopertin, or placebo once daily for 17 weeks.

For the primary endpoint, bitopertin resulted in significant, dose-dependent, and sustained reductions in whole blood PPIX levels: -21.6 percent for 20 mg and -40.7 percent for 60 mg; the placebo group had mean increases of +8.0 percent.

For the secondary endpoint, cumulative total time in sunlight between 10 a.m. and 6 p.m. on days without pain observed over the four-month treatment period: bitopertin-treated patients recorded a mean of 175.1 hours at 20 mg and 153.1 hours at 60 mg, compared with 133.9 hours for placebo; results that were not statistically significant compared to placebo. The magnitude of the improvement in the bitopertin-treated patients was comparable to that observed in the BEACON study, but the benefit in the placebo arm in the AURORA trial was greater than expected. Bitopertin was generally well tolerated in both dose groups with no serious adverse events and stable hemoglobin levels.

Photo: John Quisel, president and CEO of Disc Medicine