Disc's Bitopertin Meets All Endpoints in Pivotal Phase 3 Trial After FDA Rejection

Disc Medicine said on October 19 that its oral drug bitopertin met all primary and secondary endpoints in APOLLO, a pivotal Phase 3 trial in erythropoietic protoporphyria (EPP), including X-linked protoporphyria (XLP), according to the company's release, as republished by Finviz. The results are topline data reported by the company; Disc said it will share more detailed data at a future medical conference.

EPP is a rare inherited disease in which a photoactive substance called protoporphyrin IX (PPIX) builds up, causing severe pain, swelling and burning when patients are exposed to sunlight. Disc said there is currently one FDA-approved therapy, Scenesse (afamelanotide), a surgically implanted hormone designed to stimulate melanin production.

Trial design and results

APOLLO was a randomized, double-blind, placebo-controlled trial in adults and adolescents aged 12 or older with EPP or XLP. It enrolled 183 patients in the United States, Canada, Europe and Australia, who were randomized 1:1 to 60 mg of oral bitopertin or placebo once daily for six months.

According to Disc, bitopertin reached statistical significance on both co-primary endpoints. Whole-blood metal-free PPIX fell 41.4% compared with placebo (p<0.0001), and average monthly total time in light without pain during month 6 rose by 12.2 hours compared with placebo (p=0.0010).

The company said all secondary endpoints were also met, including a lower incidence rate of phototoxic reactions over the six-month treatment period, more cumulative pain-free time in light, and, in adults only, longer daily sunlight exposure before the onset of prodromal symptoms. Patient-reported global impression scores also improved compared with placebo.

Dizziness was the most commonly reported treatment-emergent adverse event, occurring in 50% of the bitopertin group; Disc said it was mild or moderate and generally transient. There were no treatment-emergent adverse events above Grade 3, the company said.

Bitopertin is designed to block glycine transporter 1 (GlyT1), which developing red blood cells use to supply glycine for heme production. Disc licensed global rights to the drug from Roche in May 2021. BioPharma Dive reported that Roche had previously tested the drug unsuccessfully in schizophrenia.

A second attempt at approval

The readout follows a setback with regulators. The FDA rejected Disc's request for accelerated approval in February, stating in a complete response letter that the company's trials did not clearly show a link between PPIX reductions and greater tolerance to sunlight, BioPharma Dive reported. The letter said Disc could seek a traditional approval if bitopertin succeeded in a Phase 3 trial, according to the outlet.

Based on the APOLLO results, Disc plans to resubmit a New Drug Application by the end of 2026, with an FDA decision anticipated by mid-2027. Bitopertin is investigational and is not approved in any jurisdiction, the company said.

"This is the first time a potential treatment for EPP has shown robust evidence of whole blood PPIX reduction alongside unequivocal improvement on important measures of disease severity: increased time in light, reduced phototoxic reactions, and improved Patient Reported Outcome scores," said Herbert L. Bonkovsky of Wake Forest University School of Medicine, a principal investigator of APOLLO.

Disc chief executive John Quisel said: "We look forward to engaging with regulators with the goal of bringing an important, innovative medicine to this community as efficiently as possible."

Disc shares rose by more than 35% after the announcement, BioPharma Dive reported. Leerink Partners analyst Thomas Smith wrote that the findings are "compelling" and "substantially" address the FDA's concerns, the outlet said.