Experimental EPP therapy increases pain-free time in light in trial

Disc Medicine’s experimental oral therapy bitopertin significantly reduced levels of protoporphyrin IX (PPIX), a light-sensitive molecule, and significantly increased pain-free time in light in a Phase 3 trial involving people with erythropoietic protoporphyria (EPP).

That’s according to top-line data from the global Phase 3 APOLLO trial (NCT06910358), which met both of its main goals and all secondary goals. In addition to PPIX reductions and increases in pain-free light exposure time, the therapy was associated with fewer painful skin reactions caused by light exposure (phototoxic reactions). Exploratory measures also showed greater improvements in how patients rated their health and disease severity.

Phase 3 success raises hopes for new EPP treatment

“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,” Herbert L. Bonkovsky, MD, director of gastroenterology and internal medicine and professor emeritus of medicine at Wake Forest University School of Medicine, who was a principal investigator for APOLLO, said in a press release from Disc Medicine.

In February, the U.S. Food and Drug Administration (FDA) rejected Disc Medicine’s application for accelerated approval of bitopertin for people with EPP ages 12 and older. The agency said earlier studies had not shown that reductions in PPIX were linked to improvements in light tolerance, leaving uncertainty about whether lower PPIX levels could predict clinical benefits. However, the FDA indicated that positive results from APOLLO could support traditional approval.

Following the positive results, Disc Medicine plans to resubmit its application to the FDA by year’s end. The company expects an FDA decision by mid-2027.

“Today represents a potential breakthrough in the science and treatment of EPP,” said John Quisel, PhD, president and CEO of Disc Medicine. “We look forward to engaging with regulators with the goal of bringing an important, innovative medicine to this community as efficiently as possible.”

How EPP causes painful reactions to sunlight

EPP is a type of porphyria, a group of conditions in which genetic changes interfere with the body’s ability to make heme, a molecule that helps red blood cells carry oxygen throughout the body. As a result, substances involved in making heme, called porphyrins and their precursors, can build up to harmful levels in different parts of the body.

In people with EPP, problems making heme cause PPIX, a type of porphyrin that reacts to light, to build up. Sunlight exposure can then trigger severe pain, swelling, burning sensations, and other skin reactions.

PPIX can also build up in the liver and bile ducts, which carry bile, a fluid that helps with digestion. This buildup can lead to gallstones, problems with bile flow, and liver damage. In severe cases, it can cause liver failure.

Bitopertin is an oral medication designed to block a protein called glycine transporter 1. This protein helps deliver glycine, a substance needed to make heme, to developing red blood cells. By limiting the amount of glycine entering these cells, bitopertin is designed to reduce how much PPIX the body produces and how much builds up.

The global APOLLO trial tested the safety and effectiveness of daily bitopertin compared with a placebo in people with EPP or X-linked protoporphyria, another type of protoporphyria that causes extreme sensitivity to light. Researchers assessed whether bitopertin could lower PPIX levels and help patients tolerate more time in light.

The study enrolled 183 adults and adolescents ages 12 and older, who were randomly assigned to take either 60 mg of bitopertin or a placebo once daily for six months.

Trial meets both main goals and all secondary measures

Bitopertin met both of the trial’s main goals. Compared with placebo, it significantly reduced whole-blood metal-free PPIX levels by 41.4% from baseline. During the sixth month of treatment, bitopertin also significantly increased average monthly time in light without pain by 12.2 hours compared with placebo.

All secondary goals also favored bitopertin. Compared with placebo, the treatment significantly reduced the rate of phototoxic reactions and significantly increased the total amount of pain-free time spent in light over the six-month study. Among adults, it also significantly increased the average daily time spent in sunlight before early warning symptoms appeared.

“Bitopertin demonstrated additional quality of life benefits vs. placebo,” the release stated. In separate exploratory assessments, patients taking bitopertin reported significantly greater improvements in how they rated changes in their health and the severity of their disease compared with those taking placebo.

The therapy was generally well tolerated, with no new safety signals reported. As in previous studies, dizziness was the most commonly reported adverse event among patients taking bitopertin, affecting 50% of them. The reported dizziness was mild or moderate and generally temporary.

“These results are compelling evidence of the clinical benefit of a mechanism aimed at reducing the production of PPIX, the fundamental cause of disease,” said Will Savage, MD, PhD, chief medical officer of Disc Medicine. “We plan to share more detailed data with additional insights from APOLLO at a future medical conference.”