Bitopertin seen to boost sunlight tolerance, life quality in patients

Oral therapy shows promise for EPP in early BEACON trial data

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with bitopertin, an oral therapy from Disc Medicine, led to increased sunlight tolerance and improved quality of life for people with erythropoietic protoporphyria (EPP) in the Phase 2 BEACON trial, preliminary data show.

Levels of protoporphyrin IX (PPIX), the molecule that builds up to toxic levels in EPP and drives the symptoms of the genetic disorder, also were reduced.

These findings were presented in a poster, titled “Initial data from the BEACON trial: a Phase 2, randomized, open-label trial of bitopertin in erythropoietic protoporhyria,” at the European Hematology Association (EHA) 2023 Congress, held June 8-15 in Frankfurt, Germany, and virtually. The data also were shared in a recent investor presentation.

“We’re delighted to share these initial, positive data from BEACON, which provide the first clinical evidence supporting our therapeutic hypothesis of bitopertin in EPP,” John Quisel, PhD, president and CEO at Disc, said in a company press release.

“This is an important moment for Disc as a company, and I want to extend my gratitude to our team, collaborators, and most importantly, the patients and families participating in BEACON,” Quisel said.

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2 clinical trials testing efficacy of bitopertin

The ongoing, open-label BEACON trial (ACTRN12622000799752) enrolled adults with EPP and X-linked protoporphyria (XLP) at sites in Australia. Data from all participants are expected by the end of the year.

Meanwhile, the Phase 2 AURORA trial (NCT05308472), which is recruiting patients at several U.S. sites, is seeking to evaluate bitopertin’s safety and effectiveness against a placebo. That study, slated to last 17 weeks, or about four months, will enroll up to 75 adults with EPP. Data from AURORA also are expected by the end of the year.

In EPP and XLP, mutations in genes needed to produce heme — a molecule that facilitates oxygen transport in the body — lead to the toxic buildup of PPIX, a heme precursor. Symptoms include hypersensitivity to sunlight resulting in painful skin reactions, and susceptibility to certain liver diseases.

Bitopertin was originally developed by Roche for schizophrenia. Disc obtained the global rights to develop bitopertin for porphyria in a 2021 licensing agreement. The company now is developing it for EPP and XLP, as well as for certain blood disorders.

The therapy works by inhibiting glycine transporter 1 (GlyT1), a protein that provides red blood cells with glycine, a molecule needed for heme production. In doing so, it’s expected to limit glycine availability, thereby regulating heme production and minimizing PPIX buildup.

BEACON is evaluating the safety and efficacy of bitopertin in up to 22 people with EPP or XLP. Participants are being randomly assigned to receive either 20 mg or 60 mg bitopertin once daily for 24 weeks, or about six months. After that, they have the option to continue the treatment in an additional 24-week extension phase.

The new presentations concerned data from the 15 participants who were enrolled as of the cut-off date of May 8, and who had been treated with bitopertin from 18 days to six months.

Results showed that bitopertin led to consistent and dose-dependent reductions in PPIX levels, with a mean reduction of more than 40% compared with the study’s start, or baseline.

These PPIX reductions also were accompanied by reductions in sunlight sensitivity.

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Toxic reactions to sunlight reduced by 96% with bitopertin

For the two participants with the longest follow-up time, sunlight tolerance — the time spent in sunlight without experiencing initial symptoms signaling a pain attack — was significantly increased.

One patient receiving the 20 mg dose reported a more than eightyfold increase in sunlight tolerance by day 88 of treatment, or after about three months. This individual was able to stay in the sun for about 6.5 hours following treatment, compared with 4.5 minutes at baseline.

The other participant, being given the 60 mg dose, saw an increase, by more than 200 times, in sunlight tolerance after 74 days, or about 2.5 months. This person reported being able to stay in the sun for more than four hours without symptoms relative to 1.25 minutes at baseline.

Across all trial participants with available data, the average weekly time spent in sunlight has increased from the 344 minutes, or about 49 minutes per day, at baseline. At week 24, these individuals were spending an average of 1,200 minutes, or nearly three hours per day, in sunlight.

Moreover, about a sevenfold increase in the time to experience painful symptoms with sunlight exposure was observed after six months. That’s in addition to a higher proportion of days without symptoms (75% vs. 25%) and a greater number of sunlight exposures without symptoms (50% vs. 0%).

Overall, toxic reactions to sunlight were reduced by 96%, according to patient reports.

In the 10 patients who had completed a 43-day follow-up, all said that their disease was much or a little better in the last seven days, and all but one said their symptoms were mild or not at all severe.

While four people did not see a change in the impact of EPP on life quality, six patients reported reductions in EPP’s impact, two of whom said that EPP no longer impacted their life quality at all as of a follow-up on day 43 or later.

The treatment was well-tolerated at both doses, with no serious adverse events, treatment discontinuations, or dose reductions reported. Levels of hemoglobin, a blood protein of which heme is an essential component, were not impacted by treatment.

“We’re encouraged by the data and plan to present additional data at the end of the year,” said Will Savage, MD, PhD, chief medical officer at Disc.