Dersimelagon, an effective oral treatment for patients with erythropoietic protoporphyria: Phase 2 trial

"Dersimelagon, at both doses evaluated (100 or 300 mg once daily), significantly increased the duration of symptom-free sunlight exposure in this study population," the researchers reported.

X-linked protoporphyria and erythropoietic protoporphyria are X-linked inborn errors of heme biosynthesis that lead to increased circulating levels of metal-free phototoxicity and protoporphyrin. The characteristic of both disorders is excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that raises skin eumelanin levels. Activation of the melanocortin 1 receptor offers antioxidative and photoprotection benefits. These benefits shield those with erythropoietic protoporphyria or X-linked protoporphyria from harmful cell damage from sunlight.

Manisha Balwani, Icahn School of Medicine at Mount Sinai, New York, and colleagues set out to investigate the safety and efficacy of dersimelagon concerning the time to onset and the severity of symptoms linked with sunlight exposure in patients with X-linked protoporphyria or erythropoietic protoporphyria in a randomized, placebo-controlled, phase 2 trial.

The study included 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) aged 18 to 75 years. They were randomly assigned in a ratio of 1:1:1 to receive a placebo or dersimelagon at 100 or 300 mg once daily for 16 weeks.

The study determined the changes in the time to the first prodromal symptom associated with sunlight exposure from baseline to week 16 (primary endpoint). Patients in an electronic diary recorded daily sunlight exposure and symptom data. The researchers also assessed safety and quality of life.

Of the 102 randomization patients, 90% completed the treatment period.

The study led to the following findings:

• The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon: the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group and 62.5 minutes in the 300-mg dersimelagon group.
• There was an improvement in the quality of life in patients receiving dersimelagon compared to placebo.
• The most common adverse events that occurred or worsened during treatment were freckles, nausea, headache, and skin hyperpigmentation.

"Our findings support the safety and effectiveness of dersimelagon and its further development as a potential oral treatment option for increasing light tolerance in patients with X-linked protoporphyria or erythropoietic protoporphyria," the authors concluded.

Reference:

Balwani M, Bonkovsky HL, Levy C, Anderson KE, Bissell DM, Parker C, Takahashi F, Desnick RJ, Belongie K; Endeavor Investigators. Dersimelagon in Erythropoietic Protoporphyrias. N Engl J Med. 2023 Apr 13;388(15):1376-1385. doi: 10.1056/NEJMoa2208754. PMID: 37043653.