Dersimelagon Improves Sunlight Tolerance in EPP and XLP

Key Takeaways

• Dersimelagon significantly improved sunlight tolerance in patients with EPP/XLP, increasing time to prodromal symptoms.
• Patient-reported outcomes and reductions in phototoxic events supported clinical benefit over 16 weeks.
• The oral MC1R agonist was generally well tolerated, with adverse events consistent with its melanogenic mechanism.

Dersimelagon, an oral melanocortin 1 receptor (MC1R) agonist, significantly improved sunlight tolerance in patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), according to Phase 3 INSPIRE trial results presented by Amy Dickey Yeung, MD, at the American Academy of Dermatology (AAD) 2026 Annual Meeting.

EPP and XLP are rare inherited photodermatoses characterized by severe, painful phototoxic reactions following exposure to visible light.

“Phototoxic reactions are very, very severely painful, can last 3 to 7 days, and there is really no medication that effectively treats the symptoms of reaction,” Dr. Yeung said. “Patients cannot sleep or think or do anything but sit in a dark room until it goes away.”

In the global, randomized, placebo-controlled trial, 165 patients aged 12 years and older were assigned to dersimelagon or placebo for 16 weeks. The primary endpoint was change in time to first prodromal symptom (TTP), reflecting tolerance to sunlight exposure before onset of early warning symptoms such as tingling or burning.

Dersimelagon met the primary endpoint, significantly increasing average daily sunlight exposure time to prodrome by 23.19 minutes during Weeks 12–16 (95% CI, 7.26–39.11; P = .004). Improvements continued over time, with nearly 30 minutes of increased exposure by Week 16.

Secondary endpoints also favored dersimelagon, including patient global impression of change and reductions in sunlight-induced prodromal pain events. A numerically lower rate of non-prodromal phototoxic reactions was observed, though this endpoint did not reach statistical significance.

Mechanistically, dersimelagon stimulates eumelanin production, which provides photoprotection beyond that of traditional sunscreens.

“Melanin blocks a broader range of light than sunscreen,” Dr. Yeung noted. 

The treatment was generally well tolerated. The most common adverse events included skin hyperpigmentation, melanocytic nevi, headache, and gastrointestinal symptoms, which were mostly mild to moderate. Serious adverse events were rare, and hepatic abnormalities were infrequent.