• Manisha Balwani, Herbert L Bonkovsky, Cynthia Levy, Karl E Anderson, D Montgomery Bissell, Charles Parker, Fumihiro Takahashi, Robert J Desnick, Kirstine Belongie, and Endeavor Investigators.
• From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B., R.J.D.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami (C.L.); the Division of Gastroenterology and Hepatology and the Porphyria Center, University of Texas Medical Branch, Galveston (K.E.A.); Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B.); the Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City (C.P.); Mitsubishi Tanabe Pharma Corporation, Tokyo (F.T.); and Mitsubishi Tanabe Pharma Development America, Jersey City, NJ (K.B.).
• N. Engl. J. Med. 2023 Apr 13; 388 (15): 137613851376-1385.

BackgroundErythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin.MethodsWe conducted a randomized, placebo-controlled, phase 2 trial to investigate the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. Patients 18 to 75 years of age were randomly assigned in a 1:1:1 ratio to receive placebo or dersimelagon at a dose of 100 or 300 mg once daily for 16 weeks. The primary end point was the change from baseline to week 16 in the time to the first prodromal symptom associated with sunlight exposure. Patients recorded daily sunlight exposure and symptom data in an electronic diary. Quality of life and safety were also assessed.ResultsOf the 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) who underwent randomization, 90% completed the treatment period. 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 (P = 0.008) and 62.5 minutes in the 300-mg dersimelagon group (P = 0.003). The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation.ConclusionsAt both doses evaluated, dersimelagon significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. (Funded by Mitsubishi Tanabe Pharma; Endeavor ClinicalTrials.gov number, NCT03520036.).Copyright © 2023 Massachusetts Medical Society.

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