Title
Dersimelagon in Erythropoietic Protoporphyrias
Authors
Manisha Balwani, M.D., Herbert L. Bonkovsky, M.D., Cynthia Levy, M.D., Karl E. Anderson, M.D., D. Montgomery Bissell, M.D., Charles Parker, M.D., Fumihiro Takahashi, Ph.D., Robert J. Desnick, Ph.D., M.D., and Kirstine Belongie, Ph.D.
Journal
The New England Journal of Medicine
Abstract
BACKGROUND
Erythropoietic 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.
METHODS
We 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.
RESULTS
Of 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.
CONCLUSIONS
At 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.