1. In this randomized controlled trial, oral dersimelagon resulted in significantly increased time to first symptoms among patients with erythropoietic or X-linked protoporphyria compared to a placebo.
2. Dersimelagon was associated with mostly mild or moderate adverse effects that were self-limiting.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic conditions affecting the heme biosynthetic pathway, resulting in photoactive protoporphyrin accumulation in many tissues, including vascular endothelium. When exposed to sunlight, protoporphyrin causes inflammation, tissue damage, and severe pain. No current therapies are effective for these symptoms and sun avoidance is the primary method of prevention, which greatly impacts patients’ daily activities. Subcutaneously administered afamelanotide, a melanocyte-stimulating hormone agonist, is the only approved treatment. The current study was a phase two trial to assess the efficacy of dersimelagon, an oral selective melanocortin-1 receptor agonist that increases skin eumelanin, in the treatment of these protoporphyria conditions. Compared to placebo, dersimelagon at 100mg and 300mg doses significantly increased the mean daily time to the first prodromal symptom from sun exposure, as well as improved quality of life. Dersimelagon had an acceptable safety profile, with mostly transient mild-to-moderate adverse effects. The study was limited by a small sample size (intrinsic to the rarity of the diseases), a short follow-up period, and a lack of racial diversity. Despite its small sample size and short duration, the study found evidence to support the efficacy and safety of dersimelagon in treating erythropoietic protoporphyria.
Click here to read the study in NEJM
Relevant Reading: Afamelanotide for erythro- poietic protoporphyria
In-Depth [randomized controlled trial]: The current study was a randomized placebo-controlled trial to evaluate the efficacy and safety of dersimelagon in treating patients with erythropoietic protoporphyria or X-linked protoporphyria. Patients between 18 and 75 years of age with laboratory- or genetic testing-confirmed diagnoses were eligible for inclusion. Exclusion criteria included significant concomitant medical and psychiatric conditions. In total, 102 patients were randomized 1:1:1 to receive a placebo or dersimelagon at 100mg or 300mg once daily for 16 weeks. The primary outcome was the change from baseline in the take taken for the occurrence of the first prodromal symptom associated with sun exposure, such as burning, tingling, or itching. The mean daily time to the first sun-related prodromal symptom was significantly lengthened with dersimelagon: the least-squares mean difference from the placebo group in the change from baseline at week 16 was 53.8 minutes in those receiving 100mg dersimelagon (p=0.008) and 62.5 minutes in those receiving 300mg dersimelagon (p=0.003). The number of sun-related episodes of prodromal symptoms and phototoxic pain events was also reduced in the dersimelagon groups compared to the placebo group. Most adverse events observed during the trial were mild or moderate and were limited in duration. These included nausea, freckles, skin hyperpigmentation, and headache. Similar numbers of participants discontinued the treatment across all study groups. These results demonstrated the potential of dersimelagon as a treatment for erythropoietic and X-linked protoporphyria.
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