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Patients with severe genetically driven photosensitivity had significant improvement in sunlight tolerance when treated with the oral melanocortin 1 receptor agonist dersimelagon, a randomized placebo-controlled trial showed.

The mean time to onset of prodromal symptoms of erythropoietic protoporphyria and X-linked protoporphyria increased by about an hour with either of two doses of dersimelagon versus placebo. The increased tolerance of sunlight was associated with clinically meaningful improvement in quality of life.

The most common adverse events (AEs) were new or worsening nausea, freckles, headache, and skin hyperpigmentation, reported Kirstine Belongie, PhD, of Mitsubishi Tanabe Pharma Development America in Jersey City, New Jersey, and co-authors in the .

"Although the effect observed with the PROMIS-57 [the quality of life questionnaire] was minor in this trial, we saw a marked improvement in PGI-C [Patient Global Impression of Change] scores in both dersimelagon groups as compared with the placebo group," the authors wrote. "In addition, this clinical trial showed that the use of a patient-reported primary endpoint (time to first prodromal symptom) is of value for assessing the efficacy of treatment for erythropoietic protoporphyria or X-linked protoporphyria without triggering severe phototoxic symptoms that can last for 2 to 7 days."

The questionnaires used in the study did not completely reflect the improvement and its impact on patients' lives, said co-author Manisha Balwani, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

"As a physician managing the care of these patients for over 15 years and the PI [principal investigator] of the clinical trial at Mount Sinai, I can report firsthand that the improvements in the daily life of the patients were far greater than just what was captured by these questionnaires," she told 番茄社区 via email. "For many patients, it was the first opportunity to go to a beach or lake and be out in the sun. It has a significant effect on their daily functioning in addition to mental and emotional well-being, which is not quantifiable by these questionnaires alone."

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses that arise from disorders of the heme biosynthetic pathway. A deficiency of ferrochelatase (hematopoietic protoporphyria) or increased activity of erythroid-specific delta-aminolevulinic acid synthase 2 (X-linked protoporphyria) drives overproduction of photoactive metal-free porphyrin in bone marrow and accumulation in erythrocytes, plasma, liver, and vascular endothelium, Belongie and team explained in their introduction to the study.

With exposure to visible light, protoporphyrin in the vascular endothelium is photoactivated, causing inflammation, cellular damage, and severe pain. Characteristic prodromal symptoms that precede severe pain include tingling, itching, and burning, serving as warning signs to limit sun exposure, the authors noted.

No therapies effectively alleviate the pain, and sunlight avoidance is the primary approach to preventing symptoms, limiting patients' normal daily activities and reducing quality of life. Afamelanotide (Scenesse), a melanocyte-stimulating hormone agonist, is the only approved therapy in the U.S., Europe, and Australia. Though safe and effective, afamelanotide comes in a subcutaneous implant that must be administered by a healthcare professional. No effective oral therapy is available.

Melanocortin 1 receptor activation by oral dersimelagon effects a switch from pheomelanin to eumelanin, resulting in photoprotection and antioxidative effects. Following a demonstration of safety in healthy volunteers, investigators conducted a phase II trial to investigate dersimelagon's safety and efficacy in patients with erythropoietic protoporphyria or X-linked protoporphyria.

The primary endpoint was time to first prodromal symptom during sunlight exposure, a strategy that avoided severe phototoxicity and better reflected light-avoidance behaviors of patients, as compared with duration of direct sunlight exposure without pain (endpoint for afamelanotide's pivotal trials), Belongie and colleagues noted. The endpoint was assessed during daylight hours from 1 hour after sunrise to 1 hour before sunset.

The study involved 102 patients (all but nine with erythropoietic protoporphyria), who were randomized 1:1:1 to two different doses of dersimelagon or placebo. The primary outcome was the change from baseline to 16 weeks in time to first prodromal symptom associated with sunlight exposure versus placebo. The results showed that patients assigned to 100 mg of dersimelagon had a 53.8-minute increase in time to first prodromal symptom as compared with placebo (P=0.008), increasing to 62.5 minutes among patients assigned to 300 mg of dersimelagon (P=0.003).

During the 16-week treatment period, the total number of sunlight-exposure episodes leading to prodromal symptoms were about 40% lower in the two dersimelagon groups and episodes of phototoxic pain events were reduced by 50-60% with dersimelagon. Quality of life assessed by PGI-C was superior in both dersimelagon groups versus placebo. Analysis of PROMIS-57 scores suggested patients randomized to dersimelagon had greater improvement in physical function and greater decreases in pain intensity.

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