Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist

Abstract

Purpose To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Methods In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated. Results Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon. Conclusion Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP. Trial registration A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442, registration began July 2016.

Illuminating Dersimelagon: A Novel Agent in the Treatment of Erythropoietic Protoporphyria and X-Linked Protoporphyria

“…The first-in-human phase 1 trial conducted for dersimelagon enrolled 144 healthy participants (143 completed the trial) and demonstrated an acceptable safety profile in these patients [ 44 ]. Thirty-four of these patients received a placebo, with the remaining patients receiving at least one dose of dersimelagon (doses ranged from 1 to 600 mg).…”

“…The most common TEAEs reported were related to skin pigmentation, including lentigo, skin hyperpigmentation, and melanocytic nevi (two cases were severe but non-malignant). Additionally, there were no statistically significant effects of age or race on the pharmacokinetics of dersimelagon; however, increased exposure was observed in females compared to males, which was attributed to differences in the body weight generally observed in male versus female participants [ 44 ].…”

Afamelanotide in protoporphyria and other skin diseases: a review

“…In 2019, the Food and Drug Administration (FDA) approved EPP in the USA and in 2020 EPP was approved in Australia. A new promising molecule MT-7117 (dersimelagon) is under investigation as an oral alternative to afamelanotide for adults and adolescents [ 37 ].…”