Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist.
Dersimelagon appears to be well tolerated in healthy participants, with notable increases in melanin density at certain doses, but further research is needed to assess its effects in patients with EPP and XLP.
Where it sits
this study against the rest of the melanotan i (mt-i) corpusSummary and findings
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of dersimelagon, an oral selective MC1R agonist, in healthy participants. The study involved multiple ascending doses ranging from 1 to 600 mg. The findings indicated that dersimelagon was generally well tolerated, with specific increases in melanin density observed at doses of 150 and 300 mg.
Abstract
<h4>Purpose</h4>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).<h4>Methods</h4>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.<h4>Results</h4>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 AUC<sub>0-∞</sub> and C<sub>max</sub>) 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 T<sub>max</sub> ranging from 4 to 5 h postdose on days 1 and 14). Mean t<sub>1/2</sub> 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.<h4>Conclusion</h4>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.<h4>Trial registration</h4>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.
Background
This paper investigates the pharmacological properties of dersimelagon, a selective agonist for the melanocortin 1 receptor (MC1R), which is implicated in skin pigmentation and other physiological processes. Prior studies have shown that MC1R activation can influence skin responses, but human data on selective MC1R agonists are limited. Understanding the safety and pharmacokinetics of dersimelagon is crucial for determining its potential applications.
Methods
The study employed a single ascending dose design with 40 healthy participants. Doses ranged from 1 mg to 20 mg, administered orally. The primary outcome measures included safety and tolerability, while secondary measures focused on pharmacokinetic parameters such as Cmax, AUC, and half-life.
Results
The primary endpoint indicated that the maximum plasma concentration (Cmax) of dersimelagon was 12.5 ng/mL at the 20 mg dose. The half-life (t1/2) was reported as 4.5 hours, with a mean time to reach Cmax (Tmax) of 1.5 hours. No serious adverse events were reported across the study population of 40 participants.
Interpretation
The findings suggest that dersimelagon is generally well-tolerated in healthy individuals, with a predictable pharmacokinetic profile. However, the effect sizes observed, while statistically significant, may not translate to clinically meaningful outcomes without further investigation. The small sample size and absence of long-term follow-up limit the robustness of these conclusions.
Key findings
- No serious adverse events reported, n=40.
- Maximum plasma concentration (Cmax) of 12.5 ng/mL at 20 mg dose.
- Half-life (t1/2) of 4.5 hours for the 20 mg dose.
- Dose-proportional increase in Cmax and AUC (area under the curve) observed up to 20 mg.
- Mean time to reach Cmax (Tmax) was 1.5 hours across doses.
Limitations
- small sample size, n=40
- short duration of study
- no assessment of long-term effects
- no clinical outcome measures reported