Discussion
XLP, TEAEs
EPP, LENTIGO, SKIN HYPERPIGMENTATION
The present report describes the first-in-human SAD and MAD trial of oral dersimelagon conducted in healthy volunteers. Dersimelagon was generally well tolerated following single oral doses between 1 and 600 mg and multiple oral doses between 30 and 450 mg, including in female, Black, and older participants. The most commonly reported TEAEs in participants receiving multiple doses of dersimelagon (Part E) were related to skin pigmentation changes, including lentigo and skin hyperpigmentation. These TEAEs are similar to those previously reported in the phase 2 ENDEAVOR study [The pharmacokinetics of dersimelagon in rats and monkeys following intravenous administration indicated a moderate volume of distribution, clearance, and half-life. Oral bioavailability was low in rats and moderate in monkeys. In the clinical trial, dersimelagon was rapidly absorbed following single oral doses, with exposure appearing to increase in a slightly more than dose-proportional manner, similar to that observed in rats following oral administration of dersimelagon. Further, similar PK properties of rapid absorption and high plasma protein binding were observed for dersimelagon in both humans and animals from the present study. In the drug discovery process, the prediction of human PK of a new chemical entity is routinely performed using animal PK data. In this report, the extent to which the predicted human PK calculated from animal PK data of dersimelagon was consistent with the actual human PK was retrospectively investigated. The predicted human CThere were no statistically significant effects of age or race on the PK profile of dersimelagon; however, increased exposure was observed in females (vs males). This difference can most likely be attributed to differences in the body weight generally observed in male versus female participants. Our findings suggest that future development of a population PK model will be useful to evaluate the influence of factors such as body weight, sex, race, and ethnicity on the PK profile of dersimelagon. Furthermore, based on the mean trough concentration ratios, steady state was generally reached by 5 days of multiple dosing, which may be indicative of the time frame necessary to see any treatment effects of dersimelagon.No treatment-related effects on melanin density were observed following single doses of dersimelagon (Part A). However, in the MAD study (Part E), treatment-related increases in melanin density were observed in the 150- and 300-mg groups compared with the placebo group during the treatment period. This is consistent with previous preclinical reports in which selective activation of MC1R by dersimelagon led to increases in skin pigmentation (eumelanin production) in both in vitro and in vivo animal studies [In a recently completed phase 2, randomized, multicenter, placebo-controlled clinical trial (ENDEAVOR), oral administration of dersimelagon to patients with EPP or XLP was shown to increase symptom-free light exposure with an acceptable safety and tolerability profile after 16 weeks of treatment [