Background/Purpose: Zunsemetinib is an orally available potent and selective small molecule inhibitor of the p38α MAPK/MK2 signaling axis. Aclaris Therapeutics, Inc. is developing zunsemetinib for potential treatment of immuno-inflammatory disorders in which anti-TNFα, anti-IL-1α, anti-IL-1β, anti-IL-6, and anti-IL-17 biotherapeutics have been shown to be efficacious (e.g., RA, HS, PsA). The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of zunsemetinib at steady state.

Methods: In this Phase I, placebo-controlled, observer-blind study, 20 subjects (6 female, 14 male) were randomized into 2 cohorts of 10 subjects each. Cohort 1 received oral doses of 80 mg zunsemetinib (n=8) or placebo (n=2) twice-daily (BID) for 7 days. Cohort 2 received oral doses of 120 mg zunsemetinib (n=8) or placebo (n=2) BID for 7 days. The primary objective was to assess the safety, tolerability, and PK profile of zunsemetinib at the 80 mg and 120 mg BID dose in healthy subjects.

Results: Thirty-one treatment emergent adverse events (TEAEs) were reported by 12 (75.0%) subjects who received zunsemetinib, and 2 TEAEs were reported by 1 (25.0%) subject who received placebo. The most frequently reported ( >2 subjects) TEAEs in the subjects who received zunsemetinib were headache (9 [56.3%] subjects overall; 2 [25.0%] subjects in the 80 mg cohort and 7 [87.5%] subjects in the 120 mg cohort), dizziness (8 [50.0%] subjects overall; 2 [25.0%] subjects in the 80 mg cohort and 6 [75.0%] subjects in the 120 mg cohort), and dry skin (6 [37.5%] subjects overall; 1 [12%] subject in the 80 mg and 5 [62.5%] subjects in the 120 mg cohort). There were no deaths or serious adverse events (SAEs), no subjects discontinued due to TEAEs, and all TEAEs were transient and mild in severity. No subjects had clinically significant findings with respect to vital signs, ECGs, or clinical laboratory. Zunsemetinib was rapidly absorbed with a median T_max of 2 hours (range 1 – 4 hours). Day 1 C_max, AUC_last, and AUC_0-t for zunsemetinib increased dose-proportionally from 80 mg to 120 mg with 1.5-, 1.4-, and 1.4-fold increases, respectively. Trough concentrations of zunsemetinib were similar from Days 2-7 in both cohorts. At steady-state, Day 7 C_max and AUC_0-t from the 80 mg cohort were consistently 1.5-fold higher than those on Day 1, while C_max and AUC_0-t from the 120 mg cohort were similar between Day 1 and 7 with only 1.07- and 1.05-fold increases, respectively. The median elimination half-life t_1/2 of zunsemetinib was 13.4 hours (range 8.8 – 25.8 hours) in the 80 mg cohort and 8.7 hours (range 5.5 – 12.3 hours) in the 120 mg cohort. When combined with data from 10, 30 and 50 mg dose levels from a prior study, zunsemetinib exposure following the BID dosing regimen appears to be dose-proportional over the full dose range tested (10 – 120 mg). Furthermore, adjusting for baseline subject weight improves dose-linearity particularly for Day 1 C_max.

Conclusion: Multiple oral doses of zunsemetinib (up to 120 mg BID) administered to healthy subjects in this study were generally safe and well tolerated.The exposure was dose proportional over the full dose range tested (10 – 120 mg) following 7 days of BID dosing.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-study-to-investigate-the-safety-tolerability-and-pharmacokinetics-of-zunsemetinib-an-investigational-oral-mk2-inhibitor-at-80-mg-and-120-mg-twice-daily-dose-levels-in-healthy-subjects/