PII-091 - SAFETY, PHARMACODYNAMICS, AND PHARMACOKINETICS OF IN-115314, A NOVEL SELECTIVE JAK1 INHIBITOR, AFTER A SINGLE OR MULTIPLE ORAL ADMINISTRATION IN HEALTHY MALE PARTICIPANTS.

J. Kang¹, H. Jang², S. Lee³, I. Jang³, K. Huh³; ¹Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, Seoul, Jongno-gu, Republic of Korea, ²HK inno.N Corp., Seoul, Jung-gu, Republic of Korea, ³Seoul National University College of Medicine and Hospital, Seoul, Jongno-gu, Republic of Korea.

Background: Atopic dermatitis (AD), a chronic inflammatory skin disease, has unmet needs regarding refractory responses to current therapies. And selective Janus kinase 1 (JAK1) inhibitors can effectively suppress pathogenesis of AD with fewer adverse events. IN-115314 is a novel, potent and selective JAK1 inhibitor developed as an oral formulation (IN-A002). To assess the safety, pharmacodynamics (PDs), and pharmacokinetics (PKs) of IN-115314, we conducted a first-in-human study in healthy male participants.

Methods: The study was a randomized, double-blind, placebo-controlled trial with single and multiple ascending doses, consisting of 6 cohorts. The participants in cohorts 1 and 2 received a single dose of 2.5 or 10 mg of IN-A002 or placebo, and the other 4 cohorts received both single and multiple doses of IN-A002 or placebo over 7 days at 25, 50, 100, and 200 mg. Participants were randomly assigned to receive either IN-A002 or placebo in an 8:2 ratio, except for a 4:1 ratio in cohort 1. Routine safety monitoring was performed during the study. JAK1 and JAK2 inhibition was assessed by the change from baseline in IL-6-induced pSTAT1 and GM-CSF-induced pSTAT5, respectively, up to 24 hours post-dose after a single dose and at steady-state. Blood and urine PK samples were collected up to 72 hours after single dose and at steady state. PD and PK parameters were estimated using noncompartmental analysis.

Results: A total of 54 participants completed the study. Fifteen participants reported 25 treatment-emergent adverse events, which were all mild in severity, with no serious adverse event. IN-115314 demonstrated an immediate JAK1 inhibition, and exposure-response relationship was well described by Emax model. IN-115314 was rapidly absorbed and eliminated with a half-life ranging 0.57-2.46 hours after single dose, and renal excretion was minimal ( < 2%). IN-115314 was not significantly accumulated (accumulation ratio 1.12-1.52) and time-dependent PK changes were not observed. Elimination of IN-115314 was saturable at higher doses.

Conclusion: IN-115314 was safe and well tolerated after single and multiple oral administrations up to 200 mg. IN-115314 was absorbed and eliminated rapidly, and it immediately and selectively inhibited JAK1 with a clear exposure-response relationship.