Safety, pharmacodynamics and pharmacokinetics of a novel JAK1‐selective inhibitor, IN‐115314, in healthy participants: A first‐in‐human study
Ki Young Huh, Jaegu Kang, Haerim Jang, Deborah Kang, In‐Jin Jang, Seung Hwan LeeAims
Selective JAK1 inhibition can control inflammation in immune‐mediated diseases with reduced haematological toxicity. IN‐115314, a selective JAK1 inhibitor, was evaluated in a first‐in‐human, randomized, double‐blind, placebo‐controlled study in healthy participants for safety, pharmacokinetics (PK) and pharmacodynamics (PD).
Methods
In six cohorts, participants received IN‐115314 or placebo as single oral doses of 2.5 and 10 mg (cohorts 1 and 2) or single and 7‐day multiple doses of 25, 50, 100 and 200 mg (cohorts 3–6). JAK1 and JAK2 inhibition was evaluated by changes from baseline in IL‐6–induced phosphorylated STAT1 (pSTAT1) and GM‐CSF–induced pSTAT5. PD samples were collected up to 24 h post‐dose after a single dose and at steady state, whereas blood and urine PK samples for IN‐115314 and IN‐116118 were collected up to 72 h, with dose‐proportionality assessment.
Results
Of 55 randomized participants, 54 completed the study. Adverse events occurred in 13 of 44 (29.5%) IN‐115314 recipients and 2 of 11 (18.2%) placebo recipients; all were mild, with no serious adverse events. IN‐115314 demonstrated significant, dose‐dependent JAK1 inhibition, with maximal inhibition (97.5%) at 200 mg. Plasma concentrations and JAK1 inhibition were well described by a sigmoidal I max model. JAK2 inhibition was minimal, with no relevant changes in absolute neutrophil or reticulocyte counts. IN‐115314 was rapidly absorbed and eliminated, with a terminal half‐life of 0.57–2.46 h, supra‐dose‐proportional but time‐invariant PKs and minimal accumulation (accumulation ratio 1.12–1.52).
Conclusions
IN‐115314 was safe, well tolerated and showed rapid, dose‐dependent JAK1 inhibition consistent with its PK profile. (