Safety, pharmacodynamics and pharmacokinetics of a novel JAK1-selective inhibitor, IN-115314, in healthy participants: A first-in-human study
In brief
IN-115314 suppresses JAK1 activity by 97.5% at the highest dose
In this first-in-human study of 55 healthy participants, the highest tested dose, 200 mg, produced 97.5% JAK1 inhibition, with little JAK2 inhibition. Adverse events were mild and no serious events occurred, but the study was small and short; whether these effects translate to safe, effective treatment in people with inflammatory diseases remains unknown.
- Journal
- British journal of clinical pharmacology (Q1)
- Published
- 28 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Ki Young Huh, Jaegu Kang, Haerim Jang, Deborah Kang, In-Jin Jang, Seung Hwan Lee
- PMID
- 42806494
- DOI
- 10.1002/bcp.70847
Why clinicians should know about it
- Picked for Pharmacology (medical) (paper of the day, 30 September 2026): First‑in‑human PK/PD of selective JAK1 inhibitor
Abstract
AIMS: 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 Imax 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. (ClinicalTrials.gov registration no.: NCT04297865).
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.