A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled GDC-0214, a JAK1 Inhibitor, as Single- and Multiple-Ascending Doses in Healthy Volunteers

Inflammatory signaling in asthma is driven by multiple Janus kinase (JAK)-associated cytokines, including interleukin-13 (IL-13) and IL-4. Inhibiting these cytokine pathways has clinical efficacy in asthma. Inhaled GDC-0214 is a novel JAK1 inhibitor being developed for the treatment of asthma. This study evaluated safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses (SAD, MAD) of inhaled GDC-0214 in healthy adult volunteers. The SAD stage included 5 cohorts receiving single doses of 0.15–15-mg GDC-0214 or placebo. The MAD stage included 4 cohorts receiving 1-mg QD, 3-mg QD, 10-mg QD or 15-mg BID of GDC-0214 or placebo for 14 days. Thirty-four (SAD) and 32 (MAD) volunteers were dosed. No serious adverse events (SAEs), dose-limiting AEs, or AEs leading to discontinuation occurred. There were no concerning trends in vital signs, electrocardiograms, spirometry, or laboratory values suggestive of systemic JAK inhibition (e.g. NK cells, lipids). Seventeen (50%; SAD) and 25 (78%; MAD) subjects experienced AEs. All AEs were mild to moderate, except one severe AE in a patient receiving placebo. No major imbalance of AEs was observed between placebo and active arms. In the SAD stage, plasma GDC-0214 exhibited biphasic pharmacokinetics, with maximum concentrations ranging from 70–7270 pg/mL across cohorts and a mean terminal half-life of ∼38 (CV: 17.2%) hours. In the MAD stage, GDC-0214 achieved steady-state by ∼Day 6. Plasma pharmacokinetics for both stages was approximately dose proportional. Inhaled GDC-0214 was well tolerated in healthy volunteers with pharmacokinetics indicating low systemic exposure and long retention in the lung.