Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: a randomized, controlled, proof-of-activity trial.

ABSTRACT Background The Janus Kinase (JAK) pathway mediates activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small molecule JAK inhibitor being developed for the treatment of asthma. Objective To determine whether GDC-0214 reduces fractional exhaled nitric oxide (FeNO), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. Methods We conducted a double-blind, randomized, placebo-controlled, Phase 1 proof-of-activity study in adults with mild asthma and FeNO >40ppb. Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1mg QD, 4mg QD, 15mg QD, or 15mg BID). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in FeNO from baseline to Day 14. Baseline was defined as the average FeNO during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. Results Thirty-six subjects (mean age, 28 years; 54% female) were enrolled. Mean FeNO at baseline across all subjects was 93ppb (SD, 43ppb). At Day 14, placebo-corrected difference in FeNO was -23% (95% CI: -37.3, -9) for 15mg QD and -42% (95%CI: -57, -27.4) for 15mg BID. Higher plasma exposure was associated with greater FeNO reduction. No dose-limiting adverse events (AEs), serious AEs, or treatment discontinuations occurred. There were no major imbalances in AEs or laboratory findings, or evidence of systemic JAK inhibition. Conclusions GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in FeNO in mild asthma and was well tolerated without evidence of systemic toxicity.