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

BACKGROUND: The Janus kinase (JAK) pathway mediates the 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: We sought 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 higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). 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% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events 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.

Body mass index and vigorous physical activity in children and adolescents: an international cross-sectional study.

AIM: To examine the relationship between reported vigorous physical activity (VPA) and body mass index (BMI) in children (6-7 years) and adolescents (13-14 years). METHODS: In the International Study of Asthma and Allergies in Childhood Phase Three, 75 895 children's parents and 199 502 adolescents answered questions relating to VPA, height and weight. The association between VPA and BMI was analysed using general linear models, adjusting for country gross national index. RESULTS: Compared to children who undertook no VPA, those in the infrequent group (once or twice per week) and those in the frequent group (three or more times per week) had mean (95% CI) BMI values 0.07 kg/m2 (0.03-0.11) and 0.09 kg/m2 (0.03-0.15) greater, respectively (p = 0.001). Compared to adolescents reporting no VPA, those in the infrequent group had a BMI 0.19 kg/m2 (0.15-0.23) greater while those in the frequent group had a BMI 0.01 kg/m2 (-0.03-0.05) greater (p < 0.0001). CONCLUSION: Reported VPA is not associated with lower BMI among children and adolescents. Investigation of VPA and BMI may be best undertaken in conjunction with other variables in the energy expenditure equation. A focus on VPA alone may be an inefficient way to manage BMI.