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 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, placebocontrolled, 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 6 43 ppb. At day 14, placebo-corrected difference in FENO was 223% (95% CI, 237.3 to 29) for 15 mg QD and 242% (95% CI, 257 to 227.4) for 15 mg twice daily. Higher plasma exposure was associated with greater FENO reduction. No doselimiting 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 dosedependent reductions in FENO in mild asthma and was well tolerated without evidence of systemic toxicity. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors

“…Four JAKs have been described: JAK1, JAK2, JAK3 and TYK2. JAKs belong to the family of tyrosine kinases (TYKs), which consist of four structural domains composed of seven homologous regions named JH1-JH7 [26]. JH1 is the active catalytic phosphotransferase domain and the target of the JAK-inhibitors developed so far, which compete with adenosine triphosphate at the catalytic site [27,28].…”

Type‐2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide

“…The early phase clinical development of novel asthma treatments targeting T2‐inflammation requires biomarkers to measure pharmacological effects. 5 , 6 , 7 , 8 These biomarkers can help with dose selection decisions and provide information regarding mechanism of action. These early phase studies often involve patients with mild asthma in order to provide initial safety assessment before proceeding to larger studies in patients with more severe asthma.…”

“…Patients with mild asthma were studied because this subgroup is often enrolled in early phase asthma studies for reasons of safety. 6 , 8 The validation of POSTN , CLCA1 , and SERPINB2 and the identification of other T2 bronchial epithelial biomarkers in this asthma subgroup would enable future early asthma clinical trials to use these biomarkers to evaluate novel anti‐T2 treatments.…”

“…The early phase clinical development of novel asthma treatments targeting T2‐inflammation requires biomarkers to measure pharmacological effects 5–8 . These biomarkers can help with dose selection decisions and provide information regarding mechanism of action.…”

“…The main aim was to investigate the gene expression of IL‐13 pathway biomarkers (11 genes, including POSTN , CLCA1 , and SERPINB2 ) in bronchial epithelial samples from patients with T2 high mild asthma compared to healthy controls. Patients with mild asthma were studied because this subgroup is often enrolled in early phase asthma studies for reasons of safety 6,8 . The validation of POSTN , CLCA1 , and SERPINB2 and the identification of other T2 bronchial epithelial biomarkers in this asthma subgroup would enable future early asthma clinical trials to use these biomarkers to evaluate novel anti‐T2 treatments.…”