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.
RCT Entities:
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.
Authors: Steve N Georas; Rosalind J Wright; Anastasia Ivanova; Elliot Israel; Lisa M LaVange; Praveen Akuthota; Tara F Carr; Loren C Denlinger; Merritt L Fajt; Rajesh Kumar; Wanda K O'Neal; Wanda Phipatanakul; Stanley J Szefler; Mark A Aronica; Leonard B Bacharier; Allison J Burbank; Mario Castro; Laura Crotty Alexander; Julie Bamdad; Juan Carlos Cardet; Suzy A A Comhair; Ronina A Covar; Emily A DiMango; Kim Erwin; Serpil C Erzurum; John V Fahy; Jonathan M Gaffin; Benjamin Gaston; Lynn B Gerald; Eric A Hoffman; Fernando Holguin; Daniel J Jackson; John James; Nizar N Jarjour; Nicholas J Kenyon; Sumita Khatri; John P Kirwan; Monica Kraft; Jerry A Krishnan; Andrew H Liu; Mark C Liu; M Alison Marquis; Fernando Martinez; Jacob Mey; Wendy C Moore; James N Moy; Victor E Ortega; David B Peden; Emily Pennington; Michael C Peters; Kristie Ross; Maria Sanchez; Lewis J Smith; Ronald L Sorkness; Michael E Wechsler; Sally E Wenzel; Steven R White; Joe Zein; Amir A Zeki; Patricia Noel Journal: J Allergy Clin Immunol Date: 2021-11-29 Impact factor: 14.290
Authors: Magnus Nilsson; Magdalena Rhedin; Ramon Hendrickx; Susanne Berglund; Antonio Piras; Parmis Blomgran; Anders Cavallin; Mia Collins; Göran Dahl; Bilel Dekkak; Therese Ericsson; Niklas Hagberg; Ann Aurell Holmberg; Agnes Leffler; Anders J Lundqvist; Thomais Markou; James Pinkerton; Lars Rönnblom; Stacey Siu; Vanessa Taylor; Tiiu Wennberg; Dimitrios Zervas; Arian D J Laurence; Suman Mitra; Maria G Belvisi; Mark Birrell; Annika Borde Journal: Drug Des Devel Ther Date: 2022-08-31 Impact factor: 4.319