Inhaled Frevecitinib Reduces Sputum Eosinophils and Improves FEV1 and ACQ-6 in Subjects With Moderate to Severe Asthma Treated With ICS/LABA

Abstract Rationale: Multiple pro-inflammatory mediators signaling via the JAK/STAT pathway are implicated in the pathogenesis of eosinophilic and non-eosinophilic severe asthma. Frevecitinib is an inhaled novel, potent and lung selective pan-JAK inhibitor previously shown to reduce fractional exhaled nitric oxide (FeNO) levels, without safety concern, in subjects with moderate to severe asthma using ICS/LABA. Methods: Part 3 of this Phase 1b, randomized, double-blind, placebo-controlled 4-part study (NCT05006521) evaluated the pharmacodynamics of frevecitinib in subjects (n=23) with moderate to severe asthma using ICS/LABA. Participants required pre-bronchodilator FEV1 ≥ 50 and ≤ 100% predicted and ACQ-6 ≥ 0.5 and ≤ 3.0 at screening. Participants received frevecitinib 4 mg twice-daily or matching placebo for 10 consecutive days. Pre-dose spirometry was performed on Days 1-10 (serial post dose measures Days 1 and 10). Pre-dose ACQ-6 was scored on Day 1 and 10. Sputum induction was performed at screening and Day 10 in a subset of subjects (n=8). Results: Mean pre-bronchodilator FEV1 was 81.3% predicted (range 58 to 102%) and mean ACQ-6 was 1.2 (0.2 to 2.5). Treatment with frevecitinib (n=17) improved the mean Day 10 FEV1 vs. placebo (n=6), by 120 ml with an increase of 190 ml in subjects with baseline blood eosinophil levels ≥0.300 x 109/L (n=11). Frevecitinib treatment resulted in a mean placebo-corrected reduction in ACQ-6 of -0.15 points at Day 10 with a -0.46 change in subjects with blood eosinophil levels ≥0.300 x 109/L. In subjects with baseline ACQ-6 ≥0.5 points (n=18), a higher proportion (53%) of participants receiving frevecitinib achieved an ACQ-6 reduction of at least -0.5 points at Day 10 compared to placebo (33%). Of those with blood eosinophil levels ≥0.300 x 109/L (n=10), 70% of frevecitinib subjects, compared to 0% with placebo, achieved this reduction. All subjects with evaluable samples (n=8) had sputum eosinophil counts ≥3% at screening. Day 10 levels decreased in all frevecitinib subjects (n=6) versus an increase in both placebo subjects; 4 of 6 frevecitinib subjects achieved normal (<3%) levels. Sputum absolute eosinophil counts decreased in all frevecitinib subjects with a Day 10 mean placebo-corrected change of 0.220 x 106/g. Conclusions: In addition to previously reported improvements in FeNO, the 10-day administration of frevecitinib to subjects with moderate to severe asthma results in FEV1 and ACQ-6 improvements associated with a reduction in sputum eosinophil levels. These results support further Phase 2 studies of frevecitinib in subjects with uncontrolled asthma using medium to high dose ICS/LABA.