KN-002 reduces fractional exhaled nitric oxide in moderate to severe asthma

<bold>Background:</bold> Multiple pro-inflammatory mediators signal via the JAK/STAT pathway and are implicated in the pathogenesis of moderate to severe asthma. KN-002 is a novel lung selective potent pan-JAK inhibitor formulated as a dry powder for inhalation. <bold>Methods:</bold> This Phase 1b, randomized, double-blinded, placebo-controlled 4-part study (<ext-link>NCT05006521</ext-link>) evaluated the safety, pharmacokinetics, and pharmacodynamics of KN-002. Part 3 included subjects with moderate to severe asthma treated with maintenance ICS/LABA. Study participants (21 to 60 yrs) had mean baseline FeNO 51.4 ppb (19.5 to 117.8 ppb), mean pre-bronchodilator FEV1 predicted 81.5% (58 - 106%), mean blood eosinophil level 361 cells/µL (110 - 770 cells/µL) and mean ACQ-6 score 1.2 (0.2 - 2.5); subjects with pre-dose FeNO levels ≥30 ppb at Baseline or Day 1 received 4 mg BID regimen or placebo for 10 days. FeNO was measured on Days 1-10, 11-12 and 17. <bold>Results:</bold> 23 subjects (17 KN-002:6 placebo) received treatment; no subjects withdrew and no safety concerns were reported. KN-002 reduced FeNO versus placebo, from Day 1 pre-dose to Day 10; mean 21 ppb (24%). Improvement was seen after the first dose, continued to Day 10 and maintained through a 2-day no-treatment period. FeNO levels reverted to near baseline levels by Day 17. A greater proportion (59% v 33%) of subjects receiving KN-002 achieved normal (<25ppb) levels by Day 10 versus placebo. The FeNO response was independent of baseline FeNO and blood eosinophil level. <bold>Conclusions:</bold> KN-002 caused clinically relevant FeNO reduction over 10 days independent of baseline FeNO / blood eosinophils. These results support KN-002 development in eosinophilic and non-eosinophilic moderate to severe asthma.