[{"id":"itepe-copd-ph2-aer","name":"Annualized moderate-to-severe COPD exacerbation rate","type":"PRIMARY","unit":"rate ratio","results":[{"notes":"FAILED in overall population — not statistically significant","value":null,"arm_id":"itepe-copd-ph2","arm_name":"Itepekimab"},{"notes":"RR 0.58 (95% CI 0.39-0.85), p=0.0061. 42% exacerbation reduction in former smokers.","value":null,"arm_id":"subgroup-former","arm_name":"Former smokers subgroup"}],"timepoint":"Week 52","description":"Annualized rate of moderate-to-severe COPD exacerbations in overall population (current + former smokers)."}]

FAILED overall population but SUCCEEDED in former smokers subgroup: 42% exacerbation reduction (RR 0.58, p=0.006) and +90mL FEV1 (p=0.008). Smoking status fundamentally changes how IL-33 is processed — current smokers suppress ST2 on ILC2s, redirecting IL-33 signaling to macrophages/NK cells (non-type-2). Former smokers recover ILC2 function, restoring the druggable IL-33/ST2 axis.

Phase 2a (n=437): Well-tolerated. AE rates comparable between arms. No significant safety signals.

The former-smoker finding is the key insight. IL-33 biology is fundamentally different in current vs former smokers because smoking shifts ST2 expression from ILC2s (type 2 immune cells) to macrophages (type 1/neutrophilic cells). Only after quitting do ILC2s recover, restoring the IL-33→ST2→type 2 axis that itepekimab blocks. This biological insight drove the entire AERIFY program design.

IL-33 sits at the apex of the inflammatory cascade in COPD. Blocking the alarm signal should prevent both immune activation (ST2 arm) and mucus production (RAGE/EGFR arm).