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Background Biologic therapies have transformed severe asthma care, but the real-world evolution of multidimensional clinical outcomes—including symptom control, exacerbations, steroid use, and hospital admissions—remains incompletely characterised, especially in relation to biomarker profiles and broad clinical response patterns.Methods We conducted a comprehensive longitudinal cohort study of 215 adults with severe asthma treated with biologics in the Portsmouth Severe Asthma Service (2015–2024). Patients were assessed annually for symptom control (Asthma Control Questionnaire, ACQ), exacerbation frequency (oral corticosteroid-requiring events), lung function (FEV 1), maintenance oral steroid use (mOCS), and hospital admissions through Year 3. Clinically meaningful responses were defined as: ACQ improvement ≥0.5, OCS burst reduction ≥50%, FEV1 increase ≥200 mL, hospital admission reduction by ≥1, mOCS cessation, and ≥50% mOCS dose reduction. Cumulative and incremental responder rates were quantified using Kaplan-Meier-style plots, including multi-domain (quadruple- and quintuple-domain) response and time-to-benefit. Baseline demographics, biomarkers (eosinophils, FeNO), and treatment factors were compared between quadruple-domain responders and non-responders.Results By Year 3, cumulative responder rates were: OCS burst reduction 94.0%, mOCS cessation 76.1% (n=67), ACQ improvement 68.8%, FEV 1 improvement 55.8%, hospital admission reduction 60.9% (in those at risk), and ≥50% mOCS dose reduction (not weaned) 11.9%. Most benefit accrued in Year 1, but a substantial minority achieved late multi-domain response by Years 2 and 3. Quadruple-domain response (ACQ+OCS+FEV1+admission reduction) increased from 18.0% to 38.7% for benralizumab, 27.3% to 36.4% for dupilumab, 24.2% to 40.9% for mepolizumab, and 11.1% to 33.3% for omalizumab from Year 1 to Year 3. Baseline comparisons revealed no significant differences in eosinophils, FeNO, ICS dose, lung function, adherence, or smoking between quadruple-domain responders (n=87) and quadruple non-responders (n=132); only maintenance oral corticosteroid use was less common in quadruple-domain responders (p=0.005). The figure illustrates sequential accrual of benefit across all domains and therapies.Abstract S134 Figure 1Sequential cumulative responder rates for FEV1, ACQ, OCS burst reduction, hospital admission, mOCS cessation, and mOCS dose reduction (Kaplan-Meier-style curves by year)Conclusion In real-world practice, biologics provide robust, durable benefits across all asthma domains, with ongoing accrual of multi-domain (quadruple) response over three years. Quadruple-domain response was observed irrespective of biomarker profile but was less frequent among those on maintenance steroids at baseline. Tracking cumulative, multidomain outcomes is essential for optimal biologic selection and asthma management.