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Background Biologic therapies have revolutionized severe asthma management, reducing systemic corticosteroid use and exacerbations. Individual treatment response is variable and difficult to predict.Objective To characterise the clinical response to biologic therapy in patients with severe asthma and identify predictors of response and non-response.Methods We conducted a retrospective analysis of severe asthma patients treated with biologics for 12 months (March 2014– 2025). Clinical response was defined as ≥50% reduction in annualised asthma exacerbation rate (AER) and/or oral corticosteroid (OCS) dose. A stratified, weighted penalised logistic regression (PLR) model was trained (AUC-optimised) and validated using stepwise logistic regression (SLR).Results 321/374 (85.8%) achieved a clinical response at 12 months. At baseline, responders had better asthma control and health-related quality of life compared to non-responders; ACQ-6 score (2.50 [1.50 - 3.34] vs 3.33 [2.32 - 4.15]; p = 0.001) respectively; EQ-5D-5L score (10.80 [7.00 - 17.00] vs 38.77 [10.14 - 103.50]; p < 0.001) and AQLQ score 3.76 [2.63 – 4.88] vs 2.34 [1.13 – 3.91]; p < 0.001). Responders also had shorter disease duration (20.0 [5.0 - 33.9] years vs 27.0 [14.0 - 39.5] years; p = 0.008), lower blood neutrophil counts (7.01 [4.93 - 9.83] vs 8.40 [6.45 - 12.17]; p = 0.002), higher serum IgA levels (2.29 [1.67 - 2.78] vs 2.01 [1.31 - 2.35]; p = 0.006) and lower levels of Aspergillus-specific IgE (0.07 [0.02 - 0.78] vs 0.22 [0.03 - 4.94]; p = 0.004). PLR identified several predictors of response with strongest associations included higher serum IgA (OR = 1.08), male sex (OR = 1.16), and lower ACQ6 scores (OR = 0.96). In the SLR model lower ACQ6 scores (OR = 0.64, p = 0.0007) and diminished Aspergillus sensitisation (OR = 0.96, p = 0.0044) were significantly associated with treatment response and reduced blood neutrophil counts (OR = 0.93, p = 0.061), showing a trend towards significance.Conclusion Lower baseline ACQ6 scores, diminished Aspergillus sensitisation, higher serum IgA, and lower neutrophil counts were independently associated with good clinical response to biologics. Prospective studies are needed to validate these biomarkers’ performance in guiding personalised treatment.