Abstract Rationale Asthma is a common chronic inflammatory disease of the airways. Despite available therapies, there are individuals whose asthma remains uncontrolled, which can negatively affect health-related quality of life (HRQoL). Rilzabrutinib (SAR444671), an oral, selective, reversible, covalent Bruton’s tyrosine kinase inhibitor, was evaluated in adults with poorly controlled moderate-to-severe asthma despite treatment with inhaled corticosteroid (ICS)/long-acting β2 adrenergic agonist (LABA) therapy. Here we report the effect of pooled rilzabrutinib 800 mg and rilzabrutinib 1200 mg daily on HRQoL over 12 weeks. Methods This was a phase 2, double-blind, two-staggered-cohort study evaluating the efficacy and safety of rilzabrutinib (NCT05104892). A total of 196 adult participants with poorly controlled moderate-to-severe asthma on medium-to-high dose ICS/LABA therapy were randomized to receive rilzabrutinib 800 mg (n = 32) or placebo (n = 32) and rilzabrutinib 1200 mg (n = 64) or placebo (n = 68) for 12 weeks. ICS/LABA therapy was withdrawn from week 4 to week 9. The treatment effect of rilzabrutinib versus placebo on HRQoL was evaluated using the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQS). Changes from baseline in global and domain scores (range: 1 = severe impairment to 7 = no impairment) were assessed through week 12. The proportion of participants achieving a clinically meaningful improvement (≥0.5-point increase in AQLQS global score) was analyzed at week 12. Results At baseline, mean AQLQ(S) global scores were 4.94 (standard deviation SD: 0.84) and 4.67 (SD: 0.91) for pooled rilzabrutinib (n = 96) and placebo (n = 100), respectively. Improvement in AQLQ(S) global score for rilzabrutinib vs placebo was observed as early as week 4 (least squares LS mean difference from baseline: 0.36; 95% confidence interval CI: 0.11‒0.61; p = 0.0045), and sustained up to week 12 despite ICS/LABA withdrawal (LS mean difference: 0.44; 95% CI: 0.19‒0.69; p = 0.0006). Improvements in AQLQ(S) domain scores were observed by week 4 with rilzabrutinib vs placebo and sustained through week 12 (LS mean differences: symptoms, 0.43, p = 0.0013; activity limitation, 0.47, p = 0.0002; emotional function, 0.44, p = 0.0088; environmental stimuli, 0.41, p = 0.0217). At week 12, 51.4% and 37.7% of participants achieved a clinically meaningful response (≥0.5 points on AQLQS) with pooled rilzabrutinib vs placebo (p = 0.0057), respectively. Conclusions Rilzabrutinib demonstrated rapid and clinically meaningful improvements in asthma-related QoL (AQLQS) vs placebo in participants with poorly controlled moderate-to-severe asthma over 12 weeks of treatment. Improvements were maintained despite withdrawal of ICS/LABA background therapy beginning at week 4. This abstract is funded by: Sanofi
Busse et al. (Fri,) studied this question.