Abstract Rationale Despite available therapies, a high proportion of asthma patients have uncontrolled disease characterized by persistent symptoms and/or exacerbations. The contribution of exacerbation history to symptom control is unclear, and patients may experience uncontrolled symptoms despite not having a history of frequent exacerbations. Rilzabrutinib (SAR444671), an oral, selective, reversible, covalent Bruton’s tyrosine kinase inhibitor, has been shown to improve symptom control in patients with uncontrolled asthma in a phase 2 study. The subgroup analysis reported here evaluates the effect of rilzabrutinib on asthma symptom control based on exacerbation history. Methods Rilzabrutinib was evaluated in a phase 2, 12-week, double-blind, placebo-controlled study in adults with uncontrolled asthma on medium-to-high doses of inhaled corticosteroid (ICS) plus long-acting β2 adrenergic agonist (LABA) therapy (NCT05104892). Participants were required to have ≥1 severe asthma exacerbation within 2 years prior to screening. Participants were randomized in two staggered cohorts to rilzabrutinib 800 mg daily (n = 32) or matching placebo (n = 32; low-dose cohort), or rilzabrutinib 1200 mg daily (n = 64) or matching placebo (n = 68; high-dose cohort). All participants were on standardized background therapy of medium-to-high-dose ICS/LABA, which was withdrawn during weeks 4-9. Asthma symptom control was assessed by the 5-item Asthma Control Questionnaire (ACQ-5) as change from baseline. Subgroup analyses utilized pooled data from the two cohorts. Results This analysis included 196 participants. At baseline, mean ACQ-5 scores were similar between pooled rilzabrutinib and placebo arms. Nominally significant and clinically meaningful improvements in ACQ-5 were observed as early as week 2 for rilzabrutinib vs placebo (least squares LS mean: -0.47 vs -0.14; difference: -0.34; p = 0.001) and sustained up to week 12 (LS mean: -0.69 vs -0.17; difference: -0.52; p = 0.0001) despite withdrawal of ICS/LABA. In the pooled subgroup analysis based on prior exacerbations within 1 year before screening, baseline ACQ-5 scores in participants with no asthma exacerbation events (n = 46) were similar between treatment groups. Baseline ACQ-5 scores were slightly lower in participants with ≥1 exacerbation (n = 150) in the past year but similar between treatment groups. Significant improvements in ACQ-5 in both subgroups were observed early, with sustained improvements achieved with rilzabrutinib at week 12 vs placebo (LS mean difference: 0 exacerbations: -0.85, p = 0.0014; ≥1 exacerbation, -0.46, p = 0.0039) (Figure). Conclusions Rilzabrutinib was associated with rapid, clinically meaningful improvements in asthma symptom control vs placebo over 12 weeks, with improvements achieved regardless of patients’ exacerbation history. This highlights the potential for rilzabrutinib to improve asthma symptoms even among those without frequent exacerbations. This abstract is funded by: Sanofi
Cote et al. (Fri,) studied this question.