Rilzabrutinib Phase 2 Asthma Trial Reports Mixed Efficacy Signal

Key Takeaways

• Loss-of-asthma-control events were numerically lower with both rilzabrutinib doses than with placebo, but statistical significance was not reached.
• Asthma control improved by week 2 and remained better than placebo through week 12 in both rilzabrutinib cohorts.
• Diarrhea was the most frequent adverse event, and infections were not increased.

Results from the phase 2 rilzabrutinib asthma trial showed a mixed efficacy pattern in adults with uncontrolled moderate-to-severe asthma during a 12-week randomized comparison. Oral rilzabrutinib was tested during planned withdrawal of background inhaled therapy, allowing assessment of asthma control after withdrawal began. Over 12 weeks, loss-of-asthma-control events occurred in 19% of participants receiving rilzabrutinib 1200 mg and 29% receiving placebo. That numerical reduction did not meet statistical significance for the primary endpoint. Asthma control also improved more with rilzabrutinib over the same period, providing a parallel symptom signal during follow-up.

This double-blind, placebo-controlled phase 2 study was conducted at 48 centres across 13 countries and enrolled adults aged 18–70 years with asthma. Participants had physician-diagnosed moderate-to-severe asthma for at least 12 months and uncontrolled symptoms despite inhaled glucocorticoids plus a long-acting beta2-adrenergic agonist. Among 310 screened participants, 196 were randomly assigned, with 32 and 32 in the low-dose cohort and 64 and 68 in the high-dose cohort, respectively. One cohort was assigned 1:1 to rilzabrutinib 800 mg/day or placebo, and the other was assigned 1:1 to rilzabrutinib 1200 mg/day or placebo in a staggered second cohort. Background inhaled therapy was withdrawn over weeks 4–9 and resumed at week 12, and the primary endpoint was the proportion with loss-of-asthma-control during treatment in the modified intention-to-treat population.

In the 800 mg cohort, loss-of-asthma-control events occurred in 38% with rilzabrutinib and 50% with placebo. Relative risk reductions for the primary endpoint were 25% with 800 mg and 36% with 1200 mg across the two cohorts. The corresponding odds ratios were 0.57 and 0.58, with p values of 0.29 and 0.21, respectively. The direction of effect was consistent across both dose levels, although event frequencies differed between the low-dose and high-dose cohorts. Event frequency was lower with rilzabrutinib, but the primary analysis remained statistically non-significant in both cohorts.

Asthma control improvement appeared as early as week 2 and remained better than placebo through week 12 in both dose groups. These findings were measured with the 5-item Asthma Control Questionnaire, used as a key secondary endpoint during the 12-week treatment period. Least-squares mean differences were -0.59 with 800 mg and -0.54 with 1200 mg, with p values of 0.018 and 0.0013. Diarrhea was the most frequent adverse event, and no increase in infections was observed with either dose. Overall, the trial showed a numerical, non-significant reduction in loss-of-asthma-control events alongside symptom improvement over 12 weeks of inhaled-therapy withdrawal.