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Cathepsin C Inhibitor BI 1291583 Shows Promise in Reducing Bronchiectasis Exacerbations

• Phase 2 AIRLEAF trial results indicate that BI 1291583, a cathepsin C inhibitor, reduces the risk of pulmonary exacerbations in adults with bronchiectasis. • The study showed a dose-dependent benefit of BI 1291583 compared to placebo in time to first pulmonary exacerbation over 48 weeks. • A 29% decreased risk of initial pulmonary exacerbation was observed with the 5 mg dose of BI 1291583 compared to placebo, though statistical significance was not reached. • A phase 3 trial (AIRTIVITY) is planned for 2025 to further evaluate BI 1291583 in bronchiectasis patients.

The cathepsin C (CatC) inhibitor BI 1291583 has demonstrated a potential to decrease the risk of exacerbations in adult patients with bronchiectasis, according to findings from the phase 2 AIRLEAF trial published in the European Respiratory Journal. The randomized, double-blind, placebo-controlled study, conducted across 102 sites in 22 countries, evaluated the efficacy, safety, and optimal dosing of BI 1291583. These results pave the way for a phase 3 trial (AIRTIVITY) planned to begin in 2025.

AIRLEAF Trial Design and Results

The AIRLEAF trial (NCT05238675) randomized 322 participants with confirmed bronchiectasis and a history of pulmonary exacerbations requiring antibiotics to receive either placebo (n=109) or one of three once-daily doses of BI 1291583: 1 mg (n=53), 2.5 mg (n=53), or 5 mg (n=107). Treatment duration ranged from 24 to 48 weeks, followed by a 4-week safety follow-up. The primary objective was to determine if there was a dose-response relationship between the BI 1291583 doses and placebo regarding the time to first pulmonary exacerbation up to week 48.
The study revealed a significant dose-dependent benefit of BI 1291583 compared to placebo in the dose-response analysis for time to first pulmonary exacerbation up to week 48 (adjusted P = .0448). Model-predicted hazard ratios for BI 1291583 at 1 mg, 2.5 mg, and 5 mg versus placebo were 0.85 (95% CI, 0.58-1.25), 0.75 (95% CI, 0.51-1.10), and 0.68 (95% CI, 0.47-1.00), respectively.

Impact on Pulmonary Exacerbations

Pairwise comparison of the 5 mg BI 1291583 dose versus placebo showed a 29% reduced risk of initial pulmonary exacerbation up to week 48 (adjusted hazard ratio, 0.71; 95% CI, 0.48-1.05; P = .0857), although this did not reach statistical significance. The effects for the 2.5 mg and 1 mg doses compared to placebo were 0.66 (95% CI, 0.40-1.08) and 0.93 (95% CI, 0.60-1.45), respectively. Adjusted event rate ratios compared with placebo for BI 1291583 5 mg and 2.5 mg were 0.89 (95% CI, 0.63-1.26) and 0.68 (95% CI, 0.43-1.08), respectively. The rate ratio for BI 1291583 1 mg was 1.03 (95% CI, 0.69-1.56).

Safety Profile

Severe adverse events were reported in 11.9% of participants in the placebo group, compared to 9.4%, 7.5%, and 15.0% in the BI 1291583 1-mg, 2.5-mg, and 5-mg groups, respectively.

Future Directions

"Results from the AIRLEAF trial support the continued clinical development of BI 1291583 in bronchiectasis, with a phase 3 trial (AIRTIVITY) planned to begin in 2025," the investigators concluded. This next phase aims to further solidify the potential of CatC inhibition as a therapeutic strategy for bronchiectasis.
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Reference News

[1]
In Bronchiectasis, Cathepsin C Inhibitor Reduces Exacerbation Risk - Pulmonology Advisor
pulmonologyadvisor.com · Sep 25, 2024

The phase 2 AIRLEAF trial found that BI 1291583, a cathepsin C inhibitor, reduced the risk of pulmonary exacerbations in...

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