(406) The Effect of Brensocatib vs Placebo on Symptom Burden in Patients With Non-Cystic Fibrosis Bronchiectasis (Bronchiectasis) With or Without On-Study Pulmonary Exacerbations: A Post-Hoc Analysis From the ASPEN Trial

Background: : Patients (pts) with bronchiectasis endure a high symptom burden and recurrent pulmonary exacerbations (PEx). Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of neutrophil serine proteases associated with bronchiectasis progression. In the phase 3 ASPEN trial (NCT04594369), brensocatib 10 and 25mg significantly reduced PEx burden vs pbo (annualized rate, time to first, increased odds of remaining PEx-free); brensocatib 25mg also significantly reduced lung function decline and nominally significantly improved pt-reported symptoms.

Objective: : To assess the effect of brensocatib vs pbo on pt-reported symptoms using the Bronchiectasis Exacerbation and Symptom Tool (BEST) in adults with vs without on-study PEx.

Methods: : Adult pts in ASPEN had ≥2 PEx in the 12 months before screening and were randomized 1:1:1 to once-daily brensocatib (10 or 25mg) or pbo for 52 wks. PEx were adjudicated by a blinded independent committee; severe PEx required IV antibiotics and/or hospitalization. Pts completed the BEST symptom diary daily. Scores range 0-26; lower scores indicate fewer symptoms. In this post-hoc analysis, pts were categorized into 3 subgroups by on-study PEx (no PEx, any PEx, any severe PEx). Symptom onset was defined as sustained mean change from baseline in BEST >0 for ≥48 hours before the PEx; recovery was defined as return to baseline.

Results: : No PEx, any PEx, and any severe PEx subgroups included 784, 879, and 194 pts, respectively. Pts with PEx had greater symptom burden over 52 wks than pts without PEx, with highest scores for severe PEx. Brensocatib groups had greater decrease in BEST scores at wk 52 vs pbo regardless of PEx occurrence/severity (LSmean difference [95% CI] no PEx: 10mg −0.566 [−1.048, −0.083], 25mg −1.032 [−1.548, −0.517]; any PEx: 10mg 0.056 [−0.388-0.499], 25mg −0.399 [−0.870-0.072]; severe PEx: 10mg −0.643 [−1.638-0.352], 25mg −0.534 [−1.561-0.494]).
Brensocatib reduced symptom burden vs pbo 21 days before and after onset of severe PEx. For brensocatib 10 and 25mg, mean BEST scores increased from baseline 5-7 days before the severe PEx event; reaching peak mean (SD) scores of 3.45 (4.1) and 3.43 (4.4), respectively. Symptoms recovered within 21 days. In the pbo group, the BEST score was elevated >21 days before and after the severe PEx event with a peak mean (SD) score increase of 4.07 (4.4).

Conclusions: : Brensocatib 10 and 25mg reduced symptom burden vs pbo during severe PEx events and regardless of PEx occurrence, with greatest reductions in pts on 25mg and those without on-study PEx.

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