D92-04 Exposure-response Relationships of Brensocatib in Adult and Adolescent Patients With Non-Cystic Fibrosis Bronchiectasis

Rationale Brensocatib is a competitive, reversible inhibitor of dipeptidyl peptidase 1 (DPP1). By inhibiting DPP1, brensocatib reduces the formation of proinflammatory neutrophil serine proteases and is approved in patients with non-cystic fibrosis bronchiectasis, hereafter bronchiectasis. To support brensocatib dosage selection, the exposure-response (E-R) relationships for safety and efficacy in patients with bronchiectasis were explored. Methods A total of 1,431 participants with bronchiectasis from studies WILLOW (phase 2, 157 at 10/25 mg and 85 placebo; NCT03218917) and ASPEN (phase 3, 626 at brensocatib 10/25 mg and 563 placebo; NCT04594369) were available for analysis. Key clinical efficacy and safety outcomes, such as annualized pulmonary exacerbation (PEx) rate, time to first PEx (TTFPE), change from baseline in postbronchodilator FEV1 and AE of special interest (hyperkeratosis, periodontal disease, and pneumonia), in relationship with steady-state AUCτ were evaluated. Due to the differences in treatment duration and the definitions of the clinical measurements, either phase 3 data alone (PEx rate, TTFPE, FEV1, and hyperkeratosis) or pooled data from both studies (periodontal disease and pneumonia) were used for the analysis. The primary exposure variable was steady-state AUCτ either as continuous in quartiles or binary (below or above threshold). A recursive partitioning algorithm was used to identify the exposure thresholds associated with substantial efficacy differences. Results The E-R relationships for PEx rate and TTFPE were not statistically significant when AUCτ was treated as a continuous variable. However, statistically significant improvements in PEx rate and TTFPEx were observed in participants with AUCτ >1,100 ng·h/mL ( 25 mg: 100%; 10 mg: 69%), with or without inclusion of placebo. A clear relationship between AUCτ threshold (1,531) and FEV1 was observed (Figure 1). Participants with AUCτ >1,531 ng·h/mL (>99% at 25 mg and 46% at 10 mg) maintained lung function (FEV1) over treatment period while those on placebo and those with AUCτ <1,531 ng·h/mL had similar reductions in lung function. Relationships between AUCτ and periodontal disease or pneumonia were not detected. However, the incidence of hyperkeratosis (all of mild and moderate severity) showed a shallow but statistically significant exposure-dependent trend. The model predicted probability of hyperkeratosis at 10 and 25 mg was 1.55% and 3.01% in adults and 1.73% and 3.36% in adolescents, slightly higher than placebo (adults, 0.52%; adolescents, 0.52%). Conclusions The E-R relationships of brensocatib support the selection of 10 and 25 mg for the treatment of bronchiectasis in adult and pediatric patients 12 years of age or older. This abstract is funded by: Insmed Incorporated