Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis

BACKGROUND AND OBJECTIVE: Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies. METHODS: Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK–efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK–safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses. RESULTS: The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK–efficacy analysis revealed a threshold brensocatib exposure (area under the concentration–time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK–safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369). CONCLUSIONS: PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01147-w

Amikacin liposome inhalation suspension clinical benefit–risk assessment for refractory Mycobacterium avium complex lung disease

Marras et al. report a low number needed to treat and high number needed to harm supporting addition of amikacin liposome inhalation suspension to guideline-based treatments in patients with treatment-refractory Mycobacterium avium complex lung disease https://bit.ly/3tPFW7

PROMIS Physical Function Correlates with KOOS, JR in Patients with Knee Pain

Using Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) computerized adaptive test instead of the Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR) could reduce question burden for patients with knee pain. We aimed to prospectively determine the correlation between PROMIS PF and KOOS, JR to assess whether PROMIS PF could be a useful alternative measure for both research and clinical care of patients with knee pain. This was a cross-sectional study of 88 patients. We assessed the correlation between PROMIS PF and KOOS, JR using a Pearson's correlation test. Two multivariable linear regression models were used to determine the amount of variation explained by various patient-level factors. There was a strong correlation between PROMIS PF and KOOS, JR (r = 0.74, p < 0.001). KOOS, JR was an independent predictor of PROMIS PF when controlling for patient-level factors (β 0.26; p < 0.001). The results of this study support the idea of using PROMIS PF in place of joint-specific measures such as KOOS, JR for clinical care of patients with knee pain. The level of evidence for this study is Level III

Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients.

Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis

BACKGROUND Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P=0.03 for 10-mg brensocatib vs. placebo; P=0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P=0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P=0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P=0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P=0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes