Search

Bronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose-response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48-1.05 and 0.40-1.08; both p>0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo.Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis., (Copyright ©The authors 2024.)

Aims: Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil-derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects., Methods: This randomized, double-blind, placebo-controlled, parallel-group study investigated BI 1291583 in healthy Japanese male subjects (jRCT2071210111) and consisted of a single-rising-dose (SRD) part and a multiple-dose (MD) part. The primary endpoint was the percentage of subjects with drug-related treatment-emergent adverse events (AEs). Secondary PK endpoints (SRD: AUC 0-∞ and C max ; MD: AUC τ,1 and C max,1 after first dose and AUC τ,ss and C max,ss after last dose), as well as further safety and PK endpoints, were also assessed., Results: Overall, 36 subjects (n = 24 for SRD part; n = 12 for MD part) entered this Phase I trial. BI 1291583 was safe and well tolerated across the doses tested. All AEs were of mild intensity, with no drug-related treatment-emergent AEs, deaths, serious AEs or AEs of special interest reported in either part of the trial. Following both SRD and MD administration, BI 1291583 was readily absorbed, and PK was supraproportional over the doses assessed., Conclusion: The results show that BI 1291583 has an appropriate benefit-risk ratio for Japanese patients, with no safety or exposure concerns at the doses studied. Japanese patients with bronchiectasis can be safely integrated into future global clinical trials of BI 1291583, with no dose adjustment required., (© 2024 British Pharmacological Society.)

Preclinical and phase 1 study results indicate that BI 1291583 is a reversible, highly potent and highly selective CatC inhibitor that markedly inhibits active NSP production in a dose-dependent manner, supporting phase 2 trials in bronchiectasis patients https://bit.ly/47PZ8E5., Competing Interests: Conflict of interest: J.D. Chalmers reports grant support from AstraZeneca, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, Novartis and Zambon, and consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Pfizer and Zambon; and is an associate editor of this journal. Conflict of interest: P. Badorrek has nothing to disclose. Conflict of interest: C. Diefenbach, H. Kögler, W. Sauter and S. Kreideweiss are employees of Boehringer Ingelheim. Conflict of interest: J.M. Hohlfeld reports grant support paid to his institution from AltamiraPharma GmbH, Astellas Pharma GmbH, AstraZeneca AB, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, CSL Behring GmbH, Desitin Arzneimittel GmbH, EpiEndo, F. Hoffmann-La Roche AG, Genentech, Inc., M&P Pharma AG, Novartis AG, OM Pharma SA and Sanofi-Aventis Deutschland GmbH, personal fees for consultancy from Boehringer Ingelheim Pharma GmbH & Co. KG, Cureteq and Roche, personal fees for lectures from Novartis AG, and personal fees for board service from CSL Behring GmbH and Nocion., (Copyright ©The authors 2024.)

New therapies are needed to prevent exacerbations, improve quality of life and slow disease progression in bronchiectasis. Inhibition of cathepsin C (CatC) activity has the potential to decrease activation of neutrophil-derived serine proteases in patients with bronchiectasis, thereby reducing airway inflammation, improving symptoms, reducing exacerbations and preventing further airway damage. Here we present the design of a phase 2 trial (Airleaf™; NCT05238675) assessing the efficacy and safety of a novel CatC inhibitor, BI 1291583, in adult patients with bronchiectasis. This multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study has a screening period of at least 6 weeks, a treatment period of 24-48 weeks and a follow-up period of 4 weeks. ∼240 adults with bronchiectasis of multiple aetiologies will be randomised to placebo once daily, or BI 1291583 1 mg once daily, 2.5 mg once daily or 5 mg once daily in a 2:1:1:2 ratio, stratified by Pseudomonas aeruginosa infection and maintenance use of macrolides. The primary efficacy objective is to evaluate the dose-response relationship for the three oral doses of BI 1291583 versus placebo on time to first pulmonary exacerbation up to Week 48 (the primary end-point). Efficacy will be assessed using exacerbations, patient-reported outcomes, measures of symptoms, sputum neutrophil elastase activity and pulmonary function testing. Safety assessment will include adverse event reporting, physical examination, monitoring of vital signs, safety laboratory parameters, 12-lead electrocardiogram, and periodontal and dermatological assessments. If efficacy and safety are demonstrated, results will support further investigation of BI 1291583 in phase 3 trials., Competing Interests: Conflict of interest: J.D. Chalmers reports grants from GSK, Boehringer Ingelheim, Zambon, Insmed, Grifols, Novartis, Gilead and AstraZeneca, and is an associate editor of this journal. A. Gupta, A. Eleftheraki, C. Diefenbach and W. Sauter are employees of Boehringer Ingelheim International GmbH. S.H. Chotirmall reports grants paid to his institution from the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-000141), Clinical-Scientist Award (MOH-000710) and National Research Foundation Singapore under its COVID-19 Research Fund administered by the Singapore Ministry of Health's National Medical Research Council (MOH-000409), consulting fees from CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, lecture fees from AstraZeneca, and participation in Data Safety and Monitoring Committees for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University. A. Armstrong reports consulting fees from AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, BMS, Dermavant, EPI, Incyte, Nimbus, Dermira, Eli Lilly, Janssen, Leo Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Boehringer Ingelheim, Parexel and Pfizer, payment or honoraria from AbbVie, ASLAN, Boehringer Ingelheim, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi Regeneron, Parexel, Pfizer, Almirall, Arcutis, Nimbus and ModMed, participation on advisory boards for Boehringer Ingelheim and Parexel, and is on the board of directors for the American Academy of Dermatology. P. Eickholz reports payment or honoraria for lectures from Boehringer Ingelheim, Sanofi Aventis, Kulzer, CP GABA and Philips, and lectures primarily in the dental field. N. Hasegawa reports grants for a clinical trial and consulting fees from Insmed. P.J. McShane reports study funding to her institution from Boehringer Ingelheim and speaker fees from Insmed. A.E. O'Donnell reports grants for study funding from Insmed, AstraZeneca, Zambon and the US Bronchiectasis Research Registry, consulting fees from Insmed, Boehringer Ingelheim, Zambon, Electromed, AstraZeneca and Xellia, payment for CME from Vindico Medical Education, participation in a Data Safety Monitoring Board for Parexel, and a role with the US Bronchiectasis Research Registry. M. Shteinberg reports grants paid to her institution from GSK, Trumed and Novartis, consulting fees from GSK, Boehringer Ingelheim, Kamada, Zambon and Vertex, payment or honoraria from Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis and Kamada, support for attending meetings from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa, participation on advisory boards from Bonus Therapeutics (Israel), unpaid fiduciary roles for EMBARC Management and the Israel Pulmonology Society Board, and receipt of supply to a clinical trial from Trudell. H. Watz has nothing to disclose., (Copyright ©The authors 2023.)

Rationale: Sepsis often leads to long-term functional deficits and increased mortality in survivors. Postacute rehabilitation can decrease long-term sepsis mortality, but its impact on nursing care dependency, health care use, and costs is insufficiently understood. Objectives: To assess the short-term (7-12 months postdischarge) and long-term (13-36 months postdischarge) effect of inpatient rehabilitation within 6 months after hospitalization on mortality, nursing care dependency, health care use, and costs. Methods: An observational cohort study used health claims data from the health insurer AOK (Allgemeine Ortskrankenkasse). Among 23.0 million AOK beneficiaries, adult beneficiaries hospitalized with sepsis in 2013-2014 were identified by explicit codes from the International Classification of Diseases, Tenth Revision. The study included patients who were nonemployed presepsis, for whom rehabilitation is reimbursed by the AOK and thus included in the dataset, and who survived at least 6 months postdischarge. The effect of rehabilitation was estimated by statistical comparisons of patients with rehabilitation (treatment group) and those without (reference group). Possible differential effects were investigated for the subgroup of ICU-treated sepsis survivors. The study used inverse probability of treatment weighting based on propensity scores to adjust for differences in relevant covariates. Costs for rehabilitation in the 6 months postsepsis were not included in the cost analysis. Results: Among 41,918 6-month sepsis survivors, 17.2% ( n  = 7,224) received rehabilitation. There was no significant difference in short-term survival between survivors with and without rehabilitation. Long-term survival rates were significantly higher in the rehabilitation group (90.4% vs. 88.7%; odds ratio [OR] = 1.2; 95% confidence interval [95% CI] = 1.1-1.3; P  = 0.003). Survivors with rehabilitation had a higher mean number of hospital readmissions (7-12 months after sepsis: 0.82 vs. 0.76; P  = 0.014) and were more frequently dependent on nursing care (7-12 months after sepsis: 47.8% vs. 42.3%; OR = 1.2; 95% CI = 1.2-1.3; P  < 0.001; 13-36 months after sepsis: 52.5% vs. 47.5%; OR = 1.2; 95% CI = 1.1-1.3; P  < 0.001) compared with those without rehabilitation, whereas total health care costs at 7-36 months after sepsis did not differ between groups. ICU-treated sepsis patients with rehabilitation had higher short- and long-term survival rates (short-term: 93.5% vs. 90.9%; OR = 1.5; 95% CI = 1.2-1.7; P  < 0.001; long-term: 89.1% vs. 86.3%; OR = 1.3; 95% CI = 1.1-1.5; P  < 0.001) than ICU-treated sepsis patients without rehabilitation. Conclusions: Rehabilitation within the first 6 months after ICU- and non-ICU-treated sepsis is associated with increased long-term survival within 3 years after sepsis without added total health care costs. Future work should aim to confirm and explain these exploratory findings.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disorder involving production of autoantibodies against endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF). This study aimed to identify biomarkers that could be used to monitor for aPAP, particularly in patients treated with anti-GM-CSF antibodies. This was an exploratory, prospective, observational, single-center study. Pre-specified biomarkers were evaluated between baseline and Day 120 in serum/plasma, whole blood, sputum and exhaled breath condensate from patients with aPAP, healthy volunteers, and patients with chronic obstructive pulmonary disease (COPD) and asthma (not treated with anti-GM-CSF and with no evidence of aPAP). Pulmonary function tests were also performed. Overall, 144 individuals were enrolled (aPAP: n = 34, healthy volunteers: n = 24, COPD: n = 40 and asthma: n = 46). Plasma GM-CSF levels were lower, and Krebs von den Lungen 6 and GM-CSF autoantibody ranges were higher, in patients with aPAP compared with other populations. Surfactant proteins-A and -D, lactate dehydrogenase and carcinoembryonic antigen ranges partially or completely overlapped across populations. Most plasma biomarkers showed high sensitivity and specificity for detection of aPAP; GM-CSF and GM-CSF autoantibody concentrations demonstrated equivalent sensitivity for differentiating aPAP. In addition to characteristic GM-CSF autoantibodies, assessment of plasma GM-CSF may identify individuals at risk of developing aPAP.Trial registration: EudraCT, 2012-003475-19. Registered 23 July 2012- https://eudract.ema.europa.eu/ ., (© 2022. The Author(s).)