{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:35:07Z","timestamp":1791668107559,"version":"4.3.4"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil\u2010derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single\u2010rising\u2010dose study (NCT03414008) and two multiple\u2010rising\u2010dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug\u2013drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug\u2010related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra\u2010proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose\u2010dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co\u2010administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf\u2122 [NCT05238675], Clairafly\u2122 [NCT05865886], and Clairleaf\u2122 [NCT05846230]).<\/jats:p>","DOI":"10.1111\/cts.13891","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T05:48:39Z","timestamp":1724392119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel cathepsin C inhibitor, <scp>BI<\/scp> 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers"],"prefix":"10.1111","volume":"17","author":[{"given":"Philipp","family":"Badorrek","sequence":"first","affiliation":[{"name":"Department of Clinical Airway Research Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Diefenbach","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"K\u00f6gler","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH  Ingelheim Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Eleftheraki","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. KG  Biberach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4460-5867","authenticated-orcid":false,"given":"Friedeborg","family":"Seitz","sequence":"additional","affiliation":[{"name":"Clinical Research Services  Mannheim Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-6186","authenticated-orcid":false,"given":"Jens M.","family":"Hohlfeld","sequence":"additional","affiliation":[{"name":"Department of Clinical Airway Research Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)  Hannover Germany"},{"name":"Department of Respiratory Medicine Hannover Medical School  Hannover Germany"},{"name":"German Centre for Lung Research (DZL)  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1813799"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S6133"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012615-044344"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0042-3"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.08-0776"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31767-7"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201303-0411CI"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/rmed.2001.1155"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/642503"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30504-X"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198902093200606"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22115996"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb\/4.1.26"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.26.4.4473"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201605-1027OC"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00494-2021"},{"key":"e_1_2_10_18_1","first-page":"3328","article-title":"Proteinase\u20103 as a biomarker of exacerbations in bronchiectasis","volume":"56","author":"Abo\u2010Leyah H","year":"2020","journal-title":"Eur Respir J"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0213462"},{"key":"e_1_2_10_20_1","first-page":"A3213","article-title":"In vitro and in\u00a0vivo characterization of the novel cathepsin C inhibitor BI 1291583 for use in bronchiectasis","volume":"205","author":"Kreideweiss S","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tripleo.2009.03.016"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1053"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13398"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021713"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/70472"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-022-01147-w"},{"key":"e_1_2_10_27_1","volume-title":"BI 1291583 Investigator's Brochure. (Report no. c18711868\u201003)","author":"Boehringer Ingelheim International GmbH","year":"2021"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.cpm.0000171422.98696.ed"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00633-2022"},{"key":"e_1_2_10_30_1","unstructured":"ClinicalTrials.gov.A Study to Test how Well BI 1291583 is Tolerated by People with Cystic Fibrosis Bronchiectasis(Clairafly\u2122).2023Accessed September 7 2023.https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05865886"},{"key":"e_1_2_10_31_1","unstructured":"Clinicaltrials.gov.Clairleaf\u1d40\u1d39: A Study to Test Long\u2010term Treatment with BI 1291583 in People with Bronchiectasis who Took Part in a Previous Study with this Medicine.2023Accessed September 7 2023.https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05846230"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13891","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T05:26:16Z","timestamp":1724909176000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1111\/cts.13891"],"URL":"https:\/\/doi.org\/10.1111\/cts.13891","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8]]},"assertion":[{"value":"2024-05-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13891"}}