Dave Singh, Patricia Guller, Fred Reid, Sarah Doffman, Ulla Seppälä, Ioannis Psallidas, Rachel Moate, Rebecca Smith, Joanna Kiraga, Eulalia Jimenez, Dennis Brooks, Aoife Kelly, Lars H Nordenmark, Muhammad Waqas Sadiq, Luis Mateos Caballero, Chris Kell, Maria G Belvisi, Hitesh Pandya
{"title":"针对慢性阻塞性肺病患者的 IL-33 mAb tozorakimab 2a 期试验：FRONTIER-4。","authors":"Dave Singh, Patricia Guller, Fred Reid, Sarah Doffman, Ulla Seppälä, Ioannis Psallidas, Rachel Moate, Rebecca Smith, Joanna Kiraga, Eulalia Jimenez, Dennis Brooks, Aoife Kelly, Lars H Nordenmark, Muhammad Waqas Sadiq, Luis Mateos Caballero, Chris Kell, Maria G Belvisi, Hitesh Pandya","doi":"10.1183/13993003.02231-2024","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.</p><p><strong>Methods: </strong>FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV<sub>1</sub>) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV<sub>1</sub>, time-to-first COPD composite exacerbation event and safety.</p><p><strong>Results: </strong>The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV<sub>1</sub> (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV<sub>1</sub> (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements <i>versus</i> placebo in change from baseline in pre-bronchodilator FEV<sub>1</sub> (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV<sub>1</sub> (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.</p><p><strong>Conclusion: </strong>Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals <i>versus</i> placebo in a subgroup of patients with COPD with a high risk of exacerbations.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":16.6000,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256803/pdf/","citationCount":"0","resultStr":"{\"title\":\"A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4.\",\"authors\":\"Dave Singh, Patricia Guller, Fred Reid, Sarah Doffman, Ulla Seppälä, Ioannis Psallidas, Rachel Moate, Rebecca Smith, Joanna Kiraga, Eulalia Jimenez, Dennis Brooks, Aoife Kelly, Lars H Nordenmark, Muhammad Waqas Sadiq, Luis Mateos Caballero, Chris Kell, Maria G Belvisi, Hitesh Pandya\",\"doi\":\"10.1183/13993003.02231-2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.</p><p><strong>Methods: </strong>FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV<sub>1</sub>) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV<sub>1</sub>, time-to-first COPD composite exacerbation event and safety.</p><p><strong>Results: </strong>The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV<sub>1</sub> (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV<sub>1</sub> (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements <i>versus</i> placebo in change from baseline in pre-bronchodilator FEV<sub>1</sub> (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV<sub>1</sub> (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.</p><p><strong>Conclusion: </strong>Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals <i>versus</i> placebo in a subgroup of patients with COPD with a high risk of exacerbations.</p>\",\"PeriodicalId\":12265,\"journal\":{\"name\":\"European Respiratory Journal\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":16.6000,\"publicationDate\":\"2025-07-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256803/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Respiratory Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1183/13993003.02231-2024\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Respiratory Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1183/13993003.02231-2024","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4.
Background: Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.
Methods: FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV1, time-to-first COPD composite exacerbation event and safety.
Results: The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV1 (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV1 (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements versus placebo in change from baseline in pre-bronchodilator FEV1 (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV1 (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.
Conclusion: Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.
期刊介绍：
The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.
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