Phage therapy with nebulized cocktail BX004-A for chronic Pseudomonas aeruginosa infections in cystic fibrosis: a randomized first-in-human trial

作者：I. Weiner, M. Kahan-Hanum, Nufar Buchstab, L. Zelcbuch, Sharon Navok, Irit Sherman, J. Nicenboim, T. Axelrod, D. Berko-Ashur, Maya Olshina, R. Mordoch, J. Jablonska, Tamar Gera-Inbar, Ilya Vainberg-Slutskin, Britny Blumenfeld, Hila Sberro-Livnat, A. Moses, Hadas Nevenzel, I. Levy-Saar, Jenia Gold, M. Goldberg, Nina Tchernorudsky, Noa Ben-Yishay, T. Cohen, Edith Kario, Inesa Levovich, R. Safonov, Y. Tzur, Y. Zarchin, V. Lev, Yifat Elharar, Einav Safyon-Gartman, I. Gahali-Sass, S. Puttagunta, X. Ussery, R. Vilchez, U. Rappo, N. Zak, M. Golembo, Ariel Cohen, J. Koff, Eitan Kerem, R. Sorek, M. Bassan · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60598-4 · 被引用次数：34 · 研究领域：Medicine

Cystic fibrosis is a monogenetic disease complicated by recurrent bacterial lung infections that require chronic antibiotics. Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen associated with cystic fibrosis morbidity and mortality. Here, we describe the development of a three-phage cocktail (BX004-A) designed to target a wide range of P. aeruginosa strains. We evaluated BX004-A in Part 1 of a first-in-human double-blind placebo-controlled phase 1b/2a clinical trial, which included nine adult cystic fibrosis patients chronically infected with P. aeruginosa (NCT05010577). BX004-A met the primary endpoints of safety and tolerability. Exploratory endpoints included pharmacokinetics and Pseudomonas aeruginosa sputum density reduction. Efficient phage delivery to the lower respiratory tract was observed, and a potential reduction in P. aeruginosa sputum burden was noted in the phage arm. However, due to the study’s small sample size, definitive conclusions regarding efficacy are limited. These data pave the way toward further development of novel phage-based therapeutics in antibiotic-resistant pulmonary bacterial infections. In a randomized, placebo-controlled trial, an inhaled phage cocktail was well tolerated in adults with cystic fibrosis and chronic Pseudomonas aeruginosa infection, with evidence of lung delivery and signs of bacterial reduction.