Novel nebulized phage cocktail in CF patients with chronic P. aeruginosa pulmonary infection: a Ph1b/2a randomized, double-blind, placebo-controlled trial

<bold>Objectives:</bold> <italic>Pseudomonas aeruginosa</italic> (PsA) causes pulmonary infections in cystic fibrosis (CF) patients, despite use of elexacaftor/tezacaftor/ivacaftor (ETI). This study assessed the safety and efficacy of BX004-A (phage cocktail) in CF subjects with chronic PsA pulmonary infection. <bold>Methods:</bold> This Ph1b/2a randomized, double-blind, placebo-controlled, multicenter trial assessed nebulized BX004-A in 43 adult CF subjects with FEV1≥40% and chronic PsA pulmonary infection, on inhaled antibiotics. In Part 1 (n=9), subjects were randomized (3:1) to BX004-A or placebo x7d. In Part 2 (n=34), subjects were randomized (2:1) to twice daily BX004-A or placebo x10d. <bold>Results:</bold> In Part 1, the mean sputum PsA colony forming unit (CFU/g) reduction at D15 (vs baseline) was -1.42 log (BX004-A) vs -0.28 log (placebo). In Part 2, in subjects with quantitative sputum PsA CFU at baseline, 3/21 (14.3%) on BX004-A had a negative PsA sputum culture at D10 vs 0/10 (0%) on placebo. In subjects on continuous inhaled antibiotics (rather than cycling/alternating), on ETI and with FEV1 <70%, mean sputum PsA CFU reduction at D10 was -3.84 log (BX004-A) vs -1.03 log (placebo), with a relative FEV1 of +8.89% at D17 between groups (change from baseline +5.66% in BX004-A vs -3.23% in placebo). Phage was detected in the sputum of all subjects on BX004-A, with no treatment-related phage resistance. During therapy, there were no adverse events of special interest or serious adverse events. <bold>Conclusions:</bold> BX004-A showed favorable safety and notable microbiologic and clinical efficacy. Next study will assess longer treatment.