A Bispecific Monoclonal Antibody Targeting Psl and PcrV for Chronic Pseudomonas Aeruginosa Infection in Patients With Bronchiectasis: Results From a Randomized, Double-Blind Placebo-Controlled Trial (GREAT-2)
M.B. Long, Rebecca C Hull, Amy Gilmour, Kateryna Viligorska, Hollian Richardson, B.J.M. New, Chandani Hennayake, R.B. Galloway, Emma Johnson, Eve Mcintosh, Zsofia Eke, Holly Lind, Margaret Band, Harshana Bandara, Greg S. Martin, Stefano Aliberti, A. Timothy, Joyce Norwell, J.L. Whitehouse, C. Addy, Lydia Finney, Philip Mitchelmore, S. Caskey, Robert Lord, Adam T. Hill, Montserrat Vendrell, Eva Polverino, Alicia Marín, Guillermo Suárez-Cuartín, Michael R. Loebinger, Michael M. Tunney, Katharine Cartwright, Rod Hughes, A. Digiandomenico, Maria G. Belvisi, Wayne Brailsford, Charles Haworth, Oriol Sibila, John D. Stobo, James D. Chalmers
Abstract
Abstract Rationale: Pseudomonas aeruginosa airway infection is associated with increased exacerbations and poor outcomes in bronchiectasis. Our prior study (GREAT-1) showed that gremubamab—a bivalent, bispecific mAb targeting Psl exopolysaccharide and PcrV T3SS component—enhanced neutrophil clearance of P. aeruginosa and reduced virulence ex-vivo. Here we report the efficacy and safety of gremubamab in a proof-of-concept trial in bronchiectasis patients with P. aeruginosa infection. Methods: In a multi-centre, multinational (UK and Spain), randomized, double-blind, placebo-controlled trial, people with CT-confirmed bronchiectasis and sputum positive for P. aeruginosa were randomised 1:1:1 to 1500mg or 500mg gremubamab intravenous infusion, or placebo, once every four weeks for 12 weeks. Serum and sputum samples were obtained on days 1, 7, 14, 28, 56, 84 (end-of-treatment;EoT), and 168 (12-week follow-up). The primary outcome was change from baseline in quantitative sputum cultures at day 84. Key secondary outcomes included change from baseline in the St. George's Respiratory Questionnaire (SGRQ) and the quality of life bronchiectasis questionnaire (QoL-B), time to first exacerbation, FEV1 and safety. As a proof-of-concept study, statistical significance was pre-specified at the 1-sided p<0.1 level. Results: 37 participants were randomised, n=12 in the gremubamab 1500mg group (age 65.7±13.8 [mean±SD], 66.7% female), n=13 in the 500mg group (age 60.3±16.7, 84.6% female), n=12 in the placebo group (age 65.9±14.4, 66.7% female). Gremubamab treatment resulted in a significant reduction in bacterial load at EoT (day 84) with the 500mg dose compared with placebo treatment ([estimate[80%CI]]; -1.25 log-CFU (-2.33 to -0.16); 1-sided p=0.071; ANCOVA), meeting the trial primary endpoint. A non-significant directional trend was observed for the 1500mg dose (-0.66(-1.71 to 0.39); p=0.2). The SGRQ was significantly improved versus placebo at EoT (500mg: -10.8(-4.93 to -16.7), p=0.02; 1500mg: -12.1(-6.5 to -17.7), p=0.008). The proportion of patients achieving a clinically significant SGRQ improvement was higher for both gremubamab 500mg (38.5%) and 1500mg (41.7%) versus placebo (8.3%). Clinically significant benefit in favour of gremubamab treatment at EoT was observed for multiple QoL-B domains. Time to first exacerbation was significantly prolonged at the 1500mg dose versus placebo (p=0.046; restricted mean survival time method). There was no effect on FEV1. Adverse events (AEs) were reported in 91.7%, 84.6% and 89.2% of the 1500mg, 500mg and placebo groups, respectively, and severe AEs in 0%, 15.4% and 16.7%. Conclusion: Gremubamab treatment significantly reduced P. aeruginosa airway bacterial load and improved patient-reported quality of life in patients with bronchiectasis, providing proof-of-concept for specific anti-microbial monoclonal antibody therapy.