D92-10 Positive Phase 2a Study Results on Resp-x (infex702), a Highly Potent Anti-virulence Monoclonal Antibody in Development to Reduce Exacerbation Frequency in Pseudomonas Aeruginosa-colonised Non-cystic Fibrosis Bronchiectasis (ncfb) Patients

Rationale

Despite multiple antibiotic options, a large unmet need persists in NCFB patients colonised with Pseudomonas aeruginosa (P. aeruginosa). RESP-X is a novel, humanised IgG4 monoclonal antibody targeting a key virulence system of P. aeruginosa called the type 3 secretion system (T3SS). The T3SS delivers effector proteins into host cells, contributing to tissue damage, immune system evasion and P. aeruginosa persistence. RESP-X binds to the needle tip protein (PcrV) of the T3SS, blocking extrusion of effector proteins and facilitating immune recognition. RESP-X is in development as a novel therapy to reduce frequency and severity of exacerbations in P. aeruginosa-colonised NCFB patients, with excellent Phase 1 data on safety, tolerability, and pharmacokinetics (PK); here we report the findings of a Phase 2a study in NCFB patients chronically colonised with P. aeruginosa.

Methods

A single-centre, double blind, phase 2a, randomised, dose-ranging study to evaluate safety, PK and lung deposition, with additional exploratory biomarker, microbiology, quality of life and clinical endpoints, was carried out on 9 P. aeruginosa-colonised NCFB patients with a history of infective exacerbations. Patients in cohort 1 received a single intravenous dose of RESP-X 6 mg/kg (N = 5) or placebo (N = 1). Patients in cohort 2 received a single intravenous dose of RESP-X at 10 mg/kg or placebo. All patients underwent bronchoscopy/bronchoalveolar lavage (BAL) at 48 hrs post-dose to document lung deposition of RESP-X.

Results

The phase 2a study met its primary and secondary objectives demonstrating safety and tolerability in patients with NCFB, no infusion-related or infusion site reactions, no allergic reactions, nor any serious drug-related adverse events occurred. PK analysis revealed a long half-life; 6 mg/kg geometric mean t1/2 22 days,10 mg/kg geometric mean t1/2 26 days with good lung exposure (1.5% and 1.9% of serum level in 6 mg/kg group and 10 mg/kg group, respectively). Similar to phase 1 the phase 2a study showed dose proportionality. The NCFB patients had an average bronchiectasis severity index (BSI) score of > 12. All P. aeruginosa isolates analysed expressed the RESP-X antigenic target, PcrV. No drug-related anti-drug antibodies were detected. PK modelling of repeat dosing suggests a 3-month dose interval may be appropriate. Exploratory endpoint analysis is very encouraging including reductions in bronchiectasis exacerbation rate post-dose.

Conclusion

RESP-X (INFEX702) is a safe and well-tolerated novel therapy with a long half-life and significant lung deposition supporting infrequent dosing for the reduction in frequency and severity of acute pulmonary exacerbations in P. aeruginosa-colonised NCFB patients.

This abstract is funded by: INFEX Therapeutics