Phase 1 Study Evaluating Safety, Tolerability, Pharmacokinetics and Immunogenicity of REGN2222 in Healthy Adults: A New Human Monoclonal RSV-F Antibody for RSV Prevention

Abstract

Background. RSV infection is a major cause of acute respiratory infections in infants. REGN2222 is a human monoclonal IgG1 antibody against RSV-F that is effective in reducing RSV viral load in cotton rat lungs. We conducted a randomized double blinded, placebo controlled Phase 1 study in healthy adults to assess safety, tolerability, pharmacokinetics and immunogenicity of REGN2222. Methods. 132 healthy adults, age 18-60 years, were randomized into one of 5 cohorts: 3 ascending IV dose cohorts at 3 mg/kg, 10 mg/kg or 30 mg/kg, or placebo and 2 ascending IM dose cohorts at 3 mg/kg or 10 mg/kg, or placebo. Eight subjects (REGN2222/placebo; 6:2) were randomized to 3 mg/kg IV × 1 dose; 15 subjects (12:3) to cohort 10 mg/kg IV × 1 dose; 15 subjects (12:3) to 30 mg/kg IV × 2 doses (4 weeks apart); 47 subjects (40:7) to 3 mg/kg IM × 2 doses (4 weeks apart); and 47 subjects (40:7) to 10 mg/kg IM × 2 doses (4 weeks apart). Results. There were no serious treatment-emergent adverse events (TEAEs) and no deaths. No TEAE led to expansion of the cohorts or a decision not to dose-escalate to the highest dose level. Two subjects had permanent discontinuation of study treatment due to TEAE (1 subject in REGN2222 10 mg/kg IV group for a mild-moderately severe rash and nasal congestion occurring during the infusion that completely resolved without treatment 3 hours after infusion ended; the other subject in REGN2222 3 mg/kg IM group for acute cholecystitis requiring an outpatient cholecystectomy). There were no treatment-related TEAEs rated >grade 3. No dose limiting toxicity was observed and the maximum tolerated dose was not reached. No local or acute, systemic injection reaction TEAEs were observed in IM cohorts. The mean terminal half-life was 32.0 + 8.79 and 34.4 + 11.9 days after IM administration of 3 and 10 mg/kg, respectively. No subjects in the placebo group were positive for anti-drug antibody (ADA). Of the 110 subjects administered REGN2222, ADA was detected in 5 subjects (<5%): 3 subjects exhibited pre-treatment ADA; 2 subjects developed a treatment-emergent ADA response. All ADA titers were low (<1:60). Conclusion. REGN2222, a new RSV F human monoclonal antibody, was generally well tolerated in healthy adults. REGN2222 has a half-life longer than typical IgG1 monoclonal antibodies with low immunogenicity.