Comparison of Silevimig, a Novel Bispecific Anti-Rabies Monoclonal Antibody, with Human Rabies Immunoglobulin for Post-Exposure Prophylaxis: A Phase III, Randomized, Double-Blind, Non-Inferiority Trial.

Abstract

This phase III randomized, double-blind, non-inferiority trial evaluated Silevimig, a bispecific anti-rabies monoclonal antibody targeting antigenic sites I and III, as a substitute for human rabies immunoglobulin (HRIG) in post-exposure prophylaxis. Adults (>18 years) with suspected WHO category III rabies exposure were randomly assigned (3:1) to receive Silevimig or HRIG. After wound cleansing, the study drug was administered on day 0, together with a rabies vaccine given on days 0, 3, 7, 14, and 28. The co-primary endpoints were the adjusted geometric mean concentration (GMC) of rabies virus-neutralizing antibodies (RVNAs) on day 7, the proportion of participants with an RVNA level of ≥ 0.5 IU/mL (seroresponse) by day 14, and the rabies-free survival rate in 1 year (D365). Safety was assessed through adverse events (AEs) and serious adverse events (SAEs). A total of 1,200 participants were enrolled. On day 7, the adjusted GMC of RVNAs was 0.40 IU/mL in the Silevimig group versus 0.36 IU/mL in the HRIG group, meeting the non-inferiority criterion (ratio 1.11; 95% CI: 1.01-1.21). Seroresponse rates on days 14 and 90 were slightly higher with Silevimig. No rabies cases occurred during the 1-year follow-up, yielding a 100% rabies-free survival rate in both groups. Most AEs were mild to moderate. Silevimig was non-inferior to HRIG in inducing early RVNA responses, was well tolerated, and did not interfere with vaccine-induced immunity. These findings support Silevimig as a safe and effective alternative for passive rabies post-exposure prophylaxis (ClinicalTrials, NCT05846568).