Journal Article

A phase 2b, Randomized, double blinded comparison of the safety and efficacy of the monoclonal antibody mixture SYN023 and human rabies immune globulin in patients exposed to rabies

Barez, Marie Yvette, Solimen, Domingo P., Capeding, Maria Rosario, Chuang, Ariel, Payumo, Ronald Allan, Zoleta-De Jesus, Loreta, Reyes, Mari Rose De Los, Reid, Caroline, Quiambao, Beatriz P., Roa, Camilo, Borja-Tabora, Charissa Fay, Emmeline Montellano, May, Tsao, Eric, McClain, J. Bruce

2024

Overview

•SYN023-004: a large, one-year, randomized, double blind, controlled, rabies PEP study in Category III patients.•SYN023 is comprised of two humanized monoclonals against non-overlapping rabies virus epitopes.•SYN023 produces rapid and higher RVNA during the 2-week period after administration.•SYN023 safety profile appears similar to human rabies immunoglobulin. SYN023 is an anti-rabies monoclonal antibody mixture administered as part of post-exposure prophylaxis regimens. The rabies virus neutralizing antibody (RVNA) concentration generally accepted as an adequate immune response to vaccination is ≥ 0.5 IU/mL. Within 54 h of potential rabies exposure, 448 patients in two risk substrata of WHO Category III exposure were randomized to receive either 0.3 mg/kg SYN023 or 0.133 mL/kg human rabies immunoglobulin (HRIG) injected in and around the wound site(s) plus a course of rabies vaccination. Patients were followed for safety and absence of rabies for ≥ 365 days. GMT RVNA was higher with SYN023 throughout the 2-week post-treatment period. In the primary analysis group (n = 368), 99.4 % of SYN023 recipients versus 4.5 % of HRIG recipients had protective RVNA levels on Day 4. On Day 8, 98.1 % SYN023 versus 12.2 % HRIG recipients were protected. The SYN023:HRIG ratio of geometric mean titer of RVNA (RVNA GMTs) on Day 8 (19.42) exceeded the 10 % superiority margin (P < 0.0001) indicating higher Day 8 RVNA with SYN023. On Day 99, the SYN023:HRIG RVNA GMT ratio (0.66) was below the non-inferiority margin of 20 % (P = 0.9485) suggesting some moderation of vaccine immune response by SYN023 relative to HRIG. The ratio of percent SYN023:HRIG recipients achieving RVNA ≥ 0.5 IU/mL on Day 99 (0.98) met the non-inferiority margin of 20 % (P = 0.013) indicating anti-rabies immune response with SYN023 was non-inferior to HRIG despite this effect. There were no probable/confirmed rabies cases in any patient. Study regimens were well tolerated. SYN023 provided higher RVNA than HRIG soon after rabies exposure. By Day 99 post-treatment, GM RVNA with SYN023 was lower than HRIG, however, the percent of SYN023 recipients with a protective response was not inferior at this time point. No rabies cases were reported in the study. The SYN023 safety profile was acceptable. ClinicalTrials.gov ID: NCT03961555.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adolescent / Adult / Aged / Allergy and Immunology / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Antibodies, Neutralizing - blood / Antibodies, Neutralizing - immunology / Antibodies, Viral - immunology / Bats / Child / Clinical trial / Disease prevention / Double-Blind Method / Drug dosages / Enrollments / Exposure / Female / Globulins / Humans / Immune response / Immune system / Immunoglobulins / Infections / Lyssavirus / Male / Middle Aged / Mixtures / Monoclonal antibodies / Monoclonal antibody / Patients / Pharmacists / Post-exposure prophylaxis / Post-Exposure Prophylaxis - methods / Rabies / Rabies - immunology / Rabies - prevention & control / Rabies lyssavirus / Rabies Vaccines - administration & dosage / Rabies Vaccines - adverse effects / Rabies Vaccines - immunology / Rabies Vaccines - therapeutic use / Rabies virus - immunology / Rabies virus neutralizing activity (RVNA) / Response rates / risk / Safety / Sanitation / Skin / vaccination / Vaccine / Vaccines / Viruses / Young Adult