Phase I Study Evaluating a Monoclonal Fc-Silenced SARS-CoV-2 Antibody in Patients With Moderate-to-Severe COVID-19

Purpose The evolution of Severe Acute Respiratory Syndrome Coronavirus 2 challenged the effectiveness of vaccines, while monoclonal antibodies (mAbs) were discontinued due to emergent resistance. This study evaluated the safety and explored the preliminary efficacy of COR-101, a novel mAb with a silenced Fc region designed to minimize antibody-dependent enhancement in hospitalized patients with moderate-to-severe disease. Methods Thirty-three participants were enrolled across Germany and Ukraine in a randomized, double-blind, placebo-controlled Phase Ib/II trial. Patients received either a single dose of COR-101, or placebo, as add-on therapy to the standard of care. Findings COR-101 was well tolerated, with no treatment-related severe adverse events (AEs), grade ≥3 AEs, or acute infusion reactions. Four unrelated severe AEs were observed, and 2 patients died due to coronavirus disease 2019. COR-101 showed dose-proportional pharmacokinetics, long half-life, and serum concentrations above IC 50 . Patients were treated in different dose groups, and in exploratory analysis, viral clearance was observed at day 28 in 80%, 55.6%, 16.7%, and 42.9% of patients in the 4.0, 10.0, 25.0 mg/kg, and placebo groups, respectively. The predominant virus variant changed from alpha to delta and omicron, resulting in reduced in vitro neutralization, potentially explaining the observed reduced efficacy. Implications COR-101 demonstrated a favorable safety profile, but exploratory data showed limited efficacy against omicron, highlighting the tolerability of Fc-silenced mAbs and the need for adaptive therapeutic strategies against rapidly evolving viral pathogens (ClinicalTrials.gov identifier: NCT04674566).