A phase 3 clinical trial found that sipavibart, an investigational monoclonal antibody, reduced symptomatic COVID-19 cases by 34.9% (97.5% CI, 15.0 to 50.1; P < .001) in immunocompromised individuals when non–Phe456Leu-containing variants dominated, but it was ineffective against resistant SARS-CoV-2 variants. The resistant variants KP.2 and KP.3 are Phe456Leu-containing variants, which now account for more than 90% of global sequences as of November 2024.

Published in The Lancet, the SUPERNOVA trial, conducted across 18 countries with 3,349 immunocompromised participants, compared sipavibart with either tixagevimab–cilgavimab or placebo. Within 181 days, symptomatic COVID-19 occurred in 7.4% of sipavibart recipients vs 10.9% in the comparator group (relative risk reduction [RRR], 34.9%; P < .001). Against non–Phe456Leu-containing variants, sipavibart showed an RRR of 42.9% (P = .0012), but it had no efficacy against resistant variants such as KP.2 and KP.3, which now account for more than 90% of global sequences.

"The primary analysis showed efficacy and safety of sipavibart in preventing symptomatic COVID-19 in participants who are immunocompromised when susceptible (ie, non-Phe456Leu-containing) variants dominated, although no efficacy was shown against resistant (ie, Phe456Leu-containing) variants that dominate as of November 2024," explained Ghady Haidar, MD, from the Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center.

Adverse events occurred in 49.9% of sipavibart recipients and 51.5% of comparator participants, with serious treatment-related events being rare (0.1% vs 0.4%, respectively). No serious cardiovascular or thrombotic events were linked to sipavibart, and one COVID-19-related death was reported in the comparator group. Importantly, no serious hypersensitivity reactions were observed with sipavibart.

The study authors noted that developing monoclonal antibodies for COVID-19 prevention remains challenging due to the rapid evolution of SARS-CoV-2 variants. They suggested that alternative preventive measures, such as immunobridging strategies, may be necessary to address the evolving landscape of COVID-19 prophylaxis for immunocompromised patients.

Full disclosures are available in the study.