Safety, Pharmacokinetics, and Predicted Neutralizing Activity of the SARS-CoV-2 Monoclonal Antibody Sipavibart: Results from Little DIPPER and the SUPERNOVA Substudy.

INTRODUCTION: The rapid evolution of SARS-CoV-2 has necessitated efforts to accelerate the clinical evaluation of neutralizing monoclonal antibodies. Little DIPPER and the SUPERNOVA substudy explored the feasibility of immunobridging efficacy from tixagevimab-cilgavimab to sipavibart using predicted neutralizing antibody (nAb) titers. METHODS: The randomized, phase 1, Little DIPPER study evaluated the safety and pharmacokinetics of intramuscular (300 mg or 600 mg) and intravenous (300 mg, 600 mg, or 1200 mg) sipavibart in healthy participants. The randomized, phase 2, SUPERNOVA substudy evaluated the safety, predicted nAb activity, and pharmacokinetics of intravenous sipavibart 1200 mg and intramuscular tixagevimab-cilgavimab 300 mg in immunocompetent and immunocompromised individuals. Predicted nAb titers at day 29 for sipavibart against SARS-CoV-2 BA.2.86 and for tixagevimab-cilgavimab against SARS-CoV-2 Alpha were compared in a noninferiority analysis. RESULTS: In Little DIPPER, 96 participants received sipavibart (n = 80) or placebo (n = 16). Through day 91, adverse events (AEs) occurred in 23 participants (28.8%) who were administered sipavibart and one (6.3%) who was administered placebo. Sipavibart exhibited dose-proportional increases in serum exposure following intramuscular or intravenous administration. In the SUPERNOVA substudy, 468 participants received sipavibart (n = 310) or tixagevimab-cilgavimab (n = 158). Through day 29, AEs occurred in 81 participants (26.1%) who were administered sipavibart and 33 (20.9%) who were administered tixagevimab-cilgavimab. No serious hypersensitivity reactions occurred. The ratio of predicted nAb titers for sipavibart against BA.2.86 to tixagevimab-cilgavimab against Alpha (4.07) met noninferiority (90% confidence interval 3.71-4.46 [lower limit > 0.8]) and superiority (95% confidence interval 3.65-4.53 [lower limit > 1.0]) criteria. Serum sipavibart exposures were similar between immunocompetent and immunocompromised participants. CONCLUSION: These results demonstrate the feasibility and appropriateness of conducting phase 1 and 2 studies to support rapid immunobridging analyses, and accelerate the delivery of new SARS-CoV-2-neutralizing monoclonal antibodies to immunocompromised individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT05872958, NCT05648110.