Ibuzatrelvir potently reduced viral RNA levels despite a high rate of anti-S seropositivity: a post hoc analysis of serology of the phase 2b study

We previously reported that all doses of ibuzatrelvir, an oral SARS-CoV-2 Mpro inhibitor, twice daily for 5 days significantly reduced viral RNA levels (viral load [VL]) from baseline compared with placebo among adults without risk factors for severe COVID-19 during the Omicron era (Clinicaltrials.gov NCT05799495). This post hoc exploratory analysis evaluated the impact of pre-existing antibody (Ab) levels on viral clearance by treatment group. Baseline anti-Spike (S) and neutralizing Ab (nAb) were positive in 99.6% and 82.1% of the participants, respectively. Higher baseline nAb levels were significantly associated with greater change from baseline in viral load at day 5 (d5 CFB-VL) only in placebo. Modeling projected that at a mean baseline Ab level 2-fold higher than observed, placebo-adjusted d5 CFB-VL by ibuzatrelvir 600 mg would be -0.72 log10 copies/ml (95% CI: -1.29, -0.15) with nAb and -0.73 log10 copies/ml (95% CI: -1.34, -0.12) with anti-S. This analysis suggests that day 5 VL reduction by ibuzatrelvir 600 mg would still be at least 5-fold greater than placebo, even at hypothetical 2-fold higher mean baseline Ab levels than were observed in this study. Trial registration: ClinicalTrials.gov NCT05799495