P-108. Ibuzatrelvir Potently Reduced Viral RNA Levels Despite the High Rate of Anti-S Seropositivity: a Post Hoc Analysis of Serology in the Phase 2b Study in Adults Without Risk Factors for Severe COVID-19

Abstract Background We previously reported that ibuzatrelvir 600mg, an oral SARS-CoV-2 Mpro inhibitor, demonstrated significantly greater reduction from baseline (BL) in viral RNA levels (viral load [VL]) compared with placebo at day 5 (1.2 log10 copies/ml, 80% CI -1.5, -0.8) among adults with baseline VL ≥4 log10 copies/ml. In this report, we evaluated the impact of pre-existing neutralizing antibody (nAb) levels on viral clearance, where nearly all participants had positive anti-Spike (anti-S) antibodies, indicating prior COVID-19 vaccination or infection, similar to the real world. Methods This is a post hoc exploratory analysis of the phase 2b study evaluating virologic response and safety of ibuzatrelvir in adults without risk factors for severe COVID-19 during Omicron era. Participants were randomized 1:1:2:2 to receive oral ibuzatrelvir 100mg, 300mg, or 600mg or placebo twice daily for 5 days. Nasopharyngeal SARS-CoV-2 VL at BL and day 5, and serum anti-S and nAb (against XBB.1.5) levels at BL and day 10 were analyzed. The relationship between BL Ab (nAb and anti-S) levels and day 5 VL reduction by treatment group was evaluated using linear regression. The fitted mean difference in day 5 VL reduction between the ibuzatrelvir 600mg and placebo groups was estimated at a BL Ab level 2-fold higher than the observed mean Ab level. Results The mean BL anti-S level was 3.67 log10 U/ml with 99.6% anti-S positivity, while the mean nAb level was 5.06 log2 NT50 with 17% of participants below detectable levels. BL anti-S levels were significantly (r=0.65, p< 0.001) correlated with BL nAb levels. Higher BL nAb levels were significantly (p=0.004) associated with greater VL reduction at day 5 in placebo, but not in the ibuzatrelvir-treated group. Modeling of these study data projected that even at a mean BL nAb level 2-fold higher than was observed, VL reduction by ibuzatrelvir 600mg would have been approximately 5-fold (0.72 log10 copies/ml, 95% CI: 0.14, 1.29) greater than placebo (Figure A). Modeling of anti-S yielded a similar estimate (0.73 log10 copies/ml, 95% CI: 0.12, 1.35) (Figure B). Conclusion VL reduction by ibuzatrelvir was observed in the phase 2b study despite evolving immunity, and the modeling suggests that this will also occur even at higher mean Ab levels than were observed in this study. Disclosures Jin Hyang Kim, PhD. RPh, Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Alex Knutson, Ph.D., Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Justin Smith, M.S., Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Shunjie Guan, PhD in Statistics, Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Luke Chen, MBBS, Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Mahta Mortezavi, MD, Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Abigail Sloan, Ph.D., Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Anindita Banerjee, Ph.D., Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Mary Lynn Baniecki, PhD, Pfizer, Inc: Salaried Employee|Pfizer, Inc: Stocks/Bonds (Public Company) Craig Hyde, Ph.D., Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Charlotte Allerton, PhD, Pfizer: employee|Pfizer: Stocks/Bonds (Public Company) Negar Niki Alami, MD, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company)