520. Pharmacokinetic and Safety Phase 1 Study and Microneutralization Assay Results with BRII-196/BRII-198, a Novel Antibody Cocktail Active Against a Wide Range of SARS-CoV-2 Variants

Abstract

Background. BRII‐196 and BRII‐198 are human monoclonal antibodies (mAb) with an extended half‐life targeting distinct epitopes of the spike protein on SARSCoV‐2. Mutations in these epitope regions are continuously emerging, potentially conferring resistance to COVID‐19 therapeutics in development. Individual phase I studies showed that BRII‐196 or BRII‐198 alone were safe and well tolerated in healthy subjects. The BRII‐196 and BRII‐198 cocktail is currently under evaluation in Phase 2/3 studies for the treatment of COVID‐19. Methods. Preclinical study: BRII‐196 and BRII‐198 were evaluated in the microneutralization assay using pseudo‐viruses encoding mutations identified in the spike protein of a panel of SARS‐CoV‐2 variants of concerns, including strains originating in UK, SA, BR, CA, and India. The fold‐change in neutralization IC50 titers relative to wild‐type virus was calculated. Phase 1 study: healthy adults received sequential IV BRII‐196 and BRII‐198 (n=9) or placebo (n=3); and were followed for 180 days. Two dose levels (750mg/750mg and 1500mg/1500mg) were evaluated for safety, pharmacokinetics and immunogenicity. Interim analysis results are presented. Results. Preclinical: BRII‐196 and BRII‐198 exhibited neutralizing activity against pseudo‐virus variants that contained spike mutations of a panel of variants including B.1.1.7 (UK), B.1.351(SA), P.1(BR), B.1.427/429 (CA), B.1.526 (NY), and B.1.617 (IN), comparable to that against wild‐type virus. Phase I study: BRII‐196 plus BRII‐198 was well tolerated with no dose‐limiting adverse events (AEs), deaths, serious adverse events, or infusion reactions. The majority of AEs were isolated asymptomatic grade 1‐2 laboratory abnormalities. (Table 1). Each mAb displayed pharmacokinetic characteristics expected of extended half‐life YTE‐antibodies. Conclusion. The BRII‐196 and BRII‐198 cocktail was well‐tolerated, and maintains neutralization against currently reported circulating variants of concern. These preclinical and clinical results support further development of BRII‐196 and BRII‐198 as a therapeutic or prophylactic option for SARS‐CoV‐2.