SARS-CoV-2 resistance analyses from the Phase 3 OAKTREE study of obeldesivir in low-risk nonhospitalized participants with COVID-19.

Obeldesivir is an oral nucleoside analog prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated baseline and treatment-emergent viral resistance to obeldesivir in participants from OAKTREE, a multicenter, double-blind trial wherein nonhospitalized adolescents and adults with COVID-19 at low risk of developing severe disease were randomized 1:1 to receive obeldesivir or placebo twice daily for 5 days. Deep sequencing was performed on mid-turbinate nasal swab samples collected on Days 1 (baseline), 3, 5, 10, 15, 20, and 29 from participants who met sequencing analysis criteria. Amino acid substitutions detected in the SARS-CoV-2 replication complex components were phenotyped in a replicon system. Overall, 1425 participants (obeldesivir, 725; placebo, 700) met sequencing analysis criteria and had baseline sequencing data. Thirty-five baseline Nsp12 substitutions, including P323L and G671S, were observed in ≥3 participants. Phenotyping of baseline Nsp12 substitutions showed obeldesivir half-maximal effective concentration (EC50) fold changes relative to wildtype that were within assay variability (≤2.15-fold). Among participants with baseline and postbaseline sequencing data, the proportion of emergent Nsp12 substitutions was similar between groups (obeldesivir, 35/208 [16.8 %]; placebo, 23/120 [19.2 %]). Twenty-five emergent Nsp12 substitutions were detected in the obeldesivir group but not in the placebo group. Only 1 emergent Nsp12 substitution (C799F) from 1 participant in the obeldesivir group was associated with reduced obeldesivir susceptibility, with a 3.35-fold change in EC50 versus wildtype. The low-to-no change in obeldesivir susceptibility among treatment-emergent Nsp12 substitutions indicated a high barrier to development of obeldesivir resistance in low-risk, nonhospitalized patients with COVID-19. ClinicalTrials.gov identifier: NCT05715528.