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

  • 2026-01-19
  • Antiviral research 247
    • Charlotte Hedskog
    • Lauren Rodriguez
    • Yu Hu
    • Jiani Li
    • Dong Han
    • Nadine Peinovich
    • Clarissa Martinez
    • Pui Yan Ho
    • Jason K Perry
    • Juan María González Del Castillo
    • Yiannis Koullias
    • Ross Martin
    • Robert H Hyland

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 465
Population
High-risk, nonhospitalized adults with COVID-19
Methods
Phase 3, multicenter, double-blind BIRCH study; randomized to receive obeldesivir or placebo twice daily for 5 days; mid-turbinate nasal swab samples on Days 1, 3, 5, 10, and 15; deep sequencing and phenotypic analysis using a replicon system
Blinding
Double-blind
Duration
5 days
  • Large Human Trial
Obeldesivir is an oral nucleoside analog prodrug that targets and inhibits the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated the development of obeldesivir resistance in participants from the Phase 3, multicenter, double-blind BIRCH study. High-risk, nonhospitalized adults with COVID-19 were randomized to receive obeldesivir or placebo twice daily for 5 days. Mid-turbinate nasal swab samples were collected on Days 1 (baseline), 3, 5, 10, and 15. Amino acid substitutions were identified using deep sequencing and phenotyped using a replicon system. Of the 465 participants randomized and treated, 252 (obeldesivir, 190; placebo, 62) met the sequencing analysis criteria and had sequencing data at baseline. Phenotypic analysis of the 5 Nsp12 substitutions observed at baseline resulted in half-maximal effective concentration (EC50) fold changes ≤1.8 relative to the wildtype reference, indicating no change in susceptibility to obeldesivir. Among participants with baseline and postbaseline sequencing data, 12/73 (16.4 %) and 5/54 (9.3 %) participants in the obeldesivir and placebo groups, respectively, had emergent Nsp12 substitutions. Nine emergent Nsp12 substitutions were detected in the obeldesivir group postbaseline that were not observed in the placebo group. Of these, only 1 substitution (V792I) observed in 1 participant from the obeldesivir group demonstrated a low-level reduction in susceptibility to obeldesivir (EC50 fold change, 4.01). This substitution was first detected on Day 15, and the participant was never hospitalized. The low-to-no change in obeldesivir susceptibility among the treatment-emergent Nsp12 substitutions indicates a high barrier to the development of obeldesivir resistance in high-risk, nonhospitalized patients with COVID-19. Clinicaltrials.gov identifier: NCT05603143.

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