No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Charlotte Hedskog, Christoph D. Spinner, Ulrike Protzer, Dieter Hoffmann, Chunkyu Ko, Robert L. Gottlieb, Medhat Askar, Meta Roestenberg, Jutte J.C. de Vries, Ellen C. Carbo, Ross Martin, Jiani Li, Dong Han, Lauren Rodriguez, Aiyappa Parvangada, Jason K. Perry, Ricard Ferrer, Andrés Antón, Cristina Andrés, Vanessa CasaresHuldrych F. Günthard, Michael Huber, Grace A. McComsey, Navid Sadri, Judith A. Aberg, Harm van Bakel, Danielle P. Porter

Research output: Contribution to journalArticlepeer-review


Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

Original languageEnglish
Article number546
Issue number4
StatePublished - Apr 2024
Externally publishedYes


  • Nsp12
  • SARS-CoV-2
  • genotyping
  • phenotyping
  • remdesivir
  • resistance


Dive into the research topics of 'No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials'. Together they form a unique fingerprint.

Cite this