Paper

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Pitts, Jared, Martinez, Clarissa, Bilello, John P, Siegel, Dustin S, Avadhanula, Vasanthi, Marceau, Caleb, Mackman, Richard L, Mo, Hongmei, Delputte, Peter L, Svarovskaia, Jenny, Fletcher, Simon P, Babusis, Darius, Arya Vijjapurapu, Kalla, Rao, Cihlar, Tomas, Subramanian, Raju, Nair, Varsha, Cutillas, Vincent, J Lizbeth Reyes Zamora, Eng, Stacey, Perry, Jason K, Cai, Arthur, Chaudhuri, Subhra, Riola, Nicolas C, Moshiri, Jasmine, Kai-Hui, Sun, Piedra, Pedro A, Peinovich, Nadine, Chan, Josolyn, Manhas, Savrina, Vermillion, Meghan S, Ross, Martin, Stobbelaar, Kim, Richards, Christopher, Han, Dong, Aeschbacher, Thomas, Mateo, Roberto, Hedskog, Charlotte, Liu, Iris

2025

Overview

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated ~24 hours post-infection significantly reduced log10 viral RNA copies/mL×day area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.Competing Interest StatementAll authors affiliated with Gilead Sciences may hold stock or stock options in Gilead Sciences, Inc. VA, PAP, KS, and PLD received funding from Gilead Sciences Inc. to support parts of this work. PAP received grant awards and ad hoc honoraria from Merck and Shionogi for consulting and scientific boards unrelated to the work presented here. All other authors declare no competing interests.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Amino acid substitution / Antiviral activity / Clinical isolates / DNA-directed RNA polymerase / Infections / Microbiology / Morbidity / Nucleoside analogs / Respiratory syncytial virus / RNA polymerase