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

Pitts, J.; Zamora, J. L. R.; Manhas, S.; Aeschbacher, T.; Chan, J.; Cutillas, V.; Nair, V.; Riola, N. C.; Vijjapurapu, A.; Vermillion, M. S.; Eng, S.; Richards, C.; Han, D.; Perry, J. K.; Chaudhuri, S.; Liu, I.; Martinez, C.; Peinovich, N.; Sun, K.-H.; Cai, A.; Martin, R.; Moshiri, J.; Hedskog, C.; Babusis, D.; Siegel, D. S.; Kalla, R.; Avadhanula, V.; Piedra, P. A.; Stobbelaar, K.; Delputte, P. L.; Marceau, C.; Mateo, R.; Svarovskaia, J.; Mo, H.; Subramanian, R.; Mackman, R. L.; Cihlar, T.; Fletcher, S. P.; Bilello, J. P.

doi:10.1101/2025.02.24.639976

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bioRxiv · 10.1101/2025.02.24.639976

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

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Abstract

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 M). 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/mLxday 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.

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Pitts, J., Zamora, J. L. R., Manhas, S., Aeschbacher, T., Chan, J., Cutillas, V., Nair, V., Riola, N. C., Vijjapurapu, A., Vermillion, M. S., Eng, S., Richards, C., Han, D., Perry, J. K., Chaudhuri, S., Liu, I., Martinez, C., Peinovich, N., Sun, K.-H., Cai, A., Martin, R., Moshiri, J., Hedskog, C., Babusis, D., Siegel, D. S., Kalla, R., Avadhanula, V., Piedra, P. A., Stobbelaar, K., Delputte, P. L., Marceau, C., Mateo, R., Svarovskaia, J., Mo, H., Subramanian, R., Mackman, R. L., Cihlar, T., Fletcher, S. P., Bilello, J. P.. 2025-02-25. Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys. https://doi.org/10.1101/2025.02.24.639976

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