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. 2023 Oct:10.2217/fvl-2023-0115.
doi: 10.2217/fvl-2023-0115. Epub 2023 Nov 1.

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY)

Arantxa Horga  1 , Rebecca Saenz  2 , Gürdal Yilmaz  3 , Abraham Simón-Campos  4 , Keith Pietropaolo  1 , William J Stubbings  5 , Neil Collinson  6 , Laura Ishak  1 , Barbara Zrinscak  7 , Bruce Belanger  1 , Catherine Granier  6 , Kai Lin  1 , Aeron C Hurt  5 , Xiao-Jian Zhou  1 , Steffen Wildum  5 , Janet Hammond  1
Affiliations

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY)

Arantxa Horga et al. Future Virol. 2023 Oct.

Abstract

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral load and safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

Keywords: AT-527; COVID-19; SARS-CoV-2; bemnifosbuvir; oral; outpatient.

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Conflict of interest statement

Competing interests disclosure A Horga, K Pietropaolo, L Ishak and B Belanger are employees of Atea. R Saenz is an employee and owns stock for Genentech (a member of the Roche group). A Simón-Campos is a speaker and advisory board member for Pfizer, AstraZeneca, Roche and Regeneron. WJ Stubbings, N Collinson, C Granier, AC Hurt and S Wildum are employees and shareholders of F. Hoffman-La-Roche Ltd. B Zrinscak is an employee of F. Hoffman-La-Roche Ltd. K Lin is a former employee of Atea. X-J Zhou and J Hammond are employees and shareholders of Atea. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.. AT-527 mechanism of action and metabolism.
(A) Dual Mechanism of Action of AT-527. Ribbon and stick representation of the cryo-EM structure of nsp7-(nsp8)2–nsp12:AT-9010-terminated-RNA:(AT-9010)2 complex. RNA, AT-9010 and protein shown with the following colors: template RNA, green; RNA product, orange; AT-9010, magenta; nsp7, pink; nsp81 and nsp82, yellow and cyan, respectively; and nsp12in gray and blue for NiRAN and RdRp domains, respectively. Orange boxes are enlarged for RdRp domain and NiRAN domains, respectively, showing experimental cryo-EM map around AT-9010, in the RdRp, one AT-9010 monophosphate (AT-9010-MP) is incorporated at (+1) position, with an incoming AT-9010 occupying the (-1) position. In the NiRAN domain, AT-9010 is bound it its diphosphate form (AT-9010-DP). (B) Metabolism of AT-527. Metabolism of the guanine analog phosphoramidate prodrug AT-527 (top left) and its active triphosphate form AT-9010 (top right). Figure from Shannon A, et al. Nat Commun. 2022. 13(1):621 under the Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0/
Figure 1.
Figure 1.. AT-527 mechanism of action and metabolism.
(A) Dual Mechanism of Action of AT-527. Ribbon and stick representation of the cryo-EM structure of nsp7-(nsp8)2–nsp12:AT-9010-terminated-RNA:(AT-9010)2 complex. RNA, AT-9010 and protein shown with the following colors: template RNA, green; RNA product, orange; AT-9010, magenta; nsp7, pink; nsp81 and nsp82, yellow and cyan, respectively; and nsp12in gray and blue for NiRAN and RdRp domains, respectively. Orange boxes are enlarged for RdRp domain and NiRAN domains, respectively, showing experimental cryo-EM map around AT-9010, in the RdRp, one AT-9010 monophosphate (AT-9010-MP) is incorporated at (+1) position, with an incoming AT-9010 occupying the (-1) position. In the NiRAN domain, AT-9010 is bound it its diphosphate form (AT-9010-DP). (B) Metabolism of AT-527. Metabolism of the guanine analog phosphoramidate prodrug AT-527 (top left) and its active triphosphate form AT-9010 (top right). Figure from Shannon A, et al. Nat Commun. 2022. 13(1):621 under the Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0/
Figure 2.
Figure 2.. Screening, randomization and analyses.
Figure 3.
Figure 3.. Secondary Endpoints.
(A) Rate of hospitalization. BID, twice daily. Error bars denote the 97.5% confidence interval (CI). (B) Rate of COVID-19 Complications. BID, twice daily. Error bars denote the 97.5% CI. (C) Rate of medically attended visits related to COVID-19. BID, twice daily. Error bars denote the 97.5% CI.
See this image and copyright information in PMC

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