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).

Tweetable abstract

#Bemnifosbuvir is a novel, oral, nonmutagenic, nonteratogenic nucleotide analog with low potential for drug–drug interactions or resistance. Bemnifosbuvir showed a 71% reduction in hospitalization for #COVID-19 despite no symptom alleviation/viral load reduction differences. @ateapharma

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Salian VS, Wright JA, Vedell PT et al. COVID-19 transmission, current treatment, and future therapeutic strategies. Mol Pharm. 18(3), 754–771 (2021).
Medline CASGoogle Scholar
2. Di Fusco M, Shea KM, Lin J et al. Health outcomes and economic burden of hospitalized COVID-19 patients in the United States. J. Med. Econ. 24(1), 308–317 (2021).
MedlineGoogle Scholar
3. Iuliano AD, Brunkard JM, Boehmer TK et al. Trends in disease severity and health care utilization during the early omicron variant period compared with previous SARS-CoV-2 high transmission periods - United States, December 2020-January 2022. MMWR Morb. Mortal. Wkly Rep. 71(4), 146–152 (2022).
Medline CASGoogle Scholar
4. Mathieu E, Ritchie H, Ortiz-Ospina E et al. A global database of COVID-19 vaccinations. Nat. Hum. Behav. 5(7), 947–953 (2021).
MedlineGoogle Scholar
5. Steele MK, Couture A, Reed C et al. Estimated number of COVID-19 infections, hospitalizations, and deaths prevented among vaccinated persons in the US, December 2020 to September 2021. JAMA Netw. Open. 5(7), e2220385 (2022).
MedlineGoogle Scholar
6. Jang EJ, Choe YJ, Yun GW et al. Reinfection with SARS-CoV-2 in general population, South Korea; nationwide retrospective cohort study. J. Med. Virol. 94(11), 5589–5592 (2022).
Medline CASGoogle Scholar
7. Andrews N, Tessier E, Stowe J et al. Duration of protection against mild and severe disease by COVID-19 vaccines. N. Engl. J. Med. 386(4), 340–350 (2022).
Medline CASGoogle Scholar
8. Pang X, Xu W, Liu Y, Li H, Chen L. The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022. Eur. J. Med. Chem. 257, 115491 (2023).
Medline CASGoogle Scholar
9. World Health Organization. Therapeutics and COVID-19: living guideline by World Health Organization (WHO) (2021). https://apps.who.int/iris/handle/10665/345356
Google Scholar
10. Kuriakose S, Singh K, Pau AK et al. Developing treatment guidelines during a pandemic health crisis: lessons learned from COVID-19. Ann. Intern. Med. 174(8), 1151–1158 (2021).
MedlineGoogle Scholar
11. Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: progress and lessons learned. Nat. Rev. Drug Discov., doi:10.1038/s41573-023-00672-y 1–27 (2023).
MedlineGoogle Scholar
12. World Health Organization. Therapeutics and COVID-19: Living Guideline (2022). https://apps.who.int/iris/handle/10665/353403
Google Scholar
13. VEKLURY. Prescribing information. Gilead Sciences, Inc (2022).
Google Scholar
14. Wang Z, Yang L, Song XQ. Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase. Front. Immunol. 13, 1015355 (2022).
MedlineGoogle Scholar
15. Hogan JI, Duerr R, Dimartino D et al. Remdesivir resistance in transplant recipients with persistent COVID-19. Clin. Infect. Dis., doi:10.1093/cid/ciac769 (2022).
Google Scholar
16. LAGEVRIO. Emergency Use Authorization Fact Sheet. Merck Sharp & Dohme LLC (2022).
Google Scholar
17. PAXLOVID. Emergency Use Authorization Fact Sheet. Pfizer Inc (2022).
Google Scholar
18. Wen W, Chen C, Tang J et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis. Ann. Med. 54(1), 516–523 (2022).
Medline CASGoogle Scholar
19. Pepperrell T, Ellis L, Wang J, Hill A. Barriers to worldwide access for Paxlovid, a new treatment for COVID-19. Open Forum Infect. Dis. 9(9), ofac174 (2022).
MedlineGoogle Scholar
20. Molnupiravir. NIH (2023). www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/molnupiravir/
Google Scholar
21. Sanderson T, Hisner R, Donovan-Banfield IA, Peacock T, Ruis C. Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases. medRxiv doi:10.1101/2023.01.26.23284998 (2023) (Epub ahead of print).
Google Scholar
22. Vuorio A, Kovanen PT, Raal F. Cholesterol-lowering drugs for high-risk hypercholesterolemia patients with COVID-19 while on Paxlovid™ therapy. Future Virol. 17(10), 761–765 (2022).
CASGoogle Scholar
23. Batiha GE, Al-Kuraishy HM, Al-Gareeb AI et al. Targeting of neuroinflammation by glibenclamide in COVID-19: old weapon from arsenal. Inflammopharmacology. 31(1), 1–7 (2023).
Medline CASGoogle Scholar
24. Batiha GE, Al-Kuraishy HM, Al-Gareeb AI, Youssef FS, El-Sherbeni SA, Negm WA. A perspective study of the possible impact of obeticholic acid against SARS-CoV-2 infection. Inflammopharmacology. 31(1), 9–19 (2023).
Medline CASGoogle Scholar
25. Atea to advance global phase 3 registrational study of bemnifosbuvir in high-risk non-hospitalized patients with COVID-19. Press Release. Atea Pharmaceuticals (2022). https://ir.ateapharma.com/news-releases/news-release-details/atea-advance-global-phase-3-registrational-study-bemnifosbuvir
Google Scholar
26. Shannon A, Fattorini V, Sama B et al. A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase. Nat. Commun. 13(1), 621 (2022). •• This article describes the mechanism of action of AT-527 in more detail.
Medline CASGoogle Scholar
27. Takashita E, Kinoshita N, Yamayoshi S et al. Efficacy of antibodies and antiviral drugs against COVID-19 omicron variant. N. Engl. J. Med. 386(10), 995–998 (2022).
MedlineGoogle Scholar
28. Atea Pharmaceuticals reports third quarter 2022 financial results and provides business update. Press Release. Atea Pharmaceuticals (2022). https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-reports-third-quarter-2022-financial
Google Scholar
29. Atea Pharmaceuticals reports first quarter 2023 financial results and provides business update. News release. Atea Pharmaceuticals (2023). https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-reports-first-quarter-2023-financial
Google Scholar
30. Huang Q. Bemnifosbuvir (BEM, AT-527), a potent inhibitor of SARS-CoV-2 variants of concern (VOC), and a promising oral antiviral with a high resistance barrier for treatment of COVID-19 and other coronavirus infections. Lecture presented at: International Conference on Antiviral Research. Lyon, France (March 13–17 2023). •• Provides further evidence of efficacy of AT-527 for the treatment of COVID-19.
Google Scholar
31. Zhou XJ, Horga A, Puri A et al. AT-527 achieves antiviral concentrations in the human lung. Poster presented at: the 2021 ISIRV-WHO Conference. Virtual (October 19–21, 2021). •• Includes important pharmacokinetic data for AT-527.
Google Scholar
32. Atea Pharmaceuticals provides update and topline results for phase 2 MOONSONG trial evaluating AT-527 in the outpatient setting. Press Release. Atea Pharmaceuticals (2021). https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-provides-update-and-topline-results-phase-2
Google Scholar
33. Atea Pharmaceuticals reports first quarter 2022 financial results and provides business update. Press Release. Atea Pharmaceuticals (2022). https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-reports-first-quarter-2022-financial
Google Scholar
34. Clinicaltrials.Gov. Safety and efficacy of AT-527 in subjects with moderate coronavirus disease (COVID-19) in a hospital setting. NCT04396106 (2020). https://clinicaltrials.gov/ct2/show/NCT04396106
Google Scholar
35. Clinicaltrials.Gov. Study to evaluate the effects of AT-527 in non-hospitalized adult patients with mild or moderate COVID-19. NCT04709835 (2021). https://clinicaltrials.gov/ct2/show/NCT04709835
Google Scholar
36. Horga A, Kuritzkes DR, Kowalczyk JJ et al. Phase 2 study of bemnifosbuvir in high-risk participants in a hospital setting with moderate COVID-19. Future Virol. (2023). •• Includes the results of the phase II clinical trial of AT-527 for the treatment of high-risk participants in a hospital setting with moderate COVID-19.
Google Scholar
37. Vo A, Good SS, Agrawal N, Sommadossi JP. Low risk of drug-drug interactions (DDIs) for bemnifosbuvir (BEM) based upon in vitro metabolism and transporter interaction studies. Poster presented at: International Conference on Antiviral Research. Lyon, France (March 13–17, 2023).
Google Scholar
38. Zhou X-J, Morelli G, Montrond M et al. Bemnifosbuvir has low potential to interfere with P-gp, BCRP, and OATP1B1-mediated transport. Poster presented at: Conference on Retroviruses and Opportunistic Infections. Seattle, Washington (February 19–22, 2023).
Google Scholar
39. Zhou XJ, Morelli G, Montround M et al. No dose adjustments for CYP3A4 substrates when co-administered with bemnifosbuvir. Poster presented at: Conference on Retroviruses and Opportunistic Infections. Seattle, Washington (February 19–22, 2023).
Google Scholar
40. ClinicalTrials.gov. Study to evaluate the effects of RO7496998 (AT-527) in non-hospitalized adult and adolescent participants with mild or moderate COVID-19 (MORNINGSKY). NCT04889040 (2021). https://clinicaltrials.gov/ct2/show/NCT04889040
Google Scholar
41. US Food and Drug Administration. COVID-19: developing drugs and biological products for treatment or prevention: guidance for industry (2021). www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
Google Scholar
42. US Food and Drug Administration. Assessing COVID-19-related symptoms in outpatient adult and adolescent subjects in clinical trials of drugs and biological products for COVID-19 prevention or treatment. Guidance for Industry (2020). www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-trials-drugs
Google Scholar
43. Bernal J, Gomes Da Silva MM, Musungaie DB et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N. Engl. J. Med. 386(6), 509–520 (2022).
Medline CASGoogle Scholar
44. Hammond J, Leister-Tebbe H, Gardner A et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N. Engl. J. Med. 386(15), 1397–1408 (2022).
Medline CASGoogle Scholar
45. Vallejos J, Zoni R, Bangher M et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 21(1), 635 (2021).
Medline CASGoogle Scholar
46. Marquez C, Kerkhoff AD, Schrom J et al. COVID-19 symptoms and duration of direct antigen test positivity at a community testing and surveillance site, January 2021–2022. MedRxiv, doi:10.1101/2022.05.19.22274968 2022.2005.2019.22274968 (2022).
Google Scholar
47. Gottlieb RL, Vaca CE, Paredes R et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N. Engl. J. Med. 386(4), 305–315 (2022).
Medline CASGoogle Scholar
48. Ganatra S, Dani SS, Ahmad J et al. Oral nirmatrelvir and ritonavir in non-hospitalized vaccinated patients with Covid-19. Clin. Infect. Dis., doi:10.1093/cid/ciac673 (2022).
Google Scholar
49. Pfizer reports additional data on Paxlovid supporting upcoming new drug application submission to U.S. FDA. Business Wire (2022). www.businesswire.com/news/home/20220613005755/en/
Google Scholar
50. Centers for Disease Control and Prevention. COVID-19 rebound after Paxlovid treatment (2022). https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf
Google Scholar
51. Atea's AT-527, an oral antiviral drug candidate, reduces viral replication in hospitalized patients with COVID-19 in phase 2 interim analysis. Atea Pharmaceuticals (2021). https://ir.ateapharma.com/news-releases/news-release-details/ateas-527-oral-antiviral-drug-candidate-reduces-viral
Google Scholar
52. AstraZeneca. Evusheld significantly prevented COVID-19 disease progression or death in TACKLE phase III treatment trial. Press release (2022). www.astrazeneca.com/media-centre/press-releases/2022/evusheld-significantly-prevented-covid-19-disease-progression-or-death-in-tackle-phase-iii-treatment-trial.html
Google Scholar
53. Adagio Therapeutics announces ADG20 (adintrevimab) is the first monoclonal antibody to meet primary endpoints with statistical significance across pre- and post-exposure prophylaxis and treatment for COVID-19 and plans to seek U.S. emergency use authorization. Globe Newswire (2022). https://investors.adagiotx.com/news-releases/news-release-details/adagio-therapeutics-announces-adg20-adintrevimab-first
Google Scholar
54. Montgomery H, Hobbs FDR, Padilla F et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir. Med., doi:10.1016/s2213-2600(22)00180-1 (2022).
Google Scholar
55. Desai A, Gyawali B. Endpoints used in phase III randomized controlled trials of treatment options for COVID-19. EClinicalMedicine. 23, 100403 (2020).
MedlineGoogle Scholar
56. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the treatment of COVID-19 – final report. N. Engl. J. Med. 383(19), 1813–1826 (2020).
Medline CASGoogle Scholar
57. Atea Pharmaceuticals announces U.S. FDA fast track designation granted to bemnifosbuvir, an investigational oral antiviral, for the treatment of COVID-19. News release. Atea pharmaceuticals (2023). https://ir.ateapharma.com/news-releases/news-release-details/atea-pharmaceuticals-announces-us-fda-fast-track-designation-0
Google Scholar
58. Clinicaltrials.Gov. SUNRISE-3: efficacy and safety of bemnifosbuvir in high-risk outpatients with COVID-19. NCT05629962 (2022). https://clinicaltrials.gov/ct2/show/NCT05629962
Google Scholar

Vol. 18, No. 13

Supplemental Materials

Metrics

Downloaded 751 times

History

Received 13 June 2023

Accepted 29 September 2023

Published online 1 November 2023

Published in print September 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fvl-2023-0115

Author contributions

All authors contributed to study protocol development, data collection, analysis and interpretation and clinical study report compilation. All authors were involved in the decision to submit this manuscript for publication.

Acknowledgments

The authors thank the patients and their families as well as the clinical trial site investigators for their contributions to the MORNINGSKY study.

Financial disclosure

This work was supported by Atea Pharmaceuticals, Inc and F. Hoffman-La Roche Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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.

Writing assistance

Atea Pharmaceuticals, Inc. (MA, USA) enlisted and funded medical writing support from PRECISIONscientia (PA, USA), which was provided by R Myers and N Infarinato.

Ethical conduct of research

The study protocol and amendments were approved by an Institutional Review Board/Independent Ethics Committee, and written informed consent was obtained. The study was performed in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and International Conference for Harmonization Good Clinical Practice Guidelines.

Data sharing statement

The authors attest that this manuscript reports original clinical trial data. The study protocol and deidentified, individual data for this manuscript (text, tables, figures and appendices) will be available indefinitely for anyone wishing to access them. The study protocol and Statistical Analysis Plan are provided in the Supplementary Material.

Open access

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

PDF download