Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19

Руженцова, Т. А.; Чухляев, Павел; Хавкина, Д. А.; Гарбузов, Александр; Oseshnyuk, Rodion A.; Soluyanova, Tatyana N.; Shestakova, I.; Vafin, A Yu; Ep, Dmitrikova; Мустафаев, Д. М.; Domostroeva, Tatiana N.; Otpushchennikova, Maria V.; Pokrovsky, K A; Markova, T. N.; Kaplun, Elena A.; Petina, Diana V.; Rusanova, M. G.; Bistritskiy, Dmitriy A.; Kostina, N. E.; Lesina,; Scherbak, Sergey G.; Agaf'ina, Alina S.; Brook, Yury F.; Бронов, О. Ю.; Шульц, Е. И.; Samsonov, Mikhail; Krasavina, Emilia N.; Zintchenko, Arkadiy V.; Nikol'skaya, M. V.; Razzhivina,; Filon, Olga V.

doi:10.2139/ssrn.3696907

Cited by 22 publications

(31 citation statements)

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“…However, it remains unclear whether the mutations associated with the Omicron variant may affect SARS-CoV-2 sensitivity to antiviral drugs. Here, we tested the effects of EIDD-1931, ribavirin, remdesivir, favipravir (an additional RNA-dependent RNA polymerase inhibitor that displayed anti-SARS-CoV-2 activity in phase III clinical trials [9]), PF-07321332, nafamostat, camostat, and aprotinin on the replication of two SARS-CoV-2 Omicron (B.1.1.529) isolates (Omicron 1, Omicron 2, see Suppl. Methods) and one Delta (B.1.167.2) isolate (see Suppl.…”

Section: Figurementioning

confidence: 99%

Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

Bojkova

Widera

Ciesek

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant is currently causing a large number of infections in many countries. A number of antiviral agents are approved or in clinical testing for the treatment of COVID-19. Despite the high number of mutations in the Omicron variant, we here show that Omicron isolates display similar sensitivity to eight of the most important anti-SARS-CoV-2 drugs and drug candidates (including remdesivir, molnupiravir, and PF-07321332, the active compound in paxlovid), which is of timely relevance for the treatment of the increasing number of Omicron patients. Most importantly, we also found that the Omicron variant displays a reduced capability of antagonising the host cell interferon response. This provides a potential mechanistic explanation for the clinically observed reduced pathogenicity of Omicron variant viruses compared to Delta variant viruses.

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Section: Figurementioning

confidence: 99%

Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

Bojkova

Widera

Ciesek

et al. 2022

Preprint

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“…Favipiravir is in routine usage for COVID-19 in many countries, but existing trial data are mixed. Some small, open-label studies have indicated benefits in terms of clinical outcomes [25–28] or viral shedding [13, 26]. However, other studies have indicated no clinically important benefit [29, 30], including when given in early disease [31].…”

Section: Discussionmentioning

confidence: 99%

Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

Lowe

Brown

Chowdhury

et al. 2022

Preprint

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Background: Early antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early. Methods: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ClinicalTrials.gov: NCT04499677. Findings: Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm. Interpretation: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations.

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“…It has been revealed that two doses of mRNA vaccine are insufficient to provide immunity against the Omicron variant ( 34–36 ), and new vaccines that will provide more robust immunity are urgently needed. In addition, new antivirals have been developed and are expected to be approved for clinical use ( 37–39 ). While development of new vaccines and antivirals will continue, it remains important to evaluate their safety, and to pay attention to resistant mutations.…”

Section: Discussionmentioning

confidence: 99%

Characterization of various remdesivir-resistant mutations of SARS-CoV-2 by mathematical modeling and molecular dynamics simulation

Torii

Kim

Koseki

et al. 2022

Preprint

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Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.

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Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19

Cited by 22 publications

References 0 publications

Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

Characterization of various remdesivir-resistant mutations of SARS-CoV-2 by mathematical modeling and molecular dynamics simulation

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