MINIREVIEW: Favipiravir (Avigan) for COVID-19 – Review of the available literature

Author of summary: Francesca Fontana; Reviewer: Antonio Carusillo

Favipiravir (Avigan), has been proposed as a potential treatment against COVID-19. Pertinent experimental evidence is here summarized, and clinical trials registered up to June 28 listed.

In a screening of a group of drugs for antiviral activity against n2019-SARS-CoV by Wang et al [1], Favipiravir (FVP) showed some inhibition of viral replication in Vero E6 cells, with an EC50 of 62𝛍M (vs 1.7𝛍M for remdesivir and 6.7𝛍M for chloroquine). Modeling studies have addressed the potential binding of FVP to the viral RNA-dependent RNA polymerase (RdRp). Zhang et al recently reported that interaction between RdRp and FVP is possible [2]. Shah et al also included FVP in their screening, in silico, but found that, although the binding was possible, it showed poorer docking score compared to other antivirals [3].

Quoting the work of Wang et al as a rationale, one paper in the journal Engineering (not available through pubmed) by Cai et al report an open-label non-randomized trial that compared Favipiravir (FVP) to lopinavir/ritonavir (LPV/RTV), in addition to inhalatory interferon-alpha and support, COVID-19 patients [4]. FVP was administered to 35 patients with a loading dose of 1600mg x2/die followed by 600mg x2/day on days 2-14. LPV/RTV was administered at 400mg/100mg x2/day to 45 patients. Notably, critical conditions, including SpO2 <93% or organ failure were exclusion criteria. Relative to LPV/RTV, FVP-treated patients showed quicker viral clearance by qRT-PCR (p<0.01). Chest CT arbitrary scoring showed improvement at one of 4 time-points in the FVP group. No data were presented on survival [4]. Of note, a recent randomized study published on the NEJM demonstrated no therapeutic advantage of LPV/RTV versus placebo in patients with severe COVID-19 [5]. Since critical patients were excluded from the study by Cai et al, it is unclear whether LPV/RTV could substitute for placebo in this trial.

Another clinical trial by Chen et al is currently available in medrxiv as manuscript awaiting peer-review, reporting the results of clinical tiral ChiCTR2000030254. The trial reportedly included 240 patients with COVID19 pneumonia within 12 days from onset, aged 18 and older (70-75% under 65 y.o.), randomized to receive arbidol or FVP (1.6g x2 load, then 600mg x2/day for 7-10 days). Up to 75% of the patients received additional treatments, including antivirals and chloroquine, but it is uncertain how these were distributed across the two groups. The authors show an improvement in cough and fever in FVP patients with moderate COVID19, at the expense of higher side effects. However, no advantage was shown in the need for oxygen therapy or ventilation, nor in patients with severe COVID19 or co-morbidities [6]. Further, a methodological analysis, to which the original authors provided all required information, has pointed out a few issues in the statistical methods and trial design [7]

Since its registration in Japan in 2014, relatively few peer-reviewed papers have been published on the use of FVP use in patients with viral infections, mostly Ebola, with daily dosages ranging from 800 to 12000 mg/day (see table 1). Interestingly, Nguyen et al [8], show that with a loading dose of 6g/day and maintenance of 1.2g (6 tablets) twice a day, the median plasma concentration was 46.1 μg/mL at day 2, and 25.9 μg/mL from day 4, with a significant difference from the theoretical predictions. Even if Ebola seems more sensitive to FVP than 2019-SARS-CoV, Nguyen et al also reported no correlation between drug concentration in the blood and effects on viral clearance.
Summarized in table 1 are the clinical studies that have utilized FVP against Ebola [8-10, 14], severe fever with thrombocythemia syndrome [11], influenza [12], and tested its effects on healthy volunteers [13].

Ref Study Dosage Results
Bai et al 2016 [9] Ebola, (Favipiravir + support vs support), 2014-2015 Western Africa Load 800mg x2/day x2 days, 600mg x2/day x2 days, 400mg x2/day x 5 days Increase survival, reduction of main symptoms, reduced viral RNA
Nguyen et al 2017 [8]   Ebola, JIKI trial pharmacokinetics study 2014-2015 Guinea Load 6g, 1.2×2/die x9 days Lower plasma levels than expected on day 2 (median 46.1 μg/mL), much lower on day 4 (25.9 μg/mL). No correlation between drug concentration and viral response
Sissoko et al 2016 [10] Ebola (Favipiravir+support) proof-of-principle, 2014 Guinea Load 6g x1 day, then 2.4g/die x 9 days Trend for improvement in patients with low viral load, not confirmed efficacy, high doses well tolerated
Song et al 2019 [11]   SFTS (severe fever with thrombocythemia syndrome), 2 patients N/A Both patients responded
Wang Y et al 2019 [12] Influenza in critically ill patients Favipiravir +Oseltamvir vs Oseltamvir only N/A Greater effect on viral RNA of combo, no effect on symptoms or mortality
Kumagai 2015 et al [13] Healthy volunteers safety on QT 1.2g x1 vs 2.4g x1 No effect on QT interval in healthy Japanese men
Kerber et al 2019 [14] Ebola, (Favipiravir + support vs support) Guinea 2015, retrospective study on compassionate use Load 6g x1day, 2.4g/die x 9 days Non-significant trend for increased survival, hematic target concentrations were not reached

Interestingly, there seems to be a trend towards an increase in dosage across studies, especially with respect to the initial test in healthy volunteers [13]. It is possible to speculate that pharmacokinetics issues may have been noted or suspected, prompting the dose escalation. This would be in line with the observations of Kerber et al [14] in 2019, who reported a failure to obtain target hematic concentrations of FVP, despite the administration of very high doses.

Since the study by Cai et al [3] did not report hematic concentrations of FVP in their cohort, it remains unclear whether the proposed dosage of 3.2 to 1.6 g/die of FVP may reach the relatively high concentrations that would be necessary to treat COVID-19 in patients. Further hindrance to efficient repurposing, as noted by Khambholja  and Asudani [15], is that the results of ca 85% of registered clinical trials for FVP (on any disease) has not been published [15], which leaves a degree of uncertainty on the proper use of the drug.

FVP is not registered in Italy, and AIFA released a statement discouraging its use in COVID19. However, the recent registration of novel clinical trials on the use of FVP suggests that further investigation may still be available for this drug, possibly taking into consideration the reported good tolerability.

To date, 25 clinical trials that include FVP have been registered on clinicaltrials.gov.

Of note, NCT04358549 and NCT04346628 will include pharmacokinetics evaluations, which will provide crucial information for the appropriate and effective dosage of FVP in COVID-19 as well as useful data for future developments.

NCT# Status Interventions Locations
4336904 Active, not recruiting FVP|Other: Placebo Italy
4358549 Recruiting FVP + SoC| SoC USA (AZ, MA, NJ, TX)
4359615 N/Y FVP| HCQ Iran
4425460 N/Y FVP| Placebo China, Germany, Romania|
4434248 Active, not recruiting FVP| SoC Russian Federation
4349241 Completed FVP| SoC Egypt
4448119 N/Y FVP| FVP Placebo Canada (ON)
4402203 Recruiting FVP| Only SoC Bangladesh
4411433 Recruiting FVP (3200 mg + 1200 mg)| FVP (3600 mg + 1600 mg)| FVP (3200 mg + 1200 mg) combined with HCQ| FVP (3200 mg + 1200 mg) combined with Azithromycin| HCQ| HCQ combined with Azithromycin Turkey
4387760 N/Y HCQ| FVP|Other: Routine care for COVID-19 patients Bahrain
4392973 Recruiting Combination Product: FVP and HCQ Saudi Arabia
4303299 N/Y Oral Thailand
4310228 Recruiting FVP Combined With Tocilizumab| FVP| Tocilizumab China (Beijing, Hubei)
4376814 Completed FVP| HCQ| Lopinavir / Ritonavir Iran
4333589 Recruiting FVP China (Anhui, Hubei, Zhejiang)
4373733 Recruiting FVP| HCQ| Azithromycin| Zinc Sulfate| Other: SoC United Kingdom
4351295 N/Y FVP| Placebos Egypt
4346628 N/Y FVP| Placebo|Other: SoC USA (CA)
4445467 N/Y FVP  
4356495 Recruiting Dietary Supplement: Vitamins| HCQ| Imatinib| FVP| Telmisartan France
4345419 Recruiting CQ| FVP| Nitazoxanide| Ivermectin| Niclosamide| Other drugs Egypt
4444986 Completed FVP 200 mg FT| AVIGAN 200 mg FT Turkey
4400682 Active, not recruiting Test Drug 200 mg FVP| 200 mg FVP Turkey
4406194 Active, not recruiting FVP 200 mg Turkey
4407000 N/Y FVP 200 mg (LOQULAR)| FVP 200 mg (Avigan) Turkey

FVP= favipiravir, HCQ=hydroxychloroquine, CQ=chloroquine, SoC=Standard of Care

Bibliography:

[1] Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitroCell Res 30, 269–271 (2020).

[2] Chang Chen, Yi Zhang, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv 2020.03.17.20037432

[3] Shah B, Modi P, Sagar SR. In silico studies on therapeutic agents for COVID-19: Drug repurposing approachLife Sci. 2020;252:117652.

[4] Qingxian Cai, Minghui Yang, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study, Engineering, 2020, ISSN 2095-8099,

[5] Bin Cao, M.D., Yeming Wang, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19, N Engl J Med 2020; 382:1787-1799.

[6] Wilkinson, Jack, & Dahly, Darren. (2020, March 31). Statistical review of Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial (Version 1.0). Zenodo.

[7] Thi Huyen Tram Nguyen,Jérémie Guedj, et al. on behalf of the JIKI study group, Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted, PLOS Neg Trop Dis.

[8] Chang-Qing Bai, Jin-Song Mu, et al. Clinical and Virological Characteristics of Ebola Virus Disease Patients Treated With Favipiravir (T-705)—Sierra Leone, 2014Clinical Infectious Diseases, Volume 63, Issue 10, 15 November 2016, Pages 1288–1294

[9] Daouda Sissoko,Cedric Laouenan, et al. JIKI Study Group, Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea, PLOS Medicine.

[10] Song, R., Chen, Z. & Li, W. Severe fever with thrombocytopenia syndrome (SFTS) treated with a novel antiviral medication, favipiravir (T-705)Infection 48, 295–298 (2020).

[11] Yeming Wang, Guohui Fan, et al. Community-Acquired Pneumonia China Network, Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus InfectionThe Journal of Infectious Diseases, Volume 221, Issue 10, 15 May 2020, Pages 1688–1698.

[12] Yuji Kumagai, Yuji Murakawa, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. 2015; 53: 866-874.

et al. Laboratory Findings, Compassionate Use of Favipiravir, and Outcome in Patients With Ebola Virus Disease, Guinea, 2015—A Retrospective Observational StudyThe Journal of Infectious Diseases, Volume 220, Issue 2, 15 July 2019, Pages 195–202,

[14] Kapil Khambholja, Deepak Asudani, Potential repurposing of Favipiravir in COVID-19 outbreak based on current evidence, Travel Medicine and Infectious Disease, Volume 35, 2020, 101710, ISSN 1477-8939.

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