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Favipiravir - FUJIFILM Toyama Chemical

Drug Profile

Favipiravir - FUJIFILM Toyama Chemical

Alternative Names: Avigan; T-705; T-705a

Latest Information Update: 12 Oct 2020

At a glance

  • Originator Toyama Chemical
  • Developer Appili Therapeutics; BioDefense Therapeutics; Dr Reddys Laboratories; FUJIFILM Holdings Corporation; FujiFilm Pharmaceuticals USA; FUJIFILM Toyama Chemical; Institut national de la sante et de la recherche medicale; MediVector; Toyama Chemical; Zhejiang Hisun Pharmaceutical
  • Class Amides; Antivirals; Pyrazines; Small molecules
  • Mechanism of Action RNA inhibitors; RNA replicase inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed COVID 2019 infections
  • Registered Influenza virus infections
  • Phase III Viral infections
  • Phase II Ebola virus infections

Most Recent Events

  • 23 Sep 2020 FUJIFILM Toyama Chemical announces intention to submit sNDA to the Ministry of Health, Labour and Welfare for COVID-2019 infections in Early October 2020
  • 23 Sep 2020 Efficacy and adverse events data from a phase III trial in COVID-2019 infections released by FUJIFILM Toyama Chemical
  • 14 Sep 2020 Appili Therapeutics submits a new protocol to the US FDA for its open IND application in COVID-2019 infections

Development Overview

Introduction

Favipiravir is a small-molecule pyrazine derivative, that has been developed as an orally administered twice-daily treatment for multiple viral infections, including infections with H5N1 strains, influenza virus infections, COVID-2019 infections, and Ebola virus infections. Favipiravir inhibits the viral replication enzyme, RNA-dependent RNA polymerase via a novel mechanism of action, and may have activity in resistant strains. The compound was originally being developed by Toyoma Chemical in Japan but worldwide development is now being conducted by parties including FUJIFILM and MediVector. The product is approved in Japan for the treatment of influenza virus infections, but can only be made available at the request of the government during an influenza outbreak. Favipiravir is available in India, China, Saudi Arabia and UAE, and is approved in Russia, for COVID-19 infections. Clinical development for influenza viral infection, COVID-2019 infections, and Ebola virus infections is underway in several countries.

Clinical development for influenza virus infections was also conducted in Chile and Paraguay. Early research development in Ebola virus infections was conducted in the US. However, no recent reports of development were identified in these countries.

Toyama Chemical (now FUJIFILM Toyama Chemical) is majority-owned by FUJIFILM Holdings Corporation and is 34% owned by Taisho Pharmaceutical.

In October 2018, Toyama Chemical merged with FUJIFILM RI Pharma to form FUJIFILM Toyama Chemical [1] .

Company Agreements

In June 2020, FUJIFILM Corporation signed licensing agreement with Dr. Reddys Laboratories and Global Response Aid for the development, manufacture and sales of favipiravir tablets (Avigan®) to overseas deployment of a treatment drug for the COVID-2019 infections. Under the terms of agreement, FUJIFILM Toyama Chemical will grant Dr. Reddy’s and Global Response Aid (GRA) the exclusive right to develop, manufacture and sell Avigan® overseas, and, receive a lump-sum license fee and royalties on sales. Based on the Agreement, FUJIFILM Toyama Chemical will provide Dr. Reddy’s and Global Response Aid an array of data on Avigan’s preclinical and clinical studies that FUJIFILM Toyama Chemical has accumulated thus far. Dr Reddy’s and GRA, for their part, will make use of this data to swiftly implement clinical studies, targeting COVID-19 patients in India, the Middle East, and other regions where infections have been spreading. In addition, FUJIFILM Toyama Chemical will grant Dr. Reddy’s right to use Avigan’s patents of formulation and manufacturing method. Dr. Reddy’s will establish a setup for manufacturing drugs of the same quality as Avigan, and utilise GRA’s global sales network to supply the manufactured drugs swiftly and in a stable manner. [2]

In June 2016, FUJIFILM signed a patent license agreement, concerning Favipiravir, with Zhejiang Hisun Pharmaceutical. Under the terms of the agreement, Fujifilm grants Hisun Pharmaceutical a license to use its Favipiravir-related patents in China to develop, manufacture and market the product. Fujifilm will receive a lump-sum payment and royalties once influenza drug is successfully introduced to the market [3] .

In July 2015, FUJIFILM announced that it will collaborate with Standard Chemical & Pharmaceutical Company towards the manufacturing and marketing approval of the drug in Taiwan [4] .

In March 2012, MediVector secured a contract worth approximately $US138.5 million from BioDefense Therapeutics to further the development of favipiravir in the US.

It appears that BioDefense Therapeutics, a Joint Product Management office within the U.S. Department of Defense (DoD), holds rights to develop favipiravir in the US [5] .

Key Development Milestones

COVID-2019 infections

Favipiravir launched in China, Saudi Arabia and UAE for the treatment of COVID-2019 infections [6] [7] .

In August 2020, Dr. Reddy's Laboratories launched AVIGAN® (Favipiravir) 200 mg tablets in India [8] . Earlier, in July 2020, favipiravir was approved by the Drugs Controller General of India (DCGI) for the treatment of patients with mild to moderate COVID-19 disease [6] .

As of July 2020, favipiravir is approved in Russia in COVID-2019 infections [6] .

As of July 2020, the Italian Medicines Agency (AIFA) approved the tests on efficacy of favipiravir on the novel coronavirus [6] .

In June 2020, Zhejiang Hisun Pharmaceutical reported that the Japanese government recommended use of favipiravir for the treatment of COVID-2019 infections [7] .

In March 2020, Turkish Government as part of series of preventive measures incorporated favipiravir into the COVID-19 treatment scheme and sent one million favipiravir tablets purchased from Hisun to hospitals all over the country for the free treatment of patients with COVID-2019 infections. In August 2020, results from the trial under the national COVID-19 treatment protocol were released by Zhejiang Hisun Pharmaceutical [9] [10] .

Favipiravir is intended to be provided for free in 20 countries inclusive of Indonesia, Iran, Saudi Arabia and Turkey, for treatment of COVID-2019 infections. In April 2020, FUJIFILM Corporation reported that it allocated additional capacity at its FUJIFILM Wako Pure Chemical Co Ltd facility in Japan, for production of pharmaceutical intermediates used to manufacture favipiravir. This is expected to provide quicker access to the drug, for treatment of COVID-2019 infections. Fujifilm also established strategic partnerships with domestic and overseas companies for diverse manufacturing processes to source raw materials and pharmaceutical substances [11] [12] .

In August 2020, Dr. Reddy's Laboratories initiated a phase III trial to evaluate the efficacy, safety and tolerability of favipiravir as adjunctive treatment to supportive care, versus placebo with supportive care, in the acute treatment of patients with moderate to severe COVID-19, and who have tested positive for SARS-CoV-2 (CVD-04-CD-001; NCT04529499). The randomised, double blind, parallel design trial is enrolling approximately 780 patients in Kuwait [13] .

In May 2020, FUJIFILM Toyama Chemical initiated a phase III trial of favipiravir verses hydroxycholorquine and azithromycin and zinc verses standard care in patients hospitalised with COVID-19 infections (NCT04373733; EudraCT2020-001449-38; CW002). The open-label randomised trial intends to enrol 450 patients in the UK [14] .

In August 2020, the US FDA approved the IND application of favipiravir, following which the therapy is being evaluated in a prophylactic phase II trial against COVID-2019 infections, in the US. The study intends to enrol approximately 760 participants. In May 2020, Health Canada approved the clinical trial application (CTA) of Appili Therapeutics for initiating the prophylactic phase II trial of favipiravir as a preventive measure against COVID-2019 infections [15] [16] . Earlier, in the same month, Appili Therapeutics had filed the CTA with Health Canada to initiate the prophylactic phase II trial to evaluate favipiravir as a preventive measure against COVID-2019 infections in Canada. The primary endpoint of the trial is safety and efficacy of favipiravir in the prevention of COVID-2019 infections [17] [18] .

In September 2020, Appili Therapeutics submits a new protocol for its open investigational new drug application (IND) with the US FDA to conduct a phase III clinical study evaluating favipiravir in the early treatment outpatient setting for adult COVID-19 infections. The trial will be randomised, double-blind, placebo-controlled, multi-center phase III trial, will investigate the safety and efficacy of favipiravir in the early treatment outpatient setting for adult COVID-19 infections with mild to moderate symptoms. Appili plans to recruit 826 eligible participants, who are recently diagnosed as COVID-19 positive with mild to moderate symptoms, across multiple clinical trial sites in the US. The trial will start recruiting patients in fall of 2020 [19]

In July 2020, Stanford University initiated a phase II trial to evaluate the efficacy of oral favipiravir plus standard of care treatment (SOC) compared with placebo plus SOC in reducing the duration of shedding of SARS-CoV2 virus in patients with mild or asymptomatic COVID-19 (NCT04346628; 56032). The randomised trial intends to enrol approximately 120 patients in the US. Stanford Medicine in the US approved the tests on efficacy of favipiravir on the novel coronavirus [6] [20]

In April 2020, FUJIFILM Corporation initiated a phase II proof-of-concept trial to evaluate the safety and efficacy of favipiravir with standard of care (SoC) or SoC alone in patients with COVID-2019 infections (NCT04358549; FAVI-COV-US201). The primary endpoint of the trial is to determine the time to viral clearance in 29 days. The open-label, randomizsd, controlled trial intends to enrol approximately 50 pateints in the US [21] [22] .

As at April 2020, clinical development for treatment of COVID-2019 infections was underway in Middle East [12] .

Results from clinical studies in COVID-2019 infections in China released in April 2020 were generally positive, with mild side effects experienced in some patients. Earlier, in March 2020, the drug was approved for clinical development in COVID-2019 infections, in China. Updated results were released by Zhejiang Hisun Pharmaceutical in June 2020 [23] [12] .

In September 2020, FUJIFILM Toyama Chemical announced that the phase III trialmet its primary endpoint in which favipiravir significantly reduced time to negative conversion of detectable SARS-CoV 2 viral RNA. Treatment with favipiravir also alleviated symptoms related to the viral infection like reduction in body temperature, improvement in oxygen saturation and lesions in chest images. In March 2020, FUJIFILM Toyama Chemical initiated the phase III trial to assess the safety and efficacy of favipiravir, for the treatment of patients with non-severe pneumonia associated with COVID-2019 infections. The prospective, randomised, trial intends to enrol 156 patients in Japan [24] [25] [26] [27] .

As of March 2020, Zhejiang Hisun Pharmaceutical conducted a clinical trial in collaboration with Third People's Hospital of Shenzhen in 80 patients with COVID-2019 infections and results were released [28] [29] .

As of March 2020, Zhejiang Hisun Pharmaceutical conducted a clinical trial in collaboration with Zhongnan Hospital in 120 patients with COVID-2019 infections and results were released [28] [30] .

Influenza virus infection (oral formulation)

In March 2014, Toyama Chemical announced that favipiravir (Avigan® tablet 200mg) had been approved in Japan for the treatment of influenza virus infections. The product can only be made available at the request of the government during an influenza outbreak [31] .

In July 2015, FUJIFILM Holdings Corporation revealed that the Taiwanese Centres for Disease Control (CDC) has decided to import and stockpile favipiravir, prior to grating approval for the manufacturing and marketing of the drug in Taiwan. The Taiwanese CDC has commissioned Standard Chemical & Pharmaceutical Company to import favipiravir [4] .

Toyama Chemical initiated phase III development of favipiravir in Japan in October 2009. The trail in Japan was an international joint trial that involved samples in Taiwan [32] [4] . The company, in June 2010, completed a phase II study that evaluated the safety and efficacy of two doses of favipiravir, in subjects with influenza virus infection (JapicCTI080505). The study was initiated in January 2008 in Japan [33] .

In February 2015, MDVI, in collaboration with MediVector, completed a phase III trial that evaluated the safety and efficacy of favipiravir in adult patients with uncomplicated influenza (FAVOR Flu; T705US317; U1111-1147-8470; NCT02008344). The randomised, double-blind, placebo-controlled trial was initiated in December 2013. The United States Department of Defense's BioDefense Therapeutics reported that the first patient had been enrolled in the US in January 2014 [34] . Enrolment of a total of 1161 patients was completed in February 2015 in the US, Argentina, Brazil, Canada, Colombia, Dominican Republic, El Salvador, Guatemala, Mexico, Peru and Puerto Rico [35] [36] [37] .

In March 2015, FUJIFILM Pharmaceuticals completed a phase III trial that assessed the safety and efficacy of favipiravir in adult patients with uncomplicated influenza (FAVOR; T705US316; EudraCT 2013-002149-13; NCT02026349). The randomised, double-blind, placebo-controlled trial was initiated in January 2014 and enrolled 860 patients in the US, Australia, Belgium, Bulgaria, Hungary, the Netherlands, New Zealand, Poland, Russia, South Africa, Spain, Sweden, Turkey and Ukraine [35] [38] .

A multi-national, randomised, double-blind, placebo-controlled phase II trial of favipiravir was completed in May 2012 (T705aUS204; NCT01068912). The trial, which was initiated in February 2010 by Toyama Chemical, assessed the safety and efficacy of two dosing regimens of favipiravir in patients aged 55 to 80 years who had uncomplicated influenza. A total of 530 patients were recruited in the US, Chile, Paraguay, Peru, South Africa, Australia and New Zealand. Favipiravir demonstrated a significantly rapid clearance of virus, compared with placebo; the compound was also well tolerated and no adverse events were reported [35] [32] [39] . However, as of August 2015, no recent reports of development for favipiravir have been identified in Chile and Paraguay.

Results of a phase II trial showed that twice daily dosing of favipiravir demonstrated statistically significant decreases in time to alleviation of influenza symptoms. Based on these positive top-line results, MediVector plans to initiate phase III studies in November 2013 [5] .

In February 2013, FUJIFILM Pharmaceuticals completed the phase I/II trial that evaluated the safety and pharmacokinetics of different regimens of favipiravir in healthy volunteers and in patients with uncomplicated influenza (NCT01728753). The randomised, double-blind, placebo-controlled trial enrolled 550 participants in the US [40] .

Favipiravir has undergone phase I development in the US for the treatment of influenza [41] [42] . In March 2013, FUJIFILM Pharmaceuticals USA completed a phase I trial to determine the pharmacokinetics of favipiravir (T705aUS109; NCT01419457). The open-label, parallel-assignment, multiple dose trial enrolled 36 healthy volunteers and patients with hepatic impairment, in the US by invitation. Toyama Chemical initiated the trial in August 2011 [43] .

Preclinical studies in mice have demonstrated the efficacy of oral favipiravir [44] .

Influenza virus infection (injection formulation)

FUJIFILM, Zhejiang Hisun Pharmaceutical, the China-Japan Friendship Clinic and the National Engineering Research Center for the Emergency Drug signed a memorandum in October 2018 and are planning to develop injection formulation of favipiravir for serious influenza infections in China [45] .

Ebola virus infection

In April 2016, Institut National de la Santé Et de la Recherche Médicale initiated the phase II FORCE trial to assess the safety, tolerance and efficacy of favipiravir high dose in male survivour of Ebola virus disease (EVD) with Ebola virus (EBOV) RNA, in semen (C15-101; NCT02739477). The dose-escalation, open-label, single-group trial will enrol approximately 18 patients in Guinea [46] .

In December 2014, the French Institut National de la Santé Et de la Recherche Médicale (INSERM) initiated the phase I JIKI trial to assess the efficacy of favipiravir in patients with Ebola virus disease (C14-63; NCT02329054). Mortality assessed at day 14 is the defined primary endpoint of the trial. The open-label trial is expected to enrol approximately 225 patients in Guinea [47] . INSERM conducted the trial with funding from the EU. Interim efficacy and safety results were released by FUJIFILM in March 2015 [48] .

MediVector, under a contract with Medical Countermeasure Systems and BioDefense Therapeutics of United States Department of Defense, plans to submit an IND application to the FDA for supporting clinical trials in Africa. The trials are designed to evaluate the safety and antiviral activity of favipiravir against Ebola virus infections [49] .

In October 2014, FUJIFILM announced that the National Agency for Medicines and Health Products Safety (ANSM) has reported that favipiravir in combination with another unapproved drug was successfully used to treat an Ebola infected patient in France. The company also reported that it has supplied the drug to the University Hospital Frankfurt for the treatment of another patient in Germany. FUJIFILM also stated that the Government of France and Guinea are planning a medium scale clinical trial to evaluate the efficacy of favipiravir for the treatment of Ebola virus infections; and the company intends to supply the drug for these trials [50] [51] . Later in the same month, FUJIFILM announced that the company intended to initiate production of the drug, for supply in clinical trials [52] .

BioDefense Therapeutics reported in January 2014 that it is testing the efficacy of favipiravir against the Ebola virus, as well as other viruses considered threats to service members [34] .

Viral infections

In February 2018, Toyama Chemical initiated a phase III trial to evaluate the efficacy and safety of favipiravir against ixodid tick-borne infectious disease, severe fever with thrombocytopenia syndrome (SFTS) (JapicCTI183872). The open label trial intends to enrol patients in Japan [53] [54] .

In preclinical models, favipiravir was demonstrated to be efficacious against severe fever with thrombocytopenia syndrome [53] .

Financing Information

In June 2020, Appili Therapeutics announced closing of public Offering of $US15,525,000 and concurrent private placement of $US1,440,000. The net proceeds of the offering will be used primarily towards funding research and development activities for the clinical trial sponsored by the Company evaluating FUJIFILM Toyama Chemical's drug favipiravir against COVID-19. Proceeds are also intends to fund development costs for the company’s other product candidates, including the metronidazole [see Adis Insight Drug profile800050757], ATI-2307 [see Adis Insight drug profile800023157] antifungal program, the ATI-1701[see Adis Insight Drug profile800051100] tularemia vaccine program, and the antibiotic ATI-1503 program [see Adis Insight Drug profile800045182], as well as for working capital and general corporate purposes [55] [56] .

Labelling information

Favipiravir label in Japan mentions that the drug should be contraindicated for women who are pregnant or may possibly be pregnant, and in women of childbearing potential and men whose partner is of childbearing potential should be advised to use contraception. The label also indicates to have a precautionary statement about the early-embryo toxicity and teratogenicity of favipiravir to be provided in the WARNING section of the package insert [57] .

Patent Information

Favipiravir is protected by an US patent, an European patent number EP 1 112 743, a Chinese patent number ZL 99 809 897 3 and a Japanese patent number JP 3 453 362.

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Tablet, unspecified
  • Class Amides, Antivirals, Pyrazines, Small molecules
  • Target RNA; RNA replicase
  • Mechanism of Action RNA inhibitors; RNA replicase inhibitors
  • WHO ATC code

    J05A (Direct acting antivirals)

  • EPhMRA code

    J5B (Antivirals, excluding anti-HIV products)

    J5B4 (Influenza antivirals)

  • Chemical name 6-fluoro-3-hydroxypyrazine-2-carboxamide
  • Molecular formula C5 H4 F N3 O2
  • SMILES N1C(=CNC(C=1C(=O)N)=O)F
  • Chemical Structure
  • CAS Registry Number 259793-96-9

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

influenza A virus infections

Outcome Measure

DEAD/H-box helicase 11

1

influenza B virus infections

Outcome Measure

DEAD/H-box helicase 11

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Favipiravir - FUJIFILM Toyama Chemical DEAD/H-box helicase 11 Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
COVID 2019 infections - - Marketed China PO / unspecified Zhejiang Hisun Pharmaceutical 29 Jun 2020
COVID 2019 infections mild to moderate - Marketed India, Saudi Arabia, United Arab Emirates PO / Tablet Zhejiang Hisun Pharmaceutical 19 Aug 2020
COVID 2019 infections - - Registered Russia PO / Tablet Zhejiang Hisun Pharmaceutical 30 Jul 2020
COVID 2019 infections - - Phase III United Kingdom PO / unspecified FUJIFILM Holdings Corporation 01 May 2020
COVID 2019 infections - - Phase III Japan PO / Tablet FUJIFILM Holdings Corporation 31 Mar 2020
COVID 2019 infections favipiravir as adjunctive therapy to supportive care Adjunctive treatment Phase III Kuwait PO / Tablet Dr Reddys Laboratories 20 Aug 2020
COVID 2019 infections - Adjunctive treatment Phase II USA PO / Tablet FujiFilm Pharmaceuticals USA 09 Apr 2020
COVID 2019 infections - Prevention Phase II USA PO / unspecified Appili Therapeutics 11 Aug 2020
COVID 2019 infections - - Clinical Phase Unknown Turkey PO / Tablet Zhejiang Hisun Pharmaceutical 25 Mar 2020
COVID 2019 infections - - Clinical Phase Unknown Middle East PO / unspecified FUJIFILM Holdings Corporation 07 Apr 2020
Ebola virus infections - - Phase II Guinea PO / Tablet Institut national de la sante et de la recherche medicale 01 Apr 2016
Ebola virus infections - - No development reported (Research) USA PO / Tablet BioDefense Therapeutics 28 Feb 2018
Influenza virus infections - - Registered Japan PO / Tablet FUJIFILM Toyama Chemical 24 Mar 2014
Influenza virus infections - - Phase III Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Colombia, Dominican Republic, El Salvador, Guatemala, Hungary, Mexico, Netherlands, New Zealand, Peru, Poland, Puerto Rico, Russia, South Africa, Spain, Sweden, Turkey, USA, Ukraine PO / Tablet BioDefense Therapeutics, MediVector, FujiFilm Pharmaceuticals USA 01 Dec 2013
Influenza virus infections - - Phase III Taiwan PO / Tablet FUJIFILM Holdings Corporation, FUJIFILM Toyama Chemical 31 Jan 2010
Influenza virus infections - - No development reported (II) Chile, Paraguay PO / Tablet Toyama Chemical 27 Aug 2015
Viral infections severe febrile thrombocytopenia syndrome - Phase III Japan PO / unspecified FUJIFILM Toyama Chemical 23 Feb 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Toyama Chemical Originator Japan
FUJIFILM Toyama Chemical Owner Japan
Global Response Aid Market Licensee India, Middle East
Standard Chemical & Pharmaceutical Company Market Licensee Taiwan
Zhejiang Hisun Pharmaceutical Licensee China
MediVector Licensee World
Dr Reddys Laboratories Licensee India, Middle East
MDVI Collaborator
INSERM Collaborator France
BioDefense Therapeutics Collaborator USA
United States Department of Defense Collaborator USA
Institut national de la sante et de la recherche medicale Collaborator France
Appili Therapeutics Collaborator Canada
FujiFilm Pharmaceuticals USA Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Avigan FUJIFILM Holdings Corporation, FUJIFILM Toyama Chemical Ebola virus infections, Influenza virus infections Japan

Scientific Summary

Adverse Events

Phase I

Administration of 200mg of favipiravir was generally safe and well tolerated and did not indicate and treatment-related adverse events during the phase I JIKI trial in patients with Ebola virus disease. The interim results were reported from the first 80 patients treated in the trial [48] .

Preclinical

Favipiravir exhibited low in vitro cytotoxicity. CC50 (50% cell-inhibitory concentration) was > 1000 µg/ml in MDCK, Vero, HEL and L-132 cells [61] .

Favipiravir (30-300mg/kg body weight) was well tolerated at all dose levels in a mouse model of influenza. There was no evidence of toxicity and weight gain in the majority of mice. Favipiravir was tolerated at doses up to 1200mg/kg [44] .

Clinical:

In a clinical trial in patients with COVID-2019 infections, the rate of adverse reaction in favipiravir-treated patients was 11.43% and in dontrol group treated with lopinavir/ritonavir was 55.56% [23] [28] [29] .

In a phase III trial conducted in COVID-2019 patients with non-severe pneumonia (n=156), favipiravir was safe and well tolerated. There were no safety signals were identified in the trial [25] [27] .

Pharmacodynamics

Summary

Favipiravir was significantly more effective than oseltamivir for treatment of influenza in a murine model. In this study, oral treatment with T 705 100 mg/kg/day for 5 days completely prevented death in mice previously challenged with a high dose of influenza A/PR/8/34 (3 × 104 plaque-forming units). In comparison the survival rate with oseltamivir treatment was < 100%. The therapeutic effect of favipiravir was evident even when therapy was not initiated until 25h post-infection [61] .

Preclinical data from a mouse model showed that favipiravir had an inhibitory effect against four strains of H5N1 influenza. Dosages ranging from 30-300mg/kg body weight prevented death, reduced the decline of arterial oxygen saturation (Sa02), and inhibited lung consolidation and lung virus titres. When favipiravir (300mg/kg body weight) was administered four times daily, treatment could be delayed 96h post-exposure and still inhibit infection. Favipiravir administered once daily 60h after virus exposure prevented death and the decline of Sa02 [44] .

Favipiravir 30 mg/kg/day provided complete protection from death against Punta Toro virus and limited viral burden and liver disease in mouse and hamster infection models. A dose of 50 mg/kg/day treated Pichinde infection and limited viral replication and disease severity. Against bunyaviruses (La Cross, Punta Toro, Rift Valley Fever, Sandfly Fever) the 50% effective concentration was 30 mg/mL. Against the arenaviruses (Junin, Pichinde, Tacaribe) the 50% effective concentration was 0.7-1.2 mg.mL. Favipiravir was also found to be more active than ribavirin in cell based assays and in vivo [60] .

Results from a study in a Pichinde virus (PICV) hamster infection model showed that both favipiravir and ribavirin offered significant protection when given as late as day 6 of infection. However, the hamsters that received ribavirin lost significantly more weight and those that recovered did so at a much slower rate than those that received favipiravir. When treatment was started at day 5, favipiravir was found to be more effective than ribavirin (equitoxic doses), but comparable when started on day 6 [58] .

Favipiravir was efficacious in the treatment of yellow fever virus disease in hamsters, although a much higher dose (~20-fold) was required as compared with T 1106. Activity was observed in Vero cells with an EC90 of 418 ± 28 µM (SI > 9.6), which was lower than the EC90 for T 1106 of 677 µm (SI > 5.9). No significant improvement in disease parameters was seen with the oral administration 100 mg/(kg d) of favipiravir, although a trend towards improvement was observed. However, treatment of hamsters with 400 mg/(kg d) of favipiravir was shown to be effective in significantly improving survival, serum ALT and AST levels, and weight change when treatment was started at two days post-virus inoculation (dp). Significant improvement of survival was also seen with this dose of favipiravir, beginning as late as 3 dpi [59] .

Superior activity was seen when favipiravir or T 1106 were combined with ribavirin for the treatment of yellow fever virus. A synergistic effect was seen in cell culture when T 1106 or favipiravir was combined with ribavarin. Treatment of hamsters with a combination of T 1106 or favipiravir and ribavarin was superior to monotherapies [59] .

Antimicrobial Activity

Summary

Favipiravir exhibited potent in vitro activity against influenza virus in a plaque reduction assay. In this study, the compound had activity against influenza A, B and C types, including neuraminidase inhibitor-resistant virus; IC50 values were 0.02-0.6 µg/ml. The activity of favipiravir was demonstrated to be virucidal [61] .

Therapeutic Trials

The phase III trial met its primary endpoint in which favipiravir significantly reduced time to negative conversion of detectable SARS-CoV 2 viral RNA in COVID-2019 infection patients with non-severe pneumonia. The median time to negative conversion of detectable SARS-CoV 2 viral RNA (a marker of recovery) in favipiravir treated patients were 11.9 days compared with 14.7 days (2.8 days earlier, on average) for the placebo group [p value = 0.0136; adjusted HR: 1.593 (95% confidence interval of 1.024 – 2.479)]. A statistically significant percentage of the patients in the group receiving favipiravir had a rapid reduction in viral loads. Favipiravir also alleviated symptoms related to the viral infection like reduction in body temperature, improvement in oxygen saturation and lesions in chest images. The data were reported from 156 patients. Analysis therby showed patients had a statistically significant higher probability to recover when administered favipiravir compared with the patients not receiving the drug [24] [25] [27] .

In a clinical trial in patients with COVID-2019 infections, significant clinical differences were observed between the 35-patient experimental group treated with favipiravir and the 45-patient control group treated with lopinavir/ritonavir. The medians of the virus clearance time were 4 days (2.5 ~ 9 days) and 11 days (8 ~ 13 days), respectively (P < 0.001); the posttreatment fever-allaying rates within 2 days were 72.41% versus 26.30%; while the chest-imaging improvement rates were 91.43% versus 62.22% [28] [29] .

Results from a clinical trial in patients with COVID-2019 infections demonstrated that effectiveness was better in the patients treated with favipiravir than control group patients treated with abidole and was 71.43% and 55.86%, respectively. The same effects were obderved for the average antipyretic and cough remission time [28] [30] .

Updated results from a clinical trial showed that 72.41% patients treated with favipiravir recovered in two days as compared with 26.30% patients treated with kaletra. Patients administered with favipiravir tested negative for COVID-2019 after four days as compared relative to 11 days for patients in the kaletra group. Chest imaging showed an improvement rate in 91.43% patients treated with favipiravir versus 62.22% treated with kaletra. Favipiravir-treated patients had a higher clinical recovery rate at the end of the treatment (71.43%), comparing with 55.86% in the control group. The auxiliary oxygen therapy or noninvasive mechanical ventilation rate was 8.16% in the favipiravir group and 17.12% in the arbidol group. Coughing symptoms improved within 4.57 days, 1.41 days shorter than Arbidol-treated patients. Earlier reported results from 320 evaluable patients undergoing clinical development showed that patients administered with favipiravir tested negative for COVID-2019 around four days after testing positive for the virus, relative to 11 days for patients bereft of the drug. X-ray studies also revealed that 90% or more patients who were administered favipiravir, experienced improvements in lung condition, as opposed to 62% patients, devoid of the drug [23] [12] .

Results from a clinical trial under the national COVID-19 treatment protocol demonstrated rapid decrease in the rate of ICU admissions and intubation. The overall ICU patient admission rate in the country was reduced by half and that for patients under 60 years old dropped from nearly 20% to 6.6%, with a significant decline in the intubation rate. The percentage of patients requiring ICU admission diminished from 24% to 12% and the percentage intubated fell from 77% to 66%. The pneumonia rate gradually declined and in Ankara dropped from 12.1% to 5.61% [9] [10] .

Treatment with 200mg favipiravir indicated 15% mortality in patients with high or moderate viral load, compared with 30% mortality observed in patients who received basic standard of care, during the phase I JIKI trial in patients with Ebola virus disease. Favipiravir did not indicate reduction of mortality in patients with a very high viral load at the beginning of treatment, 81% of whom had refractory renal failure. The interim results were reported from the first 80 patients treated in the trial [48] .

Future Events

Expected Date Event Type Description Updated
15 Oct 2020 Regulatory Status FUJIFILM Toyama Chemical announces intention to submit sNDA to the Ministry of Health, Labour and Welfare for COVID-2019 infections in Early October 2020 [25] 24 Sep 2020
30 Sep 2020 Trial Update Appili Therapeutics plans a phase III trial in COVID-2019 infections in USA in fall of 2020 [19] 15 Sep 2020
31 Jul 2020 Trial Update FUJIFILM Corporation plans a phase II trial for COVID-2019 infections in USA (700320863) (NCT04346628) 05 Aug 2020
30 Jun 2020 Trial Update Zhejiang Hisun Pharmaceutical plans a phase III trial for COVID-19 infections in China, Germany, Romania, in June 2020 (NCT04425460) 06 Jul 2020

Development History

Event Date Update Type Comment
23 Sep 2020 Regulatory Status FUJIFILM Toyama Chemical announces intention to submit sNDA to the Ministry of Health, Labour and Welfare for COVID-2019 infections in Early October 2020 [25] Updated 24 Sep 2020
23 Sep 2020 Scientific Update Efficacy and adverse events data from a phase III trial in COVID-2019 infections released by FUJIFILM Toyama Chemical [25] [24] Updated 24 Sep 2020
14 Sep 2020 Regulatory Status Appili Therapeutics submits a new protocol to the US FDA for its open IND application in COVID-2019 infections [19] Updated 15 Sep 2020
14 Sep 2020 Regulatory Status Appili Therapeutics submits IND application in COVID-2019 infections before September 2020 [19] Updated 15 Sep 2020
11 Sep 2020 Trial Update Appili Therapeutics plans a phase III trial in COVID-2019 infections in USA in fall of 2020 [19] Updated 15 Sep 2020
26 Aug 2020 Scientific Update Efficacy data from a clinical trial in COVID-2019 infections released by Zhejiang Hisun Pharmaceutical [9] [10] Updated 31 Aug 2020
20 Aug 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections (Adjunctive treatment) in Kuwait (PO) (NCT04529499) Updated 02 Sep 2020
19 Aug 2020 Phase Change - Marketed Launched for COVID-2019 infections in India (PO) [8] Updated 27 Aug 2020
11 Aug 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections (Prevention) in USA (PO) Updated 18 Aug 2020
11 Aug 2020 Regulatory Status US FDA approves IND application for favipiravir in COVID-2019 infections (Prevention) [15] Updated 12 Aug 2020
05 Aug 2020 Trial Update Zhejiang Hisun Pharmaceutical plans a clinical trial in COVID-2019 infections in Italy [6] Updated 05 Aug 2020
30 Jul 2020 Phase Change - Marketed Launched for COVID-2019 infections in Saudi Arabia (PO) before July 2020, United Arab Emirates (PO) before July 2020 [6] Updated 05 Aug 2020
30 Jul 2020 Phase Change - Registered Registered for COVID-2019 infections in Russia (PO) before July 2020, India (PO) before July 2020 [6] Updated 05 Aug 2020
30 Jul 2020 Regulatory Status Italian Medicines Agency (AIFA) approves tests on efficacy of favipiravir in COVID-2019 infections before July 2020 [6] Updated 05 Aug 2020
12 Jul 2020 Trial Update Stanford University initiates a phase II trial in COVID-2019 infections (Adjunctive treatment) in USA (PO) (NCT04346628) Updated 05 Aug 2020
30 Jun 2020 Licensing Status Dr Reddy’s Laboratories and Global Response Aid in-licenses favipiravir from FUJIFILM to develop, manufacture and market in India, the Middle East, and other regions outside Japan [2] Updated 03 Jul 2020
30 Jun 2020 Scientific Update Updated efficacy data from a clinical trial in COVID-2019 infections released by Zhejiang Hisun Pharmaceutical [23] Updated 03 Jul 2020
29 Jun 2020 Regulatory Status The Japanese government recommends use of favipiravir for COVID-2019 infections [7] Updated 12 Oct 2020
29 Jun 2020 Phase Change - Marketed Launched for COVID-2019 infections in China (PO) [7] Updated 05 Jul 2020
17 Jun 2020 Trial Update Zhejiang Hisun Pharmaceutical plans a phase III trial for COVID-19 infections in China, Germany, Romania, in June 2020 (NCT04425460) Updated 06 Jul 2020
21 May 2020 Regulatory Status Health Canada approves clinical trial application for a planned phase II trial in COVID-2019 infections (PO) [16] Updated 28 May 2020
21 May 2020 Trial Update Appili Therapeutics plans the phase II CONTROL-COVID trial for COVID-2019 infections (Prevention) in Canada (PO) [16] (NCT04448119) Updated 28 May 2020
11 May 2020 Regulatory Status Appili Therapeutics files CTA application with the Health Canada for COVID-2019 infections (Prevention) [17] Updated 13 May 2020
01 May 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections in United Kingdom (PO) (EudraCT2020-001449-38) Updated 14 May 2020
15 Apr 2020 Trial Update FUJIFILM Corporation plans a phase II trial for COVID-2019 infections in USA (NCT04346628) Updated 05 Aug 2020
09 Apr 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections in USA (PO) [21] (NCT04358549) Updated 28 Apr 2020
07 Apr 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections in Middle East (PO) [12] Updated 13 Apr 2020
07 Apr 2020 Scientific Update Efficacy data from a clinical trial in COVID-2019 infections released by Zhejiang Hisun Pharmaceutical [12] Updated 13 Apr 2020
07 Apr 2020 Trial Update Fujifilm plans clinical development in Russia in COVID-2019 infections [12] Updated 13 Apr 2020
31 Mar 2020 Phase Change - III Phase-III clinical trials in COVID-2019 infections in Japan (PO) [26] Updated 03 Apr 2020
25 Mar 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections in Turkey (PO) [9] Updated 31 Aug 2020
19 Mar 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections in China (PO) prior to March 2020 [28] Updated 26 Mar 2020
19 Mar 2020 Scientific Update Safety and efficacy data from clinical trials in COVID-2019 infection released by Zhejiang Hisun Pharmaceutical [28] Updated 26 Mar 2020
19 Mar 2020 Trial Update Zhejiang Hisun Pharmaceutical initiates a clinical trial for COVID-2019 infections in China (PO) before March 2019 [28] Updated 26 Mar 2020
15 Mar 2020 Regulatory Status China approves favipravir for clinical development in COVID-2019 infections [12] Updated 13 Apr 2020
26 Oct 2018 Licensing Status FUJIFILM Corporation, Zhejiang Hisun Pharmaceutical, the China-Japan Friendship Clinic and the National Engineering Research Center for the Emergency Drug signed memorandum on clinical development of favipiravir injection in China [45] Updated 05 Nov 2018
01 Oct 2018 Company Involvement FUJIFILM RI Pharma has merged with Toyama Chemical to form FUJIFILM Toyama Chemical Updated 29 Oct 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
28 Feb 2018 Phase Change - No development reported No recent reports of development identified for research development in Ebola-virus-infections in USA (PO, Tablet) Updated 28 Feb 2018
23 Feb 2018 Phase Change - III Phase-III clinical trials in Viral infections in Japan (PO) (JapicCTI183872) Updated 27 Feb 2018
28 Jan 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Ebola-virus-infections in Guinea (PO, Tablet) Updated 28 Jan 2018
22 Jun 2016 Licensing Status Zhejiang Hisun Pharmaceutical in-licenses patent from FUJIFILM to develop, manufacture and market favipiravir in China [3] Updated 27 Jun 2016
24 May 2016 Regulatory Status Favipiravir is available in Japan at the request of the government during an influenza outbreak Updated 12 Oct 2020
15 Apr 2016 Trial Update Institut National de la Santé Et de la Recherche Médicale plans the phase II FORCE trial for Ebola virus infections in France and Guinea (PO) (NCT02739477) Updated 20 Apr 2016
01 Apr 2016 Phase Change - II Phase-II clinical trials in Ebola virus infections in Guinea (PO) (NCT02739477) Updated 27 Feb 2018
27 Aug 2015 Phase Change - No development reported(II) No recent reports of development identified - Phase-II for Influenza virus infections in Paraguay and Chile (PO) Updated 27 Aug 2015
12 Mar 2015 Scientific Update Interim efficacy and safety results from the phase I JIKI trial in Ebola virus disease released by FUJIFILM Holdings [48] Updated 09 Apr 2015
01 Mar 2015 Trial Update MediVector completes a phase III trial in Influenza virus infections in USA, Australia, Belgium, Bulgaria, Hungary, Netherlands, New Zealand, Poland, Russia, South Africa, Spain, Sweden, Turkey and Ukraine (NCT02026349) Updated 25 Aug 2015
17 Feb 2015 Trial Update MediVector completes enrolment in its phase III trial for Influenza virus infections in USA, Argentina, Brazil, Canada, Colombia, Dominican Republic, El Salvador, Guatemala, Mexico, Peru and Puerto Rico (9174852; NCT02008344) Updated 19 Feb 2015
17 Feb 2015 Trial Update MediVector completes enrolment in its phase III trial for Influenza virus infections in USA, Australia, Belgium, Bulgaria, Hungary, Netherlands, New Zealand, Poland, Russia, South Africa, Spain, Sweden, Turkey and Ukraine (9174852; NCT02026349; EudraCT2013-002149-13) Updated 19 Feb 2015
01 Feb 2015 Trial Update MediVector completes a phase III trial in Influenza in USA, Argentina, Brazil, Canada, Columbia, Dominican Republic, El Salvador, Guatemala, Mexico, Peru and Puerto Rico (NCT02008344) Updated 12 Mar 2015
01 Dec 2014 Phase Change - I Phase-I clinical trials in Ebola virus infections in Guinea (PO) (NCT02329054) Updated 09 Apr 2015
06 Oct 2014 Scientific Update FujiFilm supplies favipiravir as an emergency measure for two patients with Ebola [50] Updated 22 Oct 2014
24 Mar 2014 Phase Change - Registered Registered for Influenza virus infections in Japan (PO) - first global approval Updated 26 Mar 2014
04 Mar 2014 Regulatory Status Favpiravir label in Japan carries a warning for potential teratogenicity and contraindication in pregnant women [57] Updated 17 Apr 2020
07 Jan 2014 Phase Change Early research in Ebola virus infections in USA (PO) Updated 09 Jan 2014
01 Dec 2013 Phase Change - III Phase-III clinical trials in Influenza virus infections in Argentina, Brazil, Colombia, Dominican Republic, El Salvador, Guatemala, Mexico and Peru (PO) (NCT02008344) after December 2013 Updated 19 Feb 2015
01 Dec 2013 Phase Change - III Phase-III clinical trials in Influenza virus infections in Canada and Puerto Rico (PO) (NCT02008344) after December 2013 Updated 15 Oct 2014
01 Dec 2013 Phase Change - III Phase-III clinical trials in Influenza virus infections in USA (PO) (NCT02008344) Updated 09 Jan 2014
15 Nov 2013 Active Status Review Favipiravir is still in preregistration in Japan and phase II development in USA Updated 15 Nov 2013
29 Aug 2013 Phase Change - III Phase-III clinical trials in Influenza virus infections in Belgium, Poland, Russia, Spain, Turkey, Ukraine, Australia, New Zealand and South Africa (PO) (NCT02026349; EudraCT2013-002149-13) after August 2013 Updated 19 Feb 2015
29 Aug 2013 Phase Change - III Phase-III clinical trials in Influenza virus infections in Bulgaria, Hungary, Netherlands and Sweden (PO) (EudraCT2013-002149-13) Updated 09 Jan 2014
19 Mar 2013 Trial Update FujiFilm Pharmaceuticals completes a phase I trial in Influenza infections in the US (NCT01419457) Updated 11 Apr 2013
07 Feb 2013 Trial Update FujiFilm Pharmaceuticals completes the phase I/II FAVOR trial for Influenza virus infections in USA (NCT01728753) Updated 14 Mar 2013
30 Nov 2012 Trial Update FujiFilm Pharmaceuticals initiates the phase I/II FAVOR trial for Influenza virus infections in USA (NCT01728753) Updated 15 Jan 2013
01 May 2012 Trial Update Toyama Chemical completes a phase II trial in Influenza virus infections in countries worldwide (NCT01068912) Updated 29 May 2012
10 Aug 2011 Trial Update Toyama Chemical initiates enrolment by invitation in a phase I trial in Influenza virus infections in US (NCT01419457) Updated 31 Aug 2011
08 Jul 2011 Trial Update Toyama Chemical re-initiates enrolment in its phase II trial for Influenza virus infections in USA, Chile, Paraguay, Peru, South Africa, Australia and New Zealand (NCT01068912) Updated 18 Jul 2011
05 May 2011 Trial Update Toyama Chemical completes enrolment in its phase II trial for Influenza virus infections in USA, Chile, Paraguay, Peru, South Africa, Australia and New Zealand (NCT01068912) Updated 19 May 2011
01 Apr 2011 Phase Change - Preregistration Preregistration for Influenza virus infections in Japan (PO) Updated 29 Apr 2011
02 Jun 2010 Trial Update Toyama Chemical completes a phase II trial in Influenza virus infections in Japan (JapicCTI080505) Updated 28 Jun 2016
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in Australia (PO) Updated 29 Apr 2011
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in Chile (PO) Updated 29 Apr 2011
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in New Zealand (PO) Updated 29 Apr 2011
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in Paraguay (PO) Updated 29 Apr 2011
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in Peru (PO) Updated 29 Apr 2011
23 Mar 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in South Africa (PO) Updated 29 Apr 2011
23 Feb 2010 Phase Change - II Phase-II clinical trials in Influenza virus infections in USA (PO) Updated 26 Feb 2010
31 Jan 2010 Active Status Review Phase-I development is ongoing USA Updated 24 Feb 2010
29 Oct 2009 Phase Change - III Phase-III clinical trials in Influenza virus infections in Taiwan (PO) Updated 24 Jul 2015
29 Oct 2009 Phase Change - III Phase-III clinical trials in Influenza virus infections in Japan (PO) Updated 24 Feb 2010
01 Jul 2008 Company Involvement Toyama Chemical has been acquired by FUJIFILM Holdings Corporation Updated 14 Jul 2008
17 Apr 2008 Scientific Update Preclinical pharmacodynamics data presented at the 21st International Conference on Antiviral Research (ICAR-2008) [58] , [59] Updated 28 Apr 2008
08 Jan 2008 Phase Change - II Phase-II clinical trials in Influenza virus infections in Japan (PO) (JapicCTI080505) Updated 29 Jan 2008
04 May 2007 Scientific Update Preclinical data added to the adverse events and Viral Infections pharmacodynamics sections [44] Updated 04 May 2007
03 May 2007 Scientific Update Data presented at the 20th International Conference on Antiviral Research (ICAR-2007) added to the Viral Infections pharmacodynamics section [60] Updated 18 Sep 2007
09 Mar 2007 Phase Change - I Phase-I clinical trials in Influenza virus infections in USA (PO) Updated 23 Mar 2007
24 Jan 2007 Phase Change - I Phase-I clinical trials in Influenza virus infections in Japan (PO) Updated 30 Jan 2007
17 Jan 2007 Regulatory Status Toyama Chemical files an IND with the FDA in the US for influenza virus infections Updated 30 Jan 2007
26 Sep 2000 Phase Change - Preclinical Preclinical development for Influenza virus infections in Japan (PO) Updated 26 Sep 2000

References

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    Media Release
  2. Fujifilm partners with Dr. Reddy's and Global Response Aid for deployment of a COVID-19 treatment drug outside of Japan.

    Media Release
  3. Fujifilm signs a patent license agreement on its anti-influenza drug Avigan Tablet* with China's major pharmaceutical company Zhejiang Hisun Pharmaceutical.

    Media Release
  4. Taiwan's government organization decides to stockpile Fujifilm's anti-influenza drug ##8220##Avigan(R) Tablet##8221##. Fujifilm supplies Avigan(R) Tablet to Taiwan.

    Media Release
  5. DoD's BioDefense Therapeutics Announces Positive Results for Flu Treatment Drug.

    Media Release
  6. Hisun's Favipiravir continuously supports the Middle East's endeavor in fighting COVID-19.

    Media Release
  7. Zhejiang Hisun Pharmaceutical Co., Ltd.: Free of COVID-19, Governments Suggest Favipiravir.

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  8. Dr. Reddy's Laboratories announces the launch of AVIGAN(R)(Favipiravir) in India.

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  25. Anti-influenza drug Avigan(Rm) Tablet Meets Primary Endpoint in Phase III Clinical Trial in Japan for COVID-19 patients.

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  26. Fujifilm announces the start of a phase III clinical trial of influenza antiviral drug ##8220##Avigan Tablet##8221## on COVID-19 and commits to increasing production.

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  38. A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Favipiravir in Adult Subjects With Uncomplicated Influenza (T705US316)

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    ctiprofile
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    Media Release
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    Media Release
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    Media Release
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