COVID-2019 infections
Favipiravir launched in China, Saudi Arabia and UAE for the treatment of COVID-2019 infections [8] [9] .
In August 2020, Dr. Reddy's Laboratories launched AVIGAN® (Favipiravir) 200 mg tablets in India [10] . 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 [8] .
As of July 2020, favipiravir was approved in Russia in COVID-2019 infections [8] .
In December 2020, Dr. Reddy's laboratories, Global Response Aid, and Appili Therapeutics filed an application with Health Canada seeking approval for the use of favipiravir tablets for the treatment of COVID-2019 infections under Health Canada’s Interim Order Respecting the Importation, Sale and Advertising of drugs for use in relation to COVID-19. Dr. Reddy’s is working closely with Health Canada for an expedited review of the drug application. In September, the Interim Order Respecting the Importation, Sale and Advertising of Drugs for use in Relation to COVID-19 was signed by the Minister of Health in Canada to create a new authorization pathway that will help expedite the authorization of drugs and vaccines for COVID-19. According to Health Canada, favipiravir tablets are the first oral solid dosage form submitted under the interim order [11] .
As of July 2020, the Italian Medicines Agency (AIFA) approved the tests on efficacy of favipiravir for the treatment of coronavirus infections [8] .
In June 2020, Zhejiang Hisun Pharmaceutical reported that the Japanese government recommended use of favipiravir for the treatment of COVID-2019 infections [9] . In October 2020, FUJIFILM Toyama Chemical filed an application with the Ministry of Health, Labour and Welfare in Japan, for partial changes to manufacturing and marketing approval matters of favipiravir tablet (Avigan®), for the treatment of coronavirus (COVID-2019) infections. The filing seeks to add, indication, dosage and administration related to COVID-2019 to the existing manufacturing and marketing approval items of favipiravir. The application was filed based on the results of the phase III trial conducted in Japan in COVID-2019 patients with non-severe pneumonia [see below] [12] [13] .
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 [14] [15] .
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 [16] [17] .
Appili Therapeutics, in December 2020, initiated the phase III Post Exposure Prophylaxis for COVID-19 (PEPCO) trial for the prevention of COVID-2019 infection, in asymptomatic individuals with direct exposure (within 72 hours) to an infected person, in Canada. Earlier, in November 2020, Health Canada provided a No Objection Letter, whereas the US FDA accepted for review the company's submission for a protocol amendment. Approximately 1 156 volunteers are expected to be enrolled in the trial [18] [19] .
As at November 2020, Appili Therapeutics had initiated the phase III PRESECO study, that is designed to evaluate the safety and efficacy of favipiravir for the treatment of adults with mild to moderate symptoms of COVID-2019 infections (NCT04600895). Approximately 826 subjects are expected to be enrolled in the study. In December 2020, the company reported that the first patient was dosed in the trial [18] [19] [20] .
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 [21] .
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 [22] .
In September 2020, Appili Therapeutics initiated the phase II CONTROL-COVID trial to investigate the effectiveness of favipiravir as a preventative measure against COVID-19 outbreaks in long-term care (LTC) facilities (NCT04448119; CONTROL-COVID-Favipiravir-1). The primary outcome will be to control the outbreak, defined as no new microbiologically confirmed cases of COVID-19 infection for at least for 24 consecutive days up to day 40 after the start of prophylaxis. The cluster-randomized placebo-controlled trial intends to enroll approximately 760 participants in Canada and also plans to expand to the US. In October 2020, first cluster of participants were enrolled and dosed in the study [23] [24] . Earlier in August 2020, the US FDA approved the IND application of favipiravir, following which the therapy will be evaluated in a prophylactic phase II trial against COVID-2019 infections, in the US. 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 [25] [26] . Previously, 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 [27] .
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 2020 [28]
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 [8] [29]
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 [30] [31] .
As at April 2020, clinical development for treatment of COVID-2019 infections was underway in Middle East [17] .
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 [32] [17] .
In September 2020, FUJIFILM Toyama Chemical announced that the phase III trial met 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 randomised trial intends to enrol 156 patients in Japan [33] [34] [35] [13] .
As of October 2020, clinical trials for favipiravir in COVID-19 were ongoing in India [2] .
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 [36] [37] .
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 [36] [38] .
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 [39] . As of October 2020, the Japanese government has stockpiled favipiravir in preparation for the outbreak of the influenza virus infections [12] .
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 [6] .
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 [40] [6] . 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 [41] .
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 [42] . 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 [43] [44] [45] .
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 [43] [46] .
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 [43] [40] [47] . 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 [7] .
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 [48] .
Favipiravir has undergone phase I development in the US for the treatment of influenza [49] [50] . 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 [51] .
Preclinical studies in mice have demonstrated the efficacy of oral favipiravir [52] .
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 [53] .
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 [54] .
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 [55] . INSERM conducted the trial with funding from the EU. Interim efficacy and safety results were released by FUJIFILM in March 2015 [56] .
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 [57] .
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 [58] [59] . Later in the same month, FUJIFILM announced that the company intended to initiate production of the drug, for supply in clinical trials [60] .
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 [42] .
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 [61] [62] .
In preclinical models, favipiravir was demonstrated to be efficacious against severe fever with thrombocytopenia syndrome [61] .
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 [63] [64] .
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 [65] .
