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Favipiravir
Favipiravir (also known as Avigan or favilavir; development code: T-705) is an antiviral agent against a wide array of RNA viruses, jointly developed by Professor Kimiyasu Shiraki of the Faculty of Medicine at University of Toyama and Toyama Chemical Co., Ltd. (now Fujifilm Toyama Chemical, a subsidiary of Fujifilm)[1]. It was approved for medical use in Japan in January 2014[1], and was also approved in Japan for stockpiling against influenza pandemics. Fujifilm Toyama Chemical licensed API for it to Zhejiang Hisun Pharmaceutical Co., Ltd., allowing the company to produce it in the People’s Republic of China[2]. In 2019, the patent of the compound of this agent expired, and it became a generic drug that other manufacturers could produce[2].

Overview
Like other experimental antiviral drugs (such as T-1105 and T-1106), favipiravir is a pyrazinamide derivative. In addition, it has shown activity against influenza virus, West Nile virus, yellow fever virus, foot-and-mouth disease virus and other various viruses.[3] Activity against enteroviruses[4] and Rift Valley fever virus has also been demonstrated.[5] The drug has shown limited efficacy against Zika virus in animal studies but was less efficacious than other antivirals such as MK-608.[6] The agent has also shown some efficacy against rabies,[7] and has been used experimentally in some humans infected with the virus.[8]

Good absorption of oral administration, with high bioavailability. The bioavailability of a person’s single oral administration of 400 mg is greater than 90%. It reaches the maximum plasma concentrations within 0.5-1.0h. The serum protein binding ratio is 53.4 to 54.4%, with quick distribution in all body tissues including the respiratory system. The main target organs are hematopoietic tissue, liver, and testis. There is no obvious gender difference in the dynamic changes of drug levels of favipiravir in the human body’s plasma.
 * Absorption and distribution

Favipiravir is not metabolized by CYP-450, but mainly by aldehyde oxidase (AO) to M1 in human liver cytoplasm, and partly by xanthine oxidase (XO). Favipiravir can also be glucuronidated to M2, with M1 and M2 as the main inactivated metabolites. Through nucleoside monophosphate, favipiravir is converted to M4. M4 and favipiravir’s ribose conjugate M3 can be mutually converted to each other by kinases, and M3 can be converted into this medicine through desoxyribose. M4 can be further phosphorylated to M5 and M6. M6 (T705-RTP) is the active metabolite of favipiravir.
 * Metabolism

Favipiravir is mainly excreted by hydrogenation in the urine, with very minimal excretion of the prototype drug, and a small proportion of bile excretion. It is not known whether favipiravir is excreted in human breast milk, but it has shown breast milk excretion in rats. This product may be present in semen.
 * Excretion

Influenza Virus
A Phase III clinical study of favipiravir on the treatment of influenza by Fujifilm Holdings Corporation has shown that favipiravir is not inferior to oseltamivir in East Asian patients with influenza. It was an active controlled, double-blind, and placebo-controlled study conducted in 153 centers in Japan, Taiwan, and South Korea, recruiting 750 patients, 640 of whom was included in the primary efficacy endpoint analysis, where 306 subjects were in the favipiravir group and 334 subjects in the oseltamivir group. The study was aimed at evaluating the efficacy and safety of favipiravir in treating patients with influenza virus. The results indicated that favipiravir is not inferior to oseltamivir.

On December 11, 2019, the results of the Phase I study of the favipiravir treatment project for severe influenza initiated by CAP-China were published in the Journal of Infectious Diseases, an official journal of the Infectious Diseases Society of America (IDSA), which reported for the first time the exploratory results of the efficacy of using favipiravir and oseltamivir to treat severe influenza. The research was completed by the team led by Professor Cao Bin at China-Japan Friendship Hospital.

The results have shown that:


 * The viral clearance rate of the combination therapy with oseltamivir and favipiravir is significantly higher than that of oseltamivir monotherapy.
 * Compared with oseltamivir monotherapy, the combination therapy with oseltamivir and favipiravir can increase the clinical improvement rate in adults with influenza.
 * Compared with oseltamivir monotherapy, the combination therapy with oseltamivir and favipiravir can significantly reduce the virus positive rate in the body from the second day of the treatment.
 * Compared with oseltamivir monotherapy, the combination therapy with oseltamivir and favipiravir can significantly reduce the virus positive rate in the body from the second day of the treatment.
 * Compared with oseltamivir monotherapy, the combination therapy with oseltamivir and favipiravir can significantly reduce the virus positive rate in the body from the second day of the treatment.

Ebola Virus
Favipiravir may have efficacy against Ebola based on studies in mouse models, but efficacy in humans remains unaddressed.[9][10][11] During the 2014 West Africa Ebola virus outbreak, a French nurse who contracted Ebola while volunteering for MSF in Liberia reportedly recovered after receiving a course of favipiravir.[12] A JIKI clinical trial began in Guinea in December 2014.[13] Preliminary results showed a decrease in mortality in patients with low-to-moderate levels of virus in blood, but no effect on patients with high levels (the group at a higher risk of death).[14] But this does not mean that favipiravir is not beneficial to patients with high viral load, and further research is also needed to have a clear conclusion. During the research, despite the large dose of favipiravir (6,000 mg for adults on the first day, 2,400 mg per day from the next day), the patients showed good tolerance to favipiravir, and none of them discontinued because of intolerance. And their biochemical indicators returned to normal after treatment. These findings indicate that the dosage and course of favipiravir can be twice or even higher than that for influenza.

Children with Ebola virus account for a considerable proportion (22%), and their total mortality rate (73.4%) is often higher than that of adults aged 15-44 (70.8%). Considering the urgent need to evaluate potential specific interventions against Ebola in children, and that favipiravir has shown antiviral activity against EBOV, with good safety and tolerance profile, and the tablets can be crushed and mixed into food or beverages, 12 children aged 1-6 years were also included in the research. Although the JIKI clinical trial has some limitations, the research on the treatment of severe infectious diseases such as EVD, especially the research data of medication in children, will provide valuable reference for future research and application.

COVID-19
A study on SARS-CoV-2 treatment found that favipiravir was only effective at relatively high concentrations, with remdesivir considered a preferable option, possibly in part due to the way SARS-CoV-2 replicates is different from other viruses. However, the antiviral concentration requirements and effects of in vitro tests cannot indicate how well the drugs work in vivo. Favipiravir is a prodrug that can be metabolized to its active form T705-RTP only after it enters the body.

Due to COVID-19, favipiravir was approved for sale rapidly in February 2020 in China. Data from clinical trials of favipiravir against COVID-19 was published by the Ministry of Science and Technology of the People’s Republic of China at a COVID-19 themed press conference on March 17, according to which, favipiravir has shown good clinical efficacy against the disease. And its tablet form also makes it easily accessible, which helps reduce the burden on medical resources by enabling non-critically ill patients to take the medicine at home. Once favipiravir was launched in the Chinese market, it was listed as one of the Major Anti-pandemic Materials by China’s State Council, and the Chinese government has unified the allocation of favipiravir supplies. Since the outbreak of COVID-19, in addition to satisfying the domestic treatment and strategic reserve demand, the medication has also been used to support over 30 countries in battling COVID-19 and achieved good results. All Favipiravir tablets in China are manufactured by Zhejiang Hisun Pharmaceutical Co., Ltd., who recently has been honored by the Chinese State Council as the “Ordnance Factory” responding to the COVID-19 crisis.

Related clinical trials for COVID-19
Favipiravir is currently undergoing global multicenter clinical trials in treating COVID-19. The clinical data published shows that favipiravir can clear the virus fast and alleviate the pneumonia symptom of COVID-19 patients with high tolerance and few adverse reactions. Notably, in all related studies, the dosage of favipiravir is higher and the duration of medication administration is longer than those recommended in the instructions. Dosage for first day is 3,200-3,600 mg and 1,200-1,600 mg for the following days, lasting for 7-14 days.

According to the favipiravir versus Kaletra trial findings of The Third People’s Hospital of Shenzhen, patients taking favipiravir recover faster than those taking Lopinavir/Ritonavir. And it took a shorter median time for the former (averaging 4 days, ranging from 2.5 to 9 days) than the latter (averaging 11 days, ranging from 8 to 13 days) to turn negative in tests, with a significant difference (P<0.001). The favipiravir group also showed significant improvement in chest imaging, with an improvement rate of 91.43% (32/35) versus 62.22% (28/45) of the control group (P = 0.004). The favipiravir treatment is an independent influencing factor for imaging improvement and virus clearing. In the meantime, patients in the favipiravir group have high tolerance and few adverse reactions.

Zhongnan Hospital of Wuhan University conducted a 240-patient multicenter, randomized, open, positive, parallel-controlled clinical study on the efficacy of favipiravir for novel coronavirus-infected pneumonia. The clinical test using Arbidol as control group found that the drug’s efficacy on treating patients in the favipiravir group was markedly better than that of the drug taken by those in the control group. For ordinary patients with COVID-19, 7 day’s clinical recovery rate was 55.86% in the Arbidol group and 71.43% in the favipiravir group (P=0.0199). The time for patients in the favipiravir group to recover from fever was notably shorter than that of the participants in the control group, with favipiravir-treated subjects recovering from fever within 2.5 days on average versus 4.2 days for other patients. Patients who took favipiravir were able to soothe their cough within an average of 4.57 days, compared with 5.98 days for those that did not take the drug. There were statistical differences between the two groups with regard to the above evaluation indexes. Analysis showed the rate of new dyspnea during the course of treatment in the Arbidol group was 11.67% (14/120) and that in the favipiravir group was 3.45% (4/116) (P=0.0174). For ordinary patients with COVID-19, the auxiliary oxygen therapy or noninvasive mechanical ventilation rate was 8.16% (8/98) in the favipiravir group and 17.12% (19/111) in the Arbidol group (P = 0.0541; 95% CI: -0.1781, -0.0009). For COVID-19 patients with hypertension and/or diabetes, the time of fever reduction and cough relief in the favipiravir group was also significantly shorter than that in the Arbidol group (P<0.0001). All these results indicate that favipiravir may effectively prevent progression to acute respiratory distress syndrome, shock and multiple organ failure in patients with moderate COVID-19 symptoms. Favipiravir is considered the first choice to treat ordinary COVID-19 patients who have never received antiviral therapy before, because it has higher 7 day’s clinical recovery rate and can reduce incidence of fever and cough more effectively.

Another preliminary report of research carried out at Fujita Medical University, Japan on a sample of 2,158 patients with COVID-19 showed that almost all favipiravir-treated patients’ symptoms were improved: 70% of the patients with mild to moderate symptoms and 40% of those with severe symptoms recovered after a 7-day antiviral treatment, and 60% of the patients with severe symptoms recovered after a 14-day antiviral treatment.

Favipiravir has also produced encouraging results in an early clinical trial in Russia. Early data from the study showed that 60 percent of the 40 patients from six medical centers took favipiravir tablets and tested negative for the virus after five days. It was noticed that patients in the favipiravir group showed a faster improvement in the general health and clinical condition, which may lead to earlier discharge from hospital and reduce the burden on medical facilities by 30-40% in the near future. Thanks to the administration of favipiravir, most patients are not infectious as early as the fifth day of treatment, which is critical to containing the pandemic and ensuring a swift return to normal life.

The first stage of the trials has already been completed. It lasted 10 days and involved 60 patients with coronavirus infection with moderate illness. Forty people received favipiravir treatment and the other 20 patients from the control group underwent standard therapy. Favipiravir demonstrated safety with no new or previously unreported side effects detected. The drug’s efficacy was above a threshold of 80%, which is the criterion for an antiviral drug with high antiviral activity. The body temperature of 68% of the patients taking favipiravir returned to normal earlier (on the third day) than in the control group (on the sixth day). On average, the complete elimination of the virus from the body as a result of favipiravir treatment occurred on the fourth day, while in the standard therapy group this process took nine days. Following the first four days of treatment, 65% of the 40 patients who took favipiravir tested negative for coronavirus, which is twice as many as in the standard therapy group. By day 10, the number of patients whose tests returned negative results reached 35 out of 40.

On May 21, the Ministry of Health of the Russian Federation approved the launch of the final stage, which will involve 330 patients compared with 60 during the initial stage. In total, 30 medical centers in nine Russian regions will conduct studies at the final stage. The clinical trial was expected to be completed by the end of May.

On May 31, the ministry published a new national drug catalogue which shows that favipiravir has become the first drug approved by the ministry to treat COVID-19.

On June 20, Glenmark Pharmaceuticals Ltd announced that it had received Indian regulatory approval, which was part of India’s accelerated approval process, to make and sell oral antiviral drug favipiravir for treating mild-to-moderate COVID-19 infections in the country. Favipiravir also became the first drug approved in India for the treatment of COVID-19.

Timeline
On August 18, 1999, the patent protecting substance of T-705 was obtained.

In March 2014, Avigan, developed by Fujifilm Holdings Corporation, was approved for sale in Japan as a drug for treating novel or re-emerging influenza virus infections. The Japanese government has a national stockpile of the drug.

On April 19, 2016, the Institute of Pharmacology and Toxicology of the China Academy of Military Medical Sciences gained the clinical approval for producing favipiravir tablets.

On July 11, 2016, Hisun signed a patent license agreement on Avigan with Toyama Chemical Co., Ltd. of Japan.

On March 25, 2017, Hisun signed a technical cooperation agreement with the Institute of Pharmacology and Toxicology of the China Academy of Military Medical Sciences.

Between June and July 2017, Hisun completed relevant research as per the current technical requirements, and it finished the process verification for API of favipiravir.

In November 2017, Hisun accomplished the process verification for favipiravir tablets, with 120,000 tablets per batch.

In February 2019, Hisun completed the fasting BE study on its favipiravir tablets, with the original ones manufactured by Toyama Chemical Co., Ltd. as the Reference Listed Drug. The results showed that the two pharmaceutical products were bioequivalent.

On December 11, 2019, the Journal of Infectious Diseases, an official journal of the Infectious Diseases Society of America (IDSA), reported for the first time the exploratory results of treating patients of severe influenza with a combination of favipiravir and oseltamivir.

On February 3, 2020, Hisun held a Class I meeting with the Center for Drug Evaluation (CDE) of NMPA to report the situation of favipiravir. The next day, Hisun submitted product application materials to the CDE, which were reviewed and approved quickly. On February 15, Zhang Xinmin, Director of the China National Center for Biotechnology Development under the MOST, introduced that preliminary results of taking favipiravir showed obvious efficacy and few adverse reactions and the rate of patients turned negative in viral nucleic acid tests in the favipiravir group was significantly higher than that of patients in the control group on the 3rd to 4th day after receiving treatment. On the same day, favipiravir was approved for sale in China, and Hisun was granted approval to start clinical trials of the drug. On February 16, favipiravir tablets developed by Hisun were put into production. At a press conference held by the Joint Prevention and Control Mechanism of the State Council on February 21, Xu Nanping, Vice Minister of the MOST, revealed that there were three drugs in clinical trials. With regard to favipiravir, 80 patients participated in a study on its efficacy in treating COVID-19 in Shenzhen, and the results observed were good. Experts suggested that more trials should be carried out to investigate favipiravir’s efficacy in curing COVID-19 patients.

On March 9, 2020, Turkey imported favipiravir from China and sent it to 40 of its cities for the treatment of COVID-19. On March 17, Zhang Xinmin said at a press conference of the joint prevention and control mechanism of the State Council of China that, the early clinical studies of favipiravir tablets had already been completed, and since the drug showed favorable clinical efficacy and no significant adverse reactions in the studies, it was recommended to include this drug in the diagnosis and treatment protocol as soon as possible. On March 24, a thank-you letter was received from the joint prevention and control mechanism of the State Council of China, in which Hisun was recognized as a well-deserved “Ordnance Factory” responding to the COVID-19 crisis. On March 28, Japanese Prime Minister Shinzo Abe announced that its government has officially designated Avigan as Japan’s standard treatment for COVID-19. On March 31, Fujifilm announced the initiation of a clinical trial of favipiravir for the treatment of COVID-19. Other countries like South Korea, Italy, Spain and France have also carried out related clinical trials.

On April 1, 2020, CCTV reported that Thomas Rabe, a professor at the University of Heidelberg’s medical school in Germany - the grandson of John Rabe, who was dubbed the “Schindler of China” - contacted the Ministry of Industry and Information Technology through the Chinese ambassador to Germany to get donated favipiravir tablets.

On April 2, 2020, the Japanese chemicals giant Denka Company Limited (Denka) announced that it would resume production of diethyl malonate, a key raw material for favipiravir, in response to the request of the Japanese government to establish a complete nationwide supply system for manufacturing favipiravir.

On April 9, 2020, Fujifilm announced the initiation of a U.S. Phase II clinical trial of favipiravir to treat patients with COVID-19 at Massachusetts General Hospital, Brigham and Women’s Hospital and the University of Massachusetts Medical School.

On April 17, 2020, The Third People’s Hospital of Shenzhen published a paper on clinical studies of treating COVID-19 with favipiravir in Engineering, a journal of the Chinese Academy of Engineering. According to the paper, the results showed that it took a significantly shorter median time for patients in the favipiravir group (4 days) than those in the control group (11 days) to turn negative in viral nucleic acid tests. And the favipiravir group also showed significant improvement in chest imaging, with an improvement rate of 91.43% (32/35) versus 62.22% of the control group.

On April 26, 2020, more than 2,000 patients in Japan were treated with favipiravir as part of clinical trials (data analysis will be completed at the end of this August).

On April 28, 2020, clinical trials for favipiravir were also conducted on treating COVID-19 patients in Russia; in the same month, Glenmark started its Phase III clinical trials for the antiviral drug favipiravir on COVID-19 patients.

On May 15, 2020, Hisun officially launched favipiravir for the market, which would be open for sale in its Tmall flagship store.

A Message from the Developer
A message from Dr. Kimiyasu Shiraki, the developer of favipiravir, vice president of Senri Kinran University in Japan and a professor emeritus at the University of Toyama (Faculty of Medicine):

Pandemic COVID-19, a new coronavirus infection, has caused high morbidity and mortality worldwide.

Favipiravir was originally developed in Japan, and Hisun was licensed to manufacture favipiravir by Fujifilm Toyama Chemical. Hisun’s favipiravir exhibits therapeutic efficacy to COVID-19 pneumonia in China. It is a memorable achievement that favipiravir has become the first confirmed therapeutic agent in the world for COVID-19.

Consequently it is wonderful to preserve the health and lives of people not only in China and Japan but also around the world. Congratulations on your success of favipiravir.