Antiviral activity of favipiravir against Zika and SARS-CoV-2 in cynomolgus macaques

By Suchandrima BhowmikReviewed by Benedette Cuffari, M.Sc.Sep 4 2022

Favipiravir (T-705) inhibits viral ribonucleic acid (RNA) polymerase and has been approved for the treatment of noncomplicated influenza infections in Japan and is currently being studied in clinical trials in the United States. Previous studies have shown strong antiviral activity of T-705 against several RNA viruses, such as Ebola, Marburg, and Lassa viruses, both in vitro and in macaques. This has made the drug an important candidate against other emerging RNA viruses. 

Study: Antiviral efficacy of favipiravir against Zika and SARS-CoV-2 viruses in non-human primates. Image Credit: ruangrit junkong / Shutterstock.com

Background

T-705 has also been found to exhibit strong antiviral activity against the Zika virus (ZIKV). Moreover, its role as a drug candidate against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has also been evaluated.

Studies with hamster models have indicated that T-705 caused a greater reduction in clinical symptoms, as well as infectious viral titers in the lungs in vivo as compared to in vitro.

The antiviral efficacy of F-705 in these studies was found to be lower or comparable to those observed in human trials. However, the toxicity of the agent observed in some animals was difficult to translate to human doses.

Currently, T-705is being studied in more than 72 clinical trials in both hospitalized and ambulatory coronavirus disease 2019 (COVID-19) patients. Although few initial studies suggest the antiviral efficacy of T-705 in patients with mild to moderate COVID-19, most of these studies remain inconclusive.

A new Nature Communications study describes the results of three successive experiments in cynomolgus macaques to determine the antiviral efficacy of T-705 against ZIKV and SARS-CoV-2 infections.

About the study 

The current study involved a total of three experiments using cynomolgus macaques (Macaca fascicularis) that originated from Mauritian breeding centers and were between 44 and 86 months of age.

The first experiment assessed the pharmacokinetics of T-705 in four uninfected animals. These animals were administered a loading dose of 250 mg/kg twice a day (BID) on the first day through the intravenous route. The animals were subsequently administered a maintenance dose of 150 mg/kg BID subcutaneously for 14 days.

The second experiment involved 12 animals, six of which were administered a similar dosing regimen, while the other six remained untreated. However, three days post initiation of treatment, the animals were exposed to 10^6 plaque-forming units (pfu) of H/PF/13 SIKV through the subcutaneous route and followed up for 14 days.

Blood samples were then collected from the animals to determine the plasma concentrations of cytokines and T-705. Animals were euthanized between 14 to 16 days post-exposure (dpe).

The third experiment involved the evaluation of T-705 against SARS-CoV-2. The animals were divided into four groups, in which they received either a similar dose regimen, a larger maintenance dose of 180 mg/kg BID, a lower dose of 200 mg/kg BID, or were left untreated.

Exposure to 10^6 pfu of SARS-CoV-2 was completed two days post-treatment. Atropine was used for pre-medication, while medetomidine and ketamine were used for anesthesia. Animals were euthanized seven days post-exposure.

Data on body weight, respiration, food/water consumption, dehydration, oxygen saturation, heart rates, and rectal temperatures were collected from all animals in the three experiments at baseline and follow-up. Bronchoalveolar lavage (BAL) samples were obtained three and six days post-infection (dpi), whereas chest computed tomography (CT) images were obtained five dpi. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used for virus quantification of plasma, upper respiratory tract, and rectal samples.

Thereafter, the pharmacokinetics of T-705 was analyzed, followed by its impact on viral kinetic parameters. Finally, the in vitro assessment of favipiravir against SARS-CoV-2 was conducted through the use of the human airway epithelium MucilAirTM model (HAE).

Study findings

High levels of T-705 concentration were maintained over the 14-day follow-up period in the four animals of the first experiment. These values were also found to be more than the 50% effective concentrations (EC50) of T-705 against the ZIKV. 

In the second experiment, animals exposed to ZIKV and treated with T-705 showed lower viral loads as compared to untreated animals. The peak viral replication and overall viral shedding were also lower in treated animals as compared to untreated animals.

The levels of proinflammatory factors remained at high concentrations for treated animals from five to seven dpi. These animals also showed markers of hepatic cytolysis, increased uremia and lipidaemia, as well as slight cholestasis.

T-705 was not significantly effective in reducing SARS-CoV-2 viral titers, nor protecting epithelial integrity in the HAE model. Similar results were also observed in SARS-CoV-2-exposed cynomolgus macaques.

Additionally, larger viral loads were observed in treated animals, especially at larger doses. Treatment with T-705 caused 2.78%, 6.23%, 4.87%, and 6.44% weight loss in untreated, 100 mg, 150 mg, and 180 mg/kg BID groups infected with SARS-CoV-2, respectively.

Four of the 20 animals that were infected with SARS-CoV-2 and received 150 mg/kg and 180mg/kg BID were euthanized due to clinical score deterioration. These animals exhibited severe hypothermia, tachypnea, hypoxemia, bradycardia, lymphopenia, and hypotension neutrophilia.

These animals also exhibited increased levels of transaminases, impaired metabolism, increased levels of plasma triglycerides, as well as decreased levels of cholesterol and fructosamine. Acute interstitial pneumonia, high viral concentrations in the lungs, and high levels of cytokines were also observed in these animals.

Conclusions

The current study demonstrated the efficacy of T-705 against ZIKV; however, this treatment was not found to be suitable for the treatment of SARS-CoV-2 infection in the cynomolgus macaque model or the HAE system.