Molnupiravir monotherapy at the dose of given 800 mg orally, in a twice-daily dose has been studied in SARS-CoV-2 infected outpatients as well as hospitalized patients. It reduced the risk of hospitalization or death to nearly half in the outpatients with mild or moderate COVID-19 than the placebo patients, in a phase III study.

Abdelnabi et al. have demonstrated a marked activity of molnupiravir against SARS-CoV-2, with a micromolar activity in vitro and antiviral activity and reduced risk of transmission in several animal models. 

Favipiravirs antiviral activity is less well established, with an activity that ranges from 60 to ∼500 µM. Abdelnabi et al. have shown that the amalgamation of these two drugs at suboptimal doses is synergic, which causes a strong reduction of total viral load as well as an infectious virus when treatment is initiated before or very rapidly after infection. Further, this combination can also dramatically diminish the risk of infection to co-housed hamsters. 

These findings are crucial for clinical development as they propose that molnupiravir in a lower dose, along with favipiravir, can increase virus mutagenesis and carry the virus near to error catastrophe. 

Since these drugs are orally administered and remain undisturbed to mutations in the spike proteins, they could also be administered easily and dont demand rigid virological surveillance like monoclonal antibodies.

But before initiating any clinical studies for this combination, many questions need to be answered. In the experimental model of Abdelnabi et al., the synergy was achieved at doses where either drug had demonstrated antiviral activity. Currently, favipiravir still needs to demonstrate its antiviral activity in larger animal models or humans besides hamsters. The rapid metabolic activity in hamsters allows to test high doses of drugs, thus a critical point might be the complexity of favipiravir pharmacokinetics and higher doses may be needed in humans to achieve such antiviral activity. Pharmacokinetic models suggested the doses of 1600 mg BID to achieve such pertinent drug concentrations, which is much larger than the dose used in the clinical trials. Thus, pharmacokinetic and tolerance studies are a must to evaluate the potential of employing such high doses in humans. Safety will be the prime concern as this combination will primarily be utilized in patients without a highly symptomatic infection, in post-exposure prophylaxis or in the initial days that follow symptom onset.

The results of Abdenabi et al. can be implied to other RNA viruses as well. 

Undoubtedly, both favipiravir and molnupiravir have a pan viral activity, including influenza and hemorrhagic fever viruses. Their results could therefore be applied in other contexts as well, that lacks effective antiviral treatments.

Source- EBio Medicine, 2021;74(103663). DOI:https://doi.org/10.1016/j.ebiom.2021.103663