The promise of molnupiravir

Molnupiravir is an experimental antiviral drug under development to assess its effects in people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes symptoms called coronavirus disease 2019 (COVID-19). In this issue of TreatmentUpdate, we present some background information on this drug as well as its current developmental status.

Molnupiravir was discovered by scientists affiliated with Emory University in Atlanta. The drug is also known under the code names MK-4482 and EIDD-2801.

How it works

Here is a simplified explanation of how molnupiravir works. Molnupiravir is an analogue of a natural molecule called cytidine—a nucleoside. This means that molnupiravir is classified as a nucleoside analogue. Cells use cytidine to make strings of RNA. To a cell, molnupiravir looks like cytidine. When a cell makes RNA molecules and molnupiravir is present in high concentrations, cells mistakenly incorporate molnupiravir into RNA. This results in a defective string of RNA. As RNA is essential for making new copies of coronaviruses such as SARS-CoV-2, defective RNA means that the copies of the virus that the infected cell makes are defective or incomplete and cannot be used to infect other cells. Thus, production of new coronaviruses greatly slows or stops.

Many laboratories studying SARS-CoV-2 use animals such as Syrian hamsters (also known as Middle Eastern hamsters) and ferrets, as they are susceptible to infection with this virus. In lab experiments with hamsters and ferrets, molnupiravir is highly effective at preventing infection with SARS-CoV-2. Furthermore, the drug is also effective at reducing the amount of virus produced by infected animals if it is given shortly after infection.

In combination

The drug favipiravir is approved in Japan for the treatment of severe flu infections. It is sold under the brand name Avigan. On its own, favipiravir has modest antiviral activity against SARS-CoV-2. However, lab experiments with a combination of favipiravir and molnupiravir suggest that the combination has significantly greater antiviral activity than either drug alone in hamsters infected with SARS-CoV-2.

Safety

Over the past 25 years, the development of some experimental nucleoside analogues has been halted because they have caused injury to an important component of cells— mitochondria. This component functions as a power plant, producing the energy that cells need. When mitochondria are injured, cells do not receive enough energy and can malfunction or die.

Molnupiravir has been tested in lab experiments with human liver cells. Results of experiments in which these cells were exposed to the drug for up to 14 consecutive days found that molnupiravir does not harm cellular power plants. Long-term experiments are underway to assess the safety of this drug both in cells and in rats and dogs. Short-term data from animals are very promising in that no safety concerns were found. In particular, molnupiravir does not appear to cause mutations in healthy cells.

Clinical development

The pharmaceutical company Merck has taken over clinical development of molnupiravir. Data from a phase I clinical trial has been released. In this study, 65 healthy volunteers without COVID-19 took different doses of molnupiravir for up to five and a half days.

In this study, molnupiravir was found to be well absorbed and generally safe. The drug did not cause any serious side effects or death. Overall, molnupiravir seemed better tolerated than placebo, with moderate side effects such as headache and diarrhea reported by a minority of participants. One person who received molnupiravir at a very high dose developed temporary rash. The drug had no significant effect on laboratory analysis of blood and urine samples from participants. 

Molnupiravir’s absorption is not significantly reduced when it is taken with food.

Molnupiravir has entered phase II/III clinical trials. In these studies, the drug is given orally every 12 hours in different doses in capsules, as follows:

• 200 mg
• 400 mg
• 800 mg

A phase II study

At the recent Conference on Retroviruses and Opportunistic Infections (CROI), researcher Wendy Painter, MD, presented limited data from a placebo-controlled study of molnupiravir in people with COVID-19 who did not have any other conditions/infections.

All 75 participants were adults who had signs/symptoms of respiratory illness and tested positive for SARS-CoV-2 by PCR (polymerase chain reaction). Participants were randomly assigned to receive molnupiravir or placebo in a 2:1 ratio. Molnupiravir was taken in capsules at different doses twice daily for five days. Below are the pooled results of different doses of molnupiravir vs. placebo.

The proportions of participants who tested positive for SARS-CoV-2 on different days are as follows:

Day three

• molnupiravir – 20%
• placebo – 28%

Day five

• molnupiravir – 0%
• placebo – 24%

The results on day five with no detectable SARS-CoV-2 was seen with all doses of molnupiravir. The drug did not cause serious side effects. There were no details about non-serious side effects. These findings show that molnupiravir can quickly reduce the amount of SARS-CoV-2 relatively early in the course of COVID-19 in non-hospitalized people.

In development

Other clinical trials for molnupiravir have enrolled people who are ill with COVID-19, some of whom have been hospitalized. Studies are taking place in many countries, including the following:

• Canada (Toronto General Hospital)
• France
• Israel
• Philippines
• Russia
• Spain
• South Africa
• United Kingdom
• Ukraine

Merck is also investigating the potential for molnupiravir to interact with other medicines.

The clinical trials described above will be completed in a few months. If the studies confirm molnupiravir’s effectiveness and safety, it is highly likely that Merck will submit a dossier to regulatory authorities in the summer, first in the U.S. and subsequently the European Union and Canada, as it seeks approval for sale of the drug.

—Sean R. Hosein

REFERENCES:

1. Painter WP, Holman W, Bush JA, et al. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrobial Agents and Chemotherapy. 2021; in press.
2. Sticher ZM, Lu G, Mitchell DG, et al. Analysis of the potential for N4-hydroxycytidine to inhibit mitochondrial replication and function. Antimicrobial Agents and Chemotherapy. 2020 Jan 27;64(2):e01719-19.
3. Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021.
4. Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nature Microbiology. 2021 Jan;6(1):11-18.
5. Abdelnabi R, Foo CS, Kaptein SJF, et al. Molnupiravir (EIDD-2801) inhibits SARS-CoV-2 replication and enhances the efficacy of favipiravir in a Syrian hamster infection model. Submitted.
6. Painter W, Sheahan T, Baric R, et al. Reduction in infectious SARS-CoV-2 in a treatment study of COVID-19 with molnupiravir. In: Program and abstracts of the Conference on Retroviruses and Opportunistic Infections, 6 to 10 March 2021. Abstract 777.