Contents

Molnupiravir – the first antiviral pill for early COVID-19

Molnupiravir (also known as Lagevrio, MK-4482, formerly EIDD-2801) is a drug under development by the pharmaceutical companies Merck and Ridgeback Biotherapeutics. Molnupiravir works by mimicking a molecule needed by a coronavirus enzyme (called RNA polymerase). When molnupiravir is incorporated into a copy of SARS-CoV-2 it causes the resulting virus to be defective. As a result, cells infected with SARS-CoV-2 (the virus that causes COVID-19) produce copies of this virus that are not functional.

Antiviral therapies that are currently authorized for use against SARS-CoV-2 must be given via intravenous infusion. This is cumbersome and time consuming. It also requires the help of healthcare personnel. Molnupiravir’s advantage is that it can be taken in pill form.

The Move-Out study

Merck conducted a randomized, double-blind, placebo-controlled study of molnupiravir in 1,433 adults with mild-to-moderate COVID-19. This study was called Move-Out. None of the participants were hospitalized when they entered the study. Molnupiravir was taken at a dose of 800 mg every 12 hours for five consecutive days. The study took place in many countries, including Canada. Merck has released preliminary information in a press release about the study.

Results

Molnupiravir reduced the risk of hospitalization or death by about 30% over the course of one month after people started taking it. The proportions of participants who were hospitalized or died in the study were as follows:

  • molnupiravir – 6.8% (48 of 709 people)
  • placebo – 9.7% (68 of 699 people)

One of the participants who received molnupiravir died, while nine deaths occurred among people who received placebo.

Safety

As in earlier clinical trials, molnupiravir was generally well tolerated. Adverse events that were related to the study drug or placebo were distributed as follows:

  • molnupiravir – 12%
  • placebo – 11%

Molnupiravir was effective in participants with a range of variants of SARS-CoV-2, including the following:

  • gamma (P.1)
  • delta (B.1.617.2)
  • mu (B.1.621, B.1.621.1)

As molnupiravir works against an essential viral enzyme, there is no reason why it should not work against the major variants of SARS-CoV-2.

An independent data monitoring committee performed an interim analysis while the study was ongoing and determined that molnupiravir was clearly more effective than placebo. The committee then recommended that further recruitment be halted because of these positive results.

Regulatory agencies

Merck is in discussion with regulatory agencies in many countries and regions. It has submitted a dossier on the drug, seeking authorization for molnupiravir for the treatment of mild-to-moderate COVID-19 in at least Canada, the European Union, and the U.S. 

Why the excitement?

There has been a lot of media coverage about the results of the Move-Out study. Although clinical trials of antibody therapy (such as sotrovimab and Regen-CoV) have found that they are highly effective, molnupiravir appears to be somewhat less effective (to be fair, no clinical trial has directly compared molnupiravir against antibody therapy). Yet, there is excitement in medical circles about the looming authorization of molnupiravir because its advantage over currently authorized treatments is that it comes in pill form. This means that, in theory, it should be easier for people to access and take compared to antibody therapies that require an intravenous infusion and the assistance of healthcare personnel. Like other antivirals, molnupiravir works best against SARS-CoV-2 when used early in the course of disease caused by this virus.

Severity of illness is important

Merck has licensed some companies in India to make generic copies of molnupiravir so it can be sold to people in low- and middle-income countries. The Indian pharmaceutical companies Aurobindo Pharma and MSN Laboratories conducted a clinical trial of generic molnupiravir in people with COVID-19 who had moderate symptoms of disease. It did not work.

Merck notes these companies defined “moderate” differently than Merck did. Merck used a definition of “moderate” COVID-19 defined by the U.S. Food and Drug Administration (FDA). Patients in the generic study were sicker than those in Merck’s Move-Out study; they had lower levels of oxygen in their blood, suggestive of severe lung injury. If such a trial had been conducted in the U.S., the patients would likely have been classed as “severely” ill with COVID-19.

Molnupiravir is not meant for people who are severely ill with COVID-19. Indeed, Merck previously halted a clinical trial of molnupiravir in the U.S. in people with COVID-19 who required hospitalization. In the latter stages of COVID-19, inflammation causes serious complications. Drugs with potent anti-inflammatory activity are likely better candidates for consideration in clinical trials of people in late-stage COVID-19.

Mutation spotlight

Molnupiravir works by mimicking a natural molecule used by an enzyme needed by SARS-CoV-2-infected cells. As molnupiravir fools the viral enzyme RNA polymerase into using it rather than a normal molecule there are concerns that it could, in theory, interfere with human RNA molecules used by healthy cells, perhaps leading to an increased risk for mutations in cells. However, healthy cells have multiple mechanisms to screen for and correct potential mutations in their genetic material. Also, according to scientists associated with the development of molnupiravir, tests conducted so far have not found any increased risk for mutations in either healthy human cells or in animals exposed to very high doses of the drug for prolonged periods. However, Merck needs to make public the data that it has accumulated on molnupiravir’s potential effect on healthy cells in people. Merck also needs to provide guidance to physicians about the safety of molnupiravir during pregnancy.

Understanding treatment failure

As mentioned earlier, in the Move-Out study the proportions of participants who required hospitalization or died were distributed as follows:

  • molnupiravir – 6.8% (48 of 709 people)
  • placebo – 9.7% (68 of 699 people)

Merck needs to do an analysis of what happened to those 6.8% of people who deteriorated despite having received molnupiravir. There may be at least two reasons for treatment failure:

  • the severity of their underlying conditions
  • the development of SARS-CoV-2 that is resistant to molnupiravir

Uncovering the reasons for deterioration in people who received molnupiravir could help inform the deployment of this drug in the future.

Bear in mind

Molnupiravir is a very promising drug. However, it is just one drug (monotherapy). In the case of other viral infections such as HIV and hepatitis C, combination therapy is routinely used. Therefore, it is possible that molnupiravir may be more effective when combined with other oral drugs that show promise against SARS-CoV-2 infection, such as Paxlovid (mentioned later in this issue of TreatmentUpdate). However, laboratory experiments with cells and then, if these are encouraging, experiments with animals will first be necessary. Once such experiments reveal the preliminary safety of potential combinations, regulatory agencies can then consider applications for studies of combination therapy for SARS-CoV-2 in people. Laboratory experiments could also explore the effect of molnupiravir in combination with the antidepressant fluvoxamine (Luvox). Reports about fluvoxamine appear later in this issue of TreatmentUpdate.

Given the favourable publicity about molnupiravir’s effectiveness and ease of use, it is likely that demand for this drug will be high in many countries. Merck has committed to making millions of doses of the drug in the short-term. However, given the high demand, it is possible that shortages of molnupiravir may occur over the next several months. It is therefore likely that access to molnupiravir will be rationed during this time.

—Sean R. Hosein

REFERENCES:

  1. Merck. Merck and Ridgeback’s investigational oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50 percent compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of phase 3 study. Press release. 1 October 2021.
  2. Sing S, Kumar Mitra A, Arora N. Two Indian drug makers to end trials of generic Merck pill for moderate COVID-19. Reuters. 8 October 2021.
  3. Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nature Structural and Molecular Biology. 2021 Sep;28(9):740-746.
  4. Gordon CJ, Tchesnokov EP, Schinazi RF, et al. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. Journal of Biological Chemistry. 2021 Jul;297(1):100770.
  5. 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 Mar 1;65(5):e02428-20. 
  6. Painter GR, Natchus MG, Cohen O, et al. Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19. Current Opinion in Virology. 2021 Oct; 50:17-22.
  7. Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021 Mar;591(7850):451-457. 
  8. 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.
  9. Agostini ML, Pruijssers AJ, Chappell JD, et al. Small-molecule antiviral β-d-N4-Hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. Journal of Virology. 2019 Nov 26;93(24):e01348-19.
  10. Merck. Merck Canada initiates rolling submission to Health Canada for molnupiravir, an investigational oral therapeutic agent for the treatment of COVID-19. Press release. 13 August 2021.
  11. Merck. Merck and Ridgeback announce initiation of a rolling review by the European Medicines Agency for molnupiravir, an investigational oral antiviral medicine, for the treatment of COVID-19 in adults. Press release. 25 October 2021.
  12. Austin D. Why do placebos work? Scientists identify key brain pathway. Science. 27 October 2021
  13. Merck and Ridgeback Biotherapeutics Provide Update on Results from MOVe-OUT Study of Molnupiravir, an Investigational Oral Antiviral Medicine, in At Risk Adults With Mild-to-Moderate COVID-19. Press Release. 26 November 2021.