|Other names||MK-4482, EIDD-2801|
|Chemical and physical data|
|Molar mass||329.309 g·mol−1|
|3D model (JSmol)|
Molnupiravir (development codes MK-4482 and EIDD-2801) is an experimental antiviral drug. It is orally active. It was developed to treat influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication.
The drug was developed at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop the drug further.
Mechanism of action
Molnupiravir inhibits viral RNA-dependent RNA polymerase, or more precisely, promotes mutations in that enzyme's actions. It is metabolized into a ribonucleoside analog that resembles cytidine, β-D-N 4-Hydroxycytidine 5′-triphosphate (also called EIDD-1931 5′-triphosphate or NHC-TP). During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine.
Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other of which mimics uridine (U). NHC-TP is not recognized as an error by the virus' proofreading exonuclease enzymes, which can replace mutated nucleases with corrected versions. When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U. This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis.
The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.
In the first step, acetone is used as a protecting group to render two of the three hydroxy groups of uridine unreactive to treatment with the acid anhydride of isobutyric acid, which converts the third hydroxy group to its ester. Treatment with 1,2,3-triazole and phosphoryl chloride produces a reactive intermediate in which the triazole portion can be replaced with hydroxylamine. Finally, removal of the protecting group using formic acid converts the material to molnupiravir.: 93–95
History of development
Molnupiravir was developed at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE). In 2014, DRIVE began a screening project funded by the Defense Threat Reduction Agency to find an antiviral drug targeting Venezuelan equine encephalitis virus (VEEV), which led to the discovery of EIDD-1931. When turned into the pro-drug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.
Richard Plemper, a professor at Georgia State University, was the principal investigator of a grant from the National Institutes of Health to explore use of molnupiravir against influenza. In late 2019, the National Institute of Allergy and Infectious Diseases approved moving molnupiravir into Phase I clinical trials for influenza.
In March 2020, the research team pivoted to studying SARS-CoV-2, and successfully used the drug to treat human cells infected with the novel coronavirus. Plemper's group published in the journal Nature Microbiology the first demonstration that molnupiravir is orally active against SARS-CoV-2 in an animal model and established proof-of-concept that treatment completely suppresses virus transmission to untreated contacts within 24 hours.
Alleged safety concern
In May 2020, Rick Bright filed a whistleblower complaint, alleging that the Trump administration ignored his early warnings about the COVID-19 pandemic, pressured him to inappropriately fast-track unproven drugs, and illegally retaliated against him by removing him from his role as head of the Biomedical Advanced Research and Development Authority (BARDA) in April 2020.
Among these complaints, Bright objected to providing additional federal funding to Ridgeback Biotherapeutics to further develop molnupiravir into a treatment for COVID-19. He argued that although the drug had shown potential against coronaviruses including SARS-CoV-2, it had already received substantial government support. Bright also wanted to see more safety data for molnupiravir before final sign-off, due to the fact that some other nucleoside analogue drugs had caused birth defects in animal studies.
COVID-19 clinical trial
In late July 2020, Merck, which had been partnering with Ridgeback Biotherapeutics on developing the drug, announced its intention to move molnupiravir to late stage trials beginning in September 2020. On October 19, 2020, Merck began a one-year Stage 2/3 trial that focused on hospitalized patients.
In October 2021, a preliminary clinical trial reported that treatment with molnupiravir reduced the risk of hospitalization and death from COVID-19 by about 50% for newly diagnosed, high-risk patients. The drug reportedly worked equally well against different SARS-CoV-2 variants, including delta, gamma, and mu. One of Merck's Phase 3 trial boards evaluating the drug's efficacy recommended early discontinuation of the trial because it had met a predetermined endpoint, and because placebo administration might no longer be ethical in light of the drug's substantial benefit to patients. An FDA monitoring board agreed.
Approval status and availability
In June 2021, the U.S. Department of Health and Human Services committed to buy US$1.2 billion worth of molnupiravir (approximately 1.7 million courses) from Merck if it received an emergency use authorization (EUA) or approval from the U.S. Food and Drug Administration (FDA).
On 1 October 2021, Merck stated that an independent advisory board that had been monitoring the COVID-19 clinical trial recommended that recruitment into the study be stopped early because of convincing evidence of the drug's benefits, reducing the risk of hospitalization or death by 48%. Merck announced plans to seek an EUA from the FDA, and to submit marketing applications to other global drug regulators. The company announced plans to license the drug to generic manufacturers, to accelerate its availability.
In addition to the United States, various other countries have reported interest in negotiating with Merck to procure stocks of molnupiravir pills, including Britain, South Korea, and Malaysia.
Molnupiravir is predicted to reach sales estimated at over $3 billion in 2022.
- Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. (October 2019). "Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia". Science Translational Medicine. 11 (515): eaax5866. doi:10.1126/scitranslmed.aax5866. PMC 6848974. PMID 31645453.
- Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK (April 2020). "Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model". Translational Research. 218: 16–28. doi:10.1016/j.trsl.2019.12.002. PMC 7568909. PMID 31945316.
- Aleccia J (September 29, 2021). "Daily pill to treat COVID could be just months away". ABC News. Kaiser Health News. Archived from the original on 2021-09-29. Retrieved 2021-09-29.
- Lowe, Derek (October 13, 2021). "Molnupiravir Mutations". www.science.org. Science Magazine. Retrieved 2021-10-13.
- Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NC, et al. (March 2021). "Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2". Antimicrobial Agents and Chemotherapy. 65 (5). doi:10.1128/AAC.02428-20. PMC 8092915. PMID 33649113.
- Amara A, Penchala SD, Else L, Hale C, FitzGerald R, Walker L, et al. (September 2021). "The development and validation of a novel LC-MS/MS method for the simultaneous quantification of Molnupiravir and its metabolite ß-d-N4-hydroxycytidine in human plasma and saliva". Journal of Pharmaceutical and Biomedical Analysis. 206: 114356. doi:10.1016/j.jpba.2021.114356. PMC 7611757. PMID 34509661. S2CID 237493842.
- Mole B (October 2021). "Meet molnupiravir, Merck's Thor-inspired pill that hammers COVID". Ars Technica. Retrieved 2 October 2021.
- Halford B. "An emerging antiviral takes aim at COVID-19". C&EN. Retrieved 2 October 2021.
- Malone B, Campbell EA (September 2021). "Molnupiravir: coding for catastrophe". Nature Structural & Molecular Biology. 28 (9): 706–708. doi:10.1038/s41594-021-00657-8. PMID 34518697.
- US application 20200276219, Painter, George R.; Bluemling, Gregory R. & Natchus, Michael G. et al., "N4-hydroxycytidine and derivatives and anti-viral uses related thereto", published 2020-09-03, assigned to Emory University
- Emerson L. "Oral Drug Tested at Georgia State Recommended for Emergency Use Authorization to Treat COVID-19 Oral Drug Tested at Georgia State Recommended for Emergency Use Authorization to Treat COVID-19". Institute for Biomedical Sciences Georgia State University. Retrieved 3 October 2021.
- Cox RM, Wolf JD, Plemper RK (January 2021). "Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets". Nature Microbiology. 6 (1): 11–18. doi:10.1038/s41564-020-00835-2. PMC 7755744. PMID 33273742.
- Stolberg SG (14 May 2020). "'Lives Were Lost' as Warnings Went Unheeded, Whistle-Blower Tells House". New York Times. Retrieved 2 October 2021.
- Cohen J, Piller C (13 May 2020). "Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug". Science. Archived from the original on 6 August 2020. Retrieved 1 August 2020.
- "Merck's Little Brown Pill Could Transform the Fight Against Covid". Bloomberg.com. 2021-03-25. Archived from the original on 2021-10-01. Retrieved 2021-10-01.
- Court E (31 July 2020). "Merck pushes ahead on COVID-19 treatment, vaccines". Archived from the original on 14 February 2021. Retrieved 31 July 2020.
- Clinical trial number NCT04575584 for "Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)" at ClinicalTrials.gov First posted October 5, 2020; Update posted September 9, 2021
- Clinical trial number NCT04575597 for "Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)" at ClinicalTrials.gov
- Herper M (1 October 2021). "Merck's antiviral pill reduces hospitalization of Covid patients, a possible game-changer for treatment". STAT. Retrieved 2 October 2021.
- "Merck's experimental pill to treat covid-19 cuts risk of hospitalization and death in half, the pharmaceutical company reports". Washington Post. Retrieved 3 October 2021.
- Weintraub K. "New antiviral is highly effective, study finds, and is stirring hope that COVID-19 could be treated by a pill". USA TODAY. Retrieved 3 October 2021.
- "Biden Administration to Invest $3 Billion from American Rescue Plan as Part of COVID-19 Antiviral Development Strategy". U.S. Department of Health & Human Services (Press release). 2021-06-17. Archived from the original on 2021-06-17. Retrieved 2021-06-17.
- "Biden Administration announces U.S. government procurement of Merck's investigational antiviral medicine for COVID-19 treatment" (Press release). U.S. Department of Health & Human Services. June 9, 2021. Archived from the original on October 1, 2021. Retrieved October 1, 2021.
- Zimmer C (2021-06-17). "A Pill to Treat Covid-19? The U.S. Is Betting on It". The New York Times. ISSN 0362-4331. Archived from the original on 2021-06-17. Retrieved 2021-06-17.
- Robbins R (1 October 2021). "Merck says a trial shows it has produced the first effective antiviral pill for Covid". The New York Times. Archived from the original on 1 October 2021. Retrieved 1 October 2021.
- "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). Merck. 1 October 2021. Archived from the original on 1 October 2021. Retrieved 1 October 2021.
- Taylor C (1 October 2021). "Merck to seek emergency authorization for oral Covid treatment after 'compelling results' in trials". CNBC. Archived from the original on 1 October 2021. Retrieved 1 October 2021.
- Beasley D (29 September 2021). "Merck says research shows its COVID-19 pill works against variants". Reuters. Archived from the original on 2021-10-01. Retrieved 2021-10-01.
- Alexa Phillips, COVID-19: UK shows interest in antiviral pill molnupiravir after trial shows it could halve hospitalisations and deaths, Sky News (October 2, 2021).
- Korea is negotiating to advance purchase oral antiviral COVID-19 drug, The Dong-a Ilbo (October 4, 2021).
- "Malaysia in talks to procure Merck's Covid-19 pills". The Straits Times. Singapore Press Holdings. 2 October 2021. Archived from the original on 2 October 2021. Retrieved 3 October 2021.
- Lowrey T (2021-10-04). "Why the federal government has bought 300,000 doses of a COVID-treating pill that hasn't been approved yet". ABC News. Retrieved 2021-10-04.
- Kerr-Lazenby, Mina (11 October 2021). "Covid-19: Pharmac signs deal for experimental treatment pill molnupiravir". Stuff. Archived from the original on 11 October 2021. Retrieved 11 October 2021.
- Conover D (1 October 2021). "Merck's COVID Treatment Posts Strong Data". Morningstar, Inc. Morning Star.