Molnupiravir

From Wikipedia, the free encyclopedia

Molnupiravir
MK-4482.svg
Clinical data
Trade namesLagevrio,[1][2] Molulife
Other namesMK-4482, EIDD-2801
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
  • UK: POM (Prescription only) [1][3]
  • US: ℞-only via emergency use authorization[4][5]
Identifiers
  • N-Hydroxy-5'-O-isobutyryl-3,4-dihydrocytidine
    [(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate (PIN)
CAS Number
  • 2349386-89-4 checkY
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H19N3O7
Molar mass329.309 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O
InChI
  • InChI=1S/C13H19N3O7/c1-6(2)12(19)22-5-7-9(17)10(18)11(23-7)16-4-3-8(15-21)14-13(16)20/h3-4,6-7,9-11,17-18,21H,5H2,1-2H3,(H,14,15,20)/t7-,9-,10-,11-/m1/s1 checkY
  • Key:HTNPEHXGEKVIHG-QCNRFFRDSA-N checkY

Molnupiravir, sold under the brand name Lagevrio among others, is an antiviral medication that inhibits the replication of certain RNA viruses. It is used to treat COVID-19 in those infected by SARS-CoV-2.[1]

Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine and exerts its antiviral action through introduction of copying errors during viral RNA replication.[6][7]

Molnupiravir was originally developed to treat influenza at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE), but was reportedly abandoned for mutagenicity concerns.[8][9] It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.[10]

Based on positive results in placebo-controlled double-blind randomized clinical trials,[11][12] Molnupiravir was approved for medical use in the United Kingdom in November 2021.[1][2][13][14] In December 2021, the U.S. Food and Drug Administration (FDA) granted an emergency use authorization (EUA) to molnupiravir for use in certain populations where other treatments are not feasible.[4]

Medical uses[]

Molnupiravir is indicated for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19.[1][4]

Contraindications[]

Use in pregnancy is not recommended. There are no human data on use during pregnancy to assess the risk of adverse maternal or fetal outcomes. Based on animal data, the drug may cause fetal harm. During organogenesis, embryofetal lethality and teratogenicity were observed in rats, and reduced fetal weight in rats and rabbits. Breastfeeding is not recommended during treatment due to potential adverse reactions in the infant. There are no data on the presence of the drug or its metabolites in human milk. It is not known whether it has an effect on the infant or on milk production. Use in patients under 18 years of age can affect bone and cartilage growth. In rats, bone and cartilage toxicity was observed after repeated dosing.[15]

Adverse effects[]

Adverse reactions observed in the phase III MOVe-OUT study included diarrhea (2%), nausea (1%) and dizziness (1%), all of which were mild or moderate.[15]

Overdose[]

The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status.[15]

Drug interactions[]

There are no known drug interactions, although based on limited data available.[15]

Mechanism of action[]

Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase.[16] It is metabolized into a ribonucleoside analog that resembles cytidine, β-D-N4-Hydroxycytidine 5′-triphosphate (also called EIDD-1931 5′-triphosphate or NHC-TP).[17][18][19] During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine.[19]

Molnupiravir metabolism.svg

Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other of which mimics uridine (U).[20] NHC-TP is not recognized as an error by the virus' proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions.[16] When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U.[20] This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis.[21]

Molnupiravir GC bonding.svg
Molnupiravir AU bonding.svg
Top, a G.molnupiravir base pair with three hydrogen bonds. Bottom, an A.molnupiravir base pair with two hydrogen bonds. Molnupiravir can mimic both C and U.[21] The wiggly lines stand for the connection to the pentose sugar and point in the direction of the minor groove.

Chemistry[]

The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.[22]

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 1,2,4-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.[22]: 93–95 

Molnupiravir synthesis.svg

Alternative patented routes to molnupiravir have been reviewed.[23]

History[]

Molnupiravir was developed at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE).[10] 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.[20] When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.[20]

The international nonproprietary name of the drug was inspired by that of Thor's hammer, Mjölnir. The idea is that the drug will strike down the virus, like a mighty blow from the god of thunder.[19]

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.[24] In late 2019, the National Institute of Allergy and Infectious Diseases approved moving molnupiravir into Phase I clinical trials for influenza.[20]

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.[20] 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.[25]

DRIVE then licensed molnupiravir for human clinical studies to Miami-based company Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop the drug further.[20][10]

The primary data supporting the U.S. Food and Drug Administration (FDA) emergency use authorization for molnupiravir are from MOVe-OUT, a randomized, double-blind, placebo-controlled clinical trial studying molnupiravir for the treatment of non-hospitalized participants with mild to moderate COVID-19 at high risk for progression to severe COVID-19 and/or hospitalization.[4] Participants were adults 18 years of age and older with a pre-specified chronic medical condition or at increased risk of SARS-CoV-2 infection for other reasons who had not received a COVID-19 vaccine.[4] The main outcome measured in the trial was the percentage of people who were hospitalized or died due to any cause during 29 days of follow-up.[4] Of the 709 people who received molnupiravir, 6.8% were hospitalized or died within this time period compared to 9.7% of the 699 people who received a placebo.[4] Of the people who received molnupiravir one died during the follow-up period compared to nine people who received placebo.[4]

Society and culture[]

Economics[]

In September 2021, Merck signed a voluntary licensing agreement with the Medicines Patent Pool (MPP) that allows MPP to sublicense molnupiravir and supply the COVID-19 oral medication to 105 low- and middle-income countries. The cost of the initial purchase made by the US government was about $712 per course of treatment, while treatment with generics in developing countries can cost as little as $20.[26][27]

Legal status[]

Merck submitted an EUA application to the FDA on 11 October, and the FDA's Antimicrobial Drugs Advisory Committee (AMDAC) at the Center for Drug Evaluation and Research met to discuss the EUA application on 30 November.[28][29] The committee narrowly voted, (13 for and 10 opposed), to recommend authorization for adults with mild to moderate illness who are at high risk of developing severe COVID-19.[30] Concerns were expressed over the low effectiveness of the drug in preventing death, which in the final trial was only 30%, as well as the increased mutation rate caused by the drug, which could theoretically worsen the global pandemic by driving the evolution of more dangerous variants.[30][31] In December 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for molnupiravir for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate.[4]

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of molnupiravir.[32]

On 4 November 2021, molnupiravir was approved in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of established infections of COVID-19.[1] The MHRA issued a conditional marketing authorization applicable in the United Kingdom, and an emergency use authorization for Northern Ireland.[1][2][33][34]

Australia purchased 300,000 courses.[35] In October 2021, the New Zealand pharmaceutical supplier Pharmac purchased 60,000 doses.[36]

In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir.[37][38]

Names[]

Molnupiravir is the international nonproprietary name (INN).[39]

Research[]

COVID-19 clinical trial[]

In October 2021, preliminary results from a clinical trial (MOVe-OUT)[40][41][full citation needed] indicate that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID-19.[42][43] The final analysis reported a 30% reduction in hospitalizations and deaths.[11][44]

The efficacy against hospitalization or death in unvaccinated adult outpatients with mild or moderate COVID-19 and at least one risk factor for disease progression is about 30% (95% CI, 1–51%).[15] The Merck and Dohme funded phase III MOVe-OUT study found that the risk of death was about 89% (14–99%) lower.[45]

References[]

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  2. ^ a b c "First oral antiviral for COVID-19, Lagevrio (molnupiravir), approved by MHRA" (Press release). Medicines and Healthcare products Regulatory Agency (MHRA). 4 November 2021.
  3. ^ "Regulatory approval of Lagevrio (molnupiravir)". Medicines and Healthcare products Regulatory Agency (MHRA). 4 November 2021. Retrieved 4 November 2021.
  4. ^ a b c d e f g h i "Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults". U.S. Food and Drug Administration (FDA) (Press release). 23 December 2021. Retrieved 23 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ https://www.fda.gov/media/155053/download
  6. ^ 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.
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  8. ^ "Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug".
  9. ^ Cully, Megan (2021). "A tale of two antiviral targets — and the COVID-19 drugs that bind them". Nature Reviews Drug Discovery. doi:10.1038/d41573-021-00202-8. PMID 34857884. S2CID 244851870.
  10. ^ a b c Aleccia J (29 September 2021). "Daily pill to treat COVID could be just months away". ABC News. Kaiser Health News. Archived from the original on 29 September 2021. Retrieved 29 September 2021.
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  12. ^ Singh, Awadhesh Kumar; Singh, Akriti; Singh, Ritu; Misra, Anoop (November 2021). "Molnupiravir in COVID-19: A systematic review of literature". Diabetes & Metabolic Syndrome. 15 (6): 102329. doi:10.1016/j.dsx.2021.102329. ISSN 1878-0334. PMC 8556684. PMID 34742052.
  13. ^ "Merck and Ridgeback's Molnupiravir, an Oral COVID-19 Antiviral Medicine, Receives First Authorization in the World". Merck (Press release). 4 November 2021. Retrieved 4 November 2021.
  14. ^ "U.K. Authorizes Merck's Antiviral Pill for Covid-19". The New York Times. 4 November 2021. Retrieved 27 November 2021.
  15. ^ a b c d e Fact sheet for healthcare providers: Emergency Use Authorization for molnupiravir (PDF) (Technical report). Food and Drug Administration. 23 December 2021. usfshcp-mk4482-c-2112r000. Archived from the original on 24 December 2021.
  16. ^ a b Lowe D (13 October 2021). "Molnupiravir Mutations". Science (blog).
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  18. ^ 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.
  19. ^ a b c Mole B (October 2021). "Meet molnupiravir, Merck's Thor-inspired pill that hammers COVID". Ars Technica. Retrieved 2 October 2021.
  20. ^ a b c d e f g Halford B. "An emerging antiviral takes aim at COVID-19". C&EN. Retrieved 2 October 2021.
  21. ^ a b 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. S2CID 237507937.
  22. ^ a b 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 
  23. ^ Imran M, Arora MK, Asdaq SM, Khan SA, Alaqel SI, Alshammari MK, et al. (24 September 2021). "Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19". Molecules. 26 (19): 3–16. doi:10.3390/molecules26195795. PMC 8510125. PMID 3464133.
  24. ^ 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.
  25. ^ 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.
  26. ^ "The Medicines Patent Pool (MPP) and Merck Enter Into License Agreement for Molnupiravir, an Investigational Oral Antiviral COVID-19 Medicine, to Increase Broad Access in Low- and Middle-Income Countries". Merck (Press release). Retrieved 28 October 2021.
  27. ^ "Merck Will Share Formula for Its Covid Pill With Poor Countries". The New York Times. 27 October 2021. Retrieved 27 November 2021.
  28. ^ "Merck and Ridgeback Announce Submission of Emergency Use Authorization Application to the U.S. FDA for Molnupiravir, an Investigational Oral Antiviral Medicine, for the Treatment of Mild-to-Moderate COVID-19 in At Risk Adults". Merck (Press release). Retrieved 17 October 2021.
  29. ^ "FDA to Hold Advisory Committee Meeting to Discuss Merck and Ridgeback's EUA Application for COVID-19 Oral Treatment". U.S. Food and Drug Administration (FDA) (Press release). 18 October 2021. Retrieved 19 October 2021.
  30. ^ a b An FDA panel supports Merck COVID drug in mixed vote
  31. ^ Cully, Megan (2021). "A tale of two antiviral targets — and the COVID-19 drugs that bind them". Nature Reviews Drug Discovery. doi:10.1038/d41573-021-00202-8. PMID 34857884. S2CID 244851870.
  32. ^ "COVID-19: EMA starts rolling review of molnupiravir". European Medicines Agency. 25 October 2021. Retrieved 6 November 2021.
  33. ^ Reed J (4 November 2021). "First pill to treat Covid gets approval in UK". BBC News Online. Retrieved 4 November 2021.
  34. ^ Whipple T (4 November 2021). "UK first to approve 'game-changing' antiviral Covid pill". The Times. Retrieved 5 November 2021.
  35. ^ Lowrey T (4 October 2021). "Why the federal government has bought 300,000 doses of a COVID-treating pill that hasn't been approved yet". ABC News (Australia). Retrieved 4 October 2021.
  36. ^ Kerr-Lazenby M (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.
  37. ^ "Oral medicine for Covid-19 now available in Bangladesh". The Business Standard. 9 November 2021. Retrieved 10 November 2021.
  38. ^ "Eskayef's Covid pill hits market". The Daily Star. 10 November 2021. Retrieved 10 November 2021.
  39. ^ World Health Organization (2021). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85" (PDF). WHO Drug Information. 35 (1).
  40. ^ "Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19". Merck (Press release). 15 April 2021. Retrieved 28 November 2021.
  41. ^ Clinical trial number NCT04575597 NCT04575597 for " Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)" at ClinicalTrials.gov
  42. ^ "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". Merck (Press release). 1 October 2021. Retrieved 28 November 2021.
  43. ^ 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.
  44. ^ "Merck's COVID-19 pill significantly less effective in new analysis". Reuters. 26 November 2021. Retrieved 2 December 2021.
  45. ^ Bernal AJ, Silva, MM, Musungaie DB, Kovalchuk E, Gonzalez A, et al. (16 December 2021). "Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients". New England Journal of Medicine. doi:10.1056/NEJMoa2116044. ISSN 0028-4793. PMC 8693688. PMID 34914868.

External links[]

  • "Molnupiravir". Drug Information Portal. U.S. National Library of Medicine.


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