Molnupiravir

Source: Wikipedia, the free encyclopedia.

Molnupiravir
MK-4482.svg
Clinical data
Trade namesLagevrio[1][2]
Other namesMK-4482, EIDD-2801
License data
Routes of
administration
By mouth
ATC code
  • None
Legal status
Legal status
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)
  • 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 is an antiviral medication that inhibits the replication of certain RNA viruses.[1] 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.[7][8]

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.[9][10] It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.[11]

Based on positive results in placebo-controlled double-blind randomized clinical trials,[12][13] Molnupiravir was approved for medical use in the United Kingdom in November 2021.[1][2][14][15] 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.[5] The emergency use authorization was only narrowly approved (13-10) because of questions regarding efficacy and concerns that molnupiravir's mutagenic effects could create new variants that evade immunity and prolong the COVID-19 pandemic.[16][17][18]

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][5]

Contraindications

Use in pregnancy is not recommended.[medical citation needed] There are no human data on use during pregnancy to assess the risk of adverse maternal or fetal outcomes.[medical citation needed] Based on animal data, the drug may cause fetal harm.[medical citation needed] During organogenesis, embryofetal lethality and teratogenicity were observed in rats, and reduced fetal weight in rats and rabbits.[medical citation needed] Breastfeeding is not recommended during treatment due to potential adverse reactions in the infant.[medical citation needed] There are no data on the presence of the drug or its metabolites in human milk.[medical citation needed] It is not known whether it has an effect on the infant or on milk production.[medical citation needed]

Use in patients under 18 years of age can affect bone and cartilage growth.[medical citation needed] In rats, bone and cartilage toxicity was observed after repeated dosing.[19]

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.[19]

Overdose

The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status.[19]

Drug interactions

There are no known drug interactions, although based on limited data available.[19]

Mechanism of action

Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase.[20] 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).[21][22][23] During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine.[23]

Molnupiravir metabolism.svg

Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other of which mimics uridine (U).[24] NHC-TP is not recognized as an error by the virus' proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions.[20] When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U.[24] This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis.[25]

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.[25] 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.[26]

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.[26]: 93–95 

Molnupiravir synthesis.svg

Alternative patented routes to molnupiravir have been reviewed.[27]

History

Molnupiravir was developed at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE).[11] 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.[24] When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.[24]

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.[23]

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

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.[24] 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.[29]

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.[24][11]

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.[5] 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.[5] 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.[5] 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.[5] Of the people who received molnupiravir one died during the follow-up period compared to nine people who received placebo.[5]

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.[30][31]

Legal status

Merck submitted an EUA application to the FDA on 11 October 2021, 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 2021.[32][33] 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.[34] 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.[34][35] 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.[5]

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of molnupiravir.[36]

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][37][38]

Australia purchased 300,000 courses.[39] In October 2021, the New Zealand pharmaceutical supplier Pharmac purchased 60,000 doses.[40]

In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir.[41][42]

Names

Molnupiravir is the international nonproprietary name (INN).[43]

The generic version is available under the brand names Molulife (Mankind), Molena (Emcure).

Public health concerns

Multiple advisors at the AMDAC meeting on 30 November 2021 raised the concern that molnupiravir could accelerate the emergence of variants of concern.[44][45] Similar concerns were raised by other scientists both before and after the meeting.[46][18][47][17]

Research

COVID-19 clinical trial

In October 2021, preliminary results from a clinical trial (MOVe-OUT)[48][49] indicate that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID-19.[50][51] The final analysis reported a 30% reduction in hospitalizations and deaths.[12][52]

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, 151%).[19]

References

  1. ^ a b c d e f g h "Summary of Product Characteristics for Lagevrio". Medicines and Healthcare products Regulatory Agency (MHRA). 4 November 2021. Retrieved 4 November 2021.
  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. ^ "Molnupiravir capsule". DailyMed. Retrieved 4 January 2022.
  5. ^ 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.
  6. ^ O'Shaughnessy JA (23 December 2021). "Emergency Use Authorization 108". Letter to Merck Sharp & Dohme Corp. U.S. Food and Drug Administration.
  7. ^ 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.
  8. ^ 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.
  9. ^ Cohen B, Piller C (13 May 2020). "Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug".
  10. ^ Cully M (January 2022). "A tale of two antiviral targets - and the COVID-19 drugs that bind them". Nature Reviews. Drug Discovery. 21 (1): 3–5. doi:10.1038/d41573-021-00202-8. PMID 34857884. S2CID 244851870.
  11. ^ 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.
  12. ^ a b Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, et al. (December 2021). "Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients". The New England Journal of Medicine. doi:10.1056/NEJMoa2116044. PMC 8693688. PMID 34914868.
  13. ^ Singh AK, Singh A, Singh R, Misra A (November 2021). "Molnupiravir in COVID-19: A systematic review of literature". Diabetes & Metabolic Syndrome. 15 (6): 102329. doi:10.1016/j.dsx.2021.102329. PMC 8556684. PMID 34742052.
  14. ^ "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.
  15. ^ Robbins R, Khan AJ, Specia M (4 November 2021). "Britain Becomes First to Authorize an Antiviral Pill for Covid-19". The New York Times. Retrieved 27 November 2021.{{cite news}}: CS1 maint: url-status (link)
  16. ^ Kimball S (30 November 2021). "FDA advisory panel narrowly endorses Merck's oral Covid treatment pill, despite reduced efficacy and safety questions". CNBC. Retrieved 1 January 2022.
  17. ^ a b Lin MZ (24 December 2021). "A new drug to treat covid could create a breeding ground for mutant viruses". The Washington Post.
  18. ^ a b Service RF (7 November 2021). "A prominent virologist warns COVID-19 pill could unleash dangerous mutants. Others see little cause for alarm". www.science.org. Retrieved 24 December 2021.
  19. ^ a b c d e "Fact sheet for healthcare providers: Emergency Use Authorization for molnupiravir" (PDF). Merck & Co., Inc. 23 December 2021. Archived from the original on 24 December 2021.
  20. ^ a b Lowe D (13 October 2021). "Molnupiravir mutations". Science (blog).
  21. ^ 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.
  22. ^ 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.
  23. ^ a b c Mole B (October 2021). "Meet molnupiravir, Merck's Thor-inspired pill that hammers COVID". Ars Technica. Retrieved 2 October 2021.
  24. ^ a b c d e f g Halford B. "An emerging antiviral takes aim at COVID-19". C&EN. Retrieved 2 October 2021.
  25. ^ 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.
  26. ^ a b US application 20200276219, Painter GR, Bluemling GR, Natchus MG, Guthrie D, "N4-hydroxycytidine and derivatives and anti-viral uses related thereto", published 2020-09-03, assigned to Emory University 
  27. ^ Wruhs O (24 September 2021). "[Comparative study of stability following the nailing of fractures of the femur shaft. An experimental study with cadaver bones]". Wiener Klinische Wochenschrift. Supplementum (in German). 169 (19): 3–16. doi:10.3390/molecules26195795. PMC 8510125. PMID 3464133.
  28. ^ 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.
  29. ^ 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.
  30. ^ "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.
  31. ^ "Merck Will Share Formula for Its Covid Pill With Poor Countries". The New York Times. 27 October 2021. Retrieved 27 November 2021.{{cite web}}: CS1 maint: url-status (link)
  32. ^ "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.
  33. ^ "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.
  34. ^ a b An FDA panel supports Merck COVID drug in mixed vote
  35. ^ Cully M (January 2022). "A tale of two antiviral targets - and the COVID-19 drugs that bind them". Nature Reviews. Drug Discovery. 21 (1): 3–5. doi:10.1038/d41573-021-00202-8. PMID 34857884. S2CID 244851870.
  36. ^ "COVID-19: EMA starts rolling review of molnupiravir". European Medicines Agency. 25 October 2021. Retrieved 6 November 2021.
  37. ^ Reed J (4 November 2021). "First pill to treat Covid gets approval in UK". BBC News Online. Retrieved 4 November 2021.
  38. ^ Whipple T (4 November 2021). "UK first to approve 'game-changing' antiviral Covid pill". The Times. Retrieved 5 November 2021.
  39. ^ 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.
  40. ^ 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.
  41. ^ "Oral medicine for Covid-19 now available in Bangladesh". The Business Standard. 9 November 2021. Retrieved 10 November 2021.
  42. ^ "Eskayef's Covid pill hits market". The Daily Star. 10 November 2021. Retrieved 10 November 2021.
  43. ^ World Health Organization (2021). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85" (PDF). WHO Drug Information. 35 (1).
  44. ^ Kimball S (30 November 2021). "FDA advisory panel narrowly endorses Merck's oral Covid treatment pill, despite reduced efficacy and safety questions". CNBC. Retrieved 4 January 2022.
  45. ^ Walker M (30 November 2021). "FDA Panel Narrowly Backs Merck's COVID Pill". www.medpagetoday.com. Retrieved 4 January 2022.
  46. ^ Nelson CW, Otto SP (29 November 2021). "Mutagenic antivirals: the evolutionary risk of low doses". Virological. Retrieved 4 January 2022.
  47. ^ Lovett S (11 December 2021). "Scientists' caution over use of new antiviral pill in immunosuppressed". The Independent. Retrieved 4 January 2022.
  48. ^ "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.
  49. ^ 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
  50. ^ "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.
  51. ^ 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.
  52. ^ Mishra M, Erman M (26 November 2021). "Merck's COVID-19 pill significantly less effective in new analysis". Reuters. Retrieved 2 December 2021.

External links

  • "Molnupiravir". Drug Information Portal. U.S. National Library of Medicine.
This page is based on the copyrighted Wikipedia article: Molnupiravir. Articles is available under the CC BY-SA 3.0 license; additional terms may apply.