Molnupiravir

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Molnupiravir
MK-4482.svg
Names
Trade namesLagevrio, Molulife , Molena, others[1]
Other namesMK-4482, EIDD-2801
  • 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)
Clinical data
Main usesCOVID-19[1]
Side effectsDiarrhea, nausea, dizziness, headache[1]
Routes of
use
By mouth
Typical dose800 mg BID x 5 days[1]
External links
US NLMMolnupiravir
Legal
License data
Legal status
Chemical and physical data
FormulaC13H19N3O7
Molar mass329.309 g·mol−1
3D model (JSmol)
  • CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O
  • 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 names Lagevrio and Molulife among others, is an antiviral used to treat COVID-19.[1] It has been found to be useful in mild but not severe disease.[6] It is used within 5 days of the start of symptom in those at risk of developed severe disease.[1] It is not; however, a preferred treatment.[7] It is taken by mouth.[1]

Common side effects include diarrhea, nausea, dizziness, and headache.[1] Safety in pregnancy is unclear.[1] The dose does not need to be adjusted in kidney or liver disease.[1] Use is not recommended in those under 18 due to concerns regarding effects on bone and cartilage.[3] It is metabolized within the body to ribonucleoside triphosphate (NHC-TP) which results in viral error catastrophe (large numbers of viral mutations).[1][3]

Molnupiravir was approved for medical use in the United Kingdom in November 2021.[1] In December 2021, it was granted an emergency use authorization (EUA) in the United States.[3] The recommendation for EUA approval was 13 to 10 with concerns regarding efficacy and that its mutagenic effects could create new variants.[8][9] In the United States a course of treatment costs about 700 USD while this amount in the developing world is about 20 USD as of 2022.[10]

Medical uses

Molnupiravir is used to treat mild-to-moderate coronavirus disease 19 (COVID-19) in adults with positive results on direct viral testing and who are at high risk for progression to severe COVID-19.[1][4]

The criteria for being at high risk for progression include: over 60 years old, diabetes, obesity, kidney disease, heart problems, COPD, and active cancer.[1] In this group it decreases the risk of hospitalization or death from 9.7% to 6.8% (30%) over the following month.[4] There is no evidence regarding its used in those who have received a COVID-19 vaccine as of early 2022.[7]

Use is only recommended when nirmatrelvir/ritonavir, sotrovimab, and remdesivir are not options.[7]

Dosage

It is taken at a dose of 800 mg twice per day for 5 days.[1]

The dose does not need to be adjusted in kidney or liver disease.[1]

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.[11]

Side effects

Side effects included diarrhea (2%), nausea (1%) and dizziness (1%), all of which were mild or moderate.[11]

Overdose

The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status.[11]

Interactions

There are no known drug interactions, although based on limited data available.[11]

Mechanism of action

Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase.[12] 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).[13][14][15] During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine.[15]

Molnupiravir metabolism.svg

Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other of which mimics uridine (U).[16] NHC-TP is not recognized as an error by the virus' proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions.[12] When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U.[16] This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis.[17]

Chemistry

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.[17] The wiggly lines stand for the connection to the pentose sugar and point in the direction of the minor groove.

The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.[18]

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.[18]: 93–95 

Molnupiravir synthesis.svg

Alternative patented routes to molnupiravir have been reviewed.[19]

History

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.[20][21] 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.[16] When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.[16]

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.[15]

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.[22] In late 2019, the National Institute of Allergy and Infectious Diseases approved moving molnupiravir into Phase I clinical trials for influenza.[16]

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.[16] 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.[23]

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.[16][24]

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]

It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.[24] Approval was based on positive results in placebo-controlled double-blind randomized clinical trials.[25]

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 it 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 the generics in developing countries may can cost as little as $20.[26][27]

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.[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 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 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][33][34][35]

In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir.[36][37]

Availability

Australia purchased 300,000 courses of treatment.[38] In October 2021, the New Zealand pharmaceutical supplier Pharmac purchased 60,000 doses.[39]

Canada has an agreement to purchase 500,000 course of treatment as of December 2021.[40] While it is under review, it is not approved for use in Canada as of December 2021.[41]

Names

Molnupiravir is the international nonproprietary name (INN).[42]

Concerns

Multiple advisors at the AMDAC meeting on 30 November 2021 raised the concern that molnupiravir could accelerate the emergence of variants of concern.[43][44] Similar concerns were raised by other scientists both before and after the meeting.[45][46][47][48]

Research

COVID-19 clinical trial

In October 2021, preliminary results from a clinical trial (MOVe-OUT)[49][50][full citation needed] indicate that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID-19.[51][52] The final analysis reported a 30% reduction in hospitalizations and deaths.[25][53]

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%).[11] The Merck and Dohme funded phase III MOVe-OUT study found that the risk of death was about 89% (14–99%) lower.[54]

References

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External links

Identifiers:
  • "Molnupiravir". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-10-02. Retrieved 2022-01-05.