Molnupiravir
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Pronunciation | /ˌmɔːlnuˈpɪərəvɪər/ MAWL-noo-PEER-ə-veer |
Trade names | Lagevrio |
Other names | MK-4482, EIDD-2801 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a622027 |
License data |
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Pregnancy category | |
Routes of administration | By mouth |
ATC code | |
Legal status | |
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Molnupiravir, sold under the brand name Lagevrio, is an
Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine and exerts its antiviral action by introducing copying errors during viral RNA replication.[13][14]
Molnupiravir was originally developed to treat
Based on positive results in
Medical uses
In the UK, molnupiravir is
In the US molnupiravir is unapproved but is authorized under an EUA for emergency use for the treatment of adults with mild-to-moderate COVID‑19 who are at high risk for progression to severe COVID‑19, including hospitalization or death, and for whom alternative COVID‑19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.[9][10][12]
Contraindications
Use during pregnancy is not recommended.[4] There are no human data on use during pregnancy to assess the risk of adverse maternal or fetal outcomes.[4] Based on animal data, the drug may cause fetal harm.[4]
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.[12]
The US FDA prescription label contains a boxed warning.[9]
In rats, bone and cartilage toxicity was observed after repeated dosing.[12]
Overdose
The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status.[12]
Drug interactions
Based on limited available data, there are no drug interactions.[12]
Mechanism of action
Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed
Molnupiravir can swap between two forms (
Chemistry
The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.[32]
In the first step,
History
Molnupiravir was developed at Emory University by its drug innovation company, Drug Innovation Ventures at Emory (DRIVE).[17] 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.[33][unreliable medical source?] When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.[33]
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.[30]
In 2019, the National Institute of Allergy and Infectious Diseases (NIAID) approved moving molnupiravir into Phase I clinical trials for influenza.[33]
In March 2020, the research team pivoted to studying SARS-CoV-2, and successfully used molnupiravir to treat human cells infected with the novel coronavirus.[33][unreliable medical source?] A study found that it is orally active against SARS-CoV-2 in ferrets.[34]
DRIVE then licensed molnupiravir for human clinical studies to Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further.[33][17]
The primary data supporting the US
In November 2022, the British National Institute for Health and Care Excellence decided molnupiravir should not be routinely used to treat COVID‑19, as research showed it made no significant difference to hospitalization or death rates and was not cost effective.[36] The drug was added to its "not recommended" list in draft COVID‑19 treatment guidance for consultation.[37][36]
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 US government's initial purchase was about $712 per course of treatment; treatment with generics in developing countries can cost as little as $20.[38][39]
Sales of molnupiravir were $952 million in the fourth quarter of 2021.[40]
Legal status
In October 2021, Merck submitted an EUA application to the FDA, and in November 2021, the FDA's Antimicrobial Drugs Advisory Committee (AMDAC) at the
In October 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) started a rolling review of molnupiravir.[44] In February 2023, the EMA recommended the refusal of the marketing authorization for molnupiravir.[45] In June 2023, Merck Sharp & Dohme withdrew its application for a marketing authorization of molnupiravir.[46]
In 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.[7] The MHRA issued a conditional marketing authorization applicable in the UK, and an emergency use authorization for Northern Ireland.[7][20][47][48]
In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir.[49][50]
In January 2022, molnupiravir was approved for medical use in Israel[51] and in February 2022 in Russia.[52]
Brand names
Molnupiravir is the international nonproprietary name.[53][54]
Public health concerns
At a November 2021 AMDAC meeting, multiple advisors raised the concern that molnupiravir could accelerate the emergence of variants of concern.[57][58] Other scientists raised similar concerns both before and after the meeting.[59][25][60][24] These concerns were confirmed with the September 2023 publication of a study of 15 million global SARS-CoV-2 sequences: after molnupiravir had been introduced in 2022, genomic changes were more common, especially where it had been used.[26]
Research
Alternative patented routes to molnupiravir have been reviewed.[61]
COVID-19 clinical trial
In October 2021, preliminary results from a clinical trial (MOVe-OUT)[62][63][full citation needed] indicated that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID‑19.[64][65] The final analysis reported a 30% reduction in hospitalizations and deaths.[18][66]
Since December 2021, the PANORAMIC trial has been testing molnupiravir's effectiveness.[67][68] Results showed that for higher risk, vaccinated adults molnupiravir does not reduce the chances of hospitalisation and death. However it results in faster recovery and reduced viral load.[69][70]
In February 2023, Merck reported that the phase III MOVe-AHEAD trial to evaluate the safety and efficacy of Lagevrio compared to placebo in preventing the spread of SARS-CoV-2 within households did not meet its primary endpoints. With more than 1,500 participants who were free of COVID‑19 and lived with someone who was recently diagnosed with the virus, patients treated with Lagevrio were 23.6% less likely than those on placebo to develop COVID after 14 days.[71][72][73]
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Further reading
- Thorlund K, Sheldrick K, Meyerowitz-Katz G, Singh S, Hill A (March 2022). "Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial". Am J Trop Med Hyg. 106 (5): 1301–1304. S2CID 247406958.