Molnupiravir is aprodrug of the syntheticnucleoside derivativeN4-hydroxycytidine and exerts its antiviral action by introducing copying errors during viral RNA replication.[12][13]
Molnupiravir was originally developed to treatinfluenza atEmory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE), but was reportedly abandoned formutagenicity concerns.[14][15] It was then acquired by the Miami-based companyRidgeback Biotherapeutics, which later partnered withMerck & Co. to develop the drug further.[16]
Based on positive results inplacebo-controlled double-blind randomized clinical trials,[17][18] molnupiravir was approved for medical use in the United Kingdom in November 2021.[6][19][20][21] In December 2021, the USFood and Drug Administration (FDA) granted anemergency use authorization (EUA) to molnupiravir for use in certain populations where other treatments are not feasible.[9] The emergency use authorization was only narrowly approved (13–10) because of questions about efficacy and concerns that molnupiravir's mutagenic effects could create new variants that evade immunity and prolong theCOVID‑19 pandemic.[22][23][24] In September 2023, molnupiravir's viral mutagenicity was confirmed to contribute to circulating SARS-CoV-2 genomic variation in a study of global SARS CoV 2 isolates after 2022: molnupiravir-specific genomic changes were more common, especially where molnupiravir had been used.[25]
In the UK, molnupiravir isindicated for treatment of mild to moderate COVID‑19 in adults with a positive SARS-COV-2 diagnostic test and who have at least one risk factor for developing severe illness.[6]
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.[8][9][11]
Use during pregnancy is not recommended.[3] There are no human data on use during pregnancy to assess the risk of adverse maternal or fetal outcomes.[3] Based on animal data, the drug may cause fetal harm.[3]
Adverse reactions observed in the phase III MOVe-OUT study includeddiarrhea (2%),nausea (1%) anddizziness (1%), all of which were mild or moderate.[11]
Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directedRNA polymerase.[26] It is metabolized into aribonucleoside analog that resemblescytidine, β-D-N4-hydroxycytidine 5′-triphosphate (also called EIDD-1931 5′-triphosphate or NHC-TP).[27][28][29] During replication, the virus's enzyme incorporates NHC-TP into newly madeRNA instead of using real cytidine.[29]
Molnupiravir is turned into NHC-TP, the active form.
Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the otheruridine (U).[30] NHC-TP is not recognized as an error by the virus's proofreadingexonuclease enzymes, which can replace mutated nucleotides with corrected versions.[26] When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U. This causes moremutations in all downstream copies than the virus can survive, an effect called viralerror catastrophe orlethal mutagenesis.[30]
Theinternational nonproprietary name of the drug was inspired by that ofThor's hammer,Mjölnir. The idea is that the drug will strike down the virus like a mighty blow from the god of thunder.[29]
In March 2020, the research team pivoted to studyingSARS-CoV-2, and successfully used molnupiravir to treat human cells infected with the novel coronavirus.[32][unreliable medical source?] A study found that it is orally active against SARS-CoV-2 in ferrets.[33]
DRIVE then licensed molnupiravir for human clinical studies to Miami-based company Ridgeback Biotherapeutics, which later partnered withMerck & Co. to develop the drug further.[32][16]
The primary data supporting the USFood 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.[9][34] Participants were adults 18 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.[9] 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.[9] Of the 709 people who received molnupiravir, 6.8% were hospitalized or died within this period compared to 9.7% of the 699 people who received a placebo.[9]
In November 2022, the BritishNational 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.[35] The drug was added to its "not recommended" list in draft COVID‑19 treatment guidance for consultation.[36][35]
In September 2021, Merck signed a voluntary licensing agreement with theMedicines 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.[37][38]
Sales of molnupiravir were $952 million in the fourth quarter of 2021.[39]
In October 2021, Merck submitted an EUA application to the FDA, and in November 2021, the FDA's Antimicrobial Drugs Advisory Committee (AMDAC) at theCenter for Drug Evaluation and Research met to discuss the application.[40][41] 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.[42] Concerns were expressed over the drug's low effectiveness in preventing death, which in the final trial was only 30%, as well as the increased mutation rate the drug causes, which could theoretically worsen the pandemic by driving the evolution of more dangerous variants.[42][15] In December 2021, the USFood and Drug Administration (FDA) issued anemergency 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 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.[9]
In November 2021, molnupiravir was approved in the UK by theMedicines and Healthcare products Regulatory Agency (MHRA) for the treatment of established infections of COVID‑19.[6] The MHRA issued a conditional marketing authorization applicable in the UK, and an emergency use authorization for Northern Ireland.[6][19][46][47]
At a November 2021 AMDAC meeting, multiple advisors raised the concern that molnupiravir could accelerate the emergence ofvariants of concern.[56][57] Other scientists raised similar concerns both before and after the meeting.[58][24][59][23] 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.[25]
^abUS application 20200276219, Painter GR, Bluemling GR, Natchus MG, Guthrie D, "N4-hydroxycytidine and derivatives and anti-viral uses related thereto", published 3 September 2020, assigned to Emory UniversityArchived 5 October 2021 at theWayback Machine
^World Health Organization (2021). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85".WHO Drug Information.35 (1).hdl:10665/340684.
^World Health Organization (2022). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87".WHO Drug Information.36 (1).hdl:10665/352794.
^Wruhs O (1986). "[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).169:3–16.PMID3464133.
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