Molnupiravir

In the UK, molnupiravir is indicated for treatment of mild to moderate COVID19 in adults with a positive SARS-COV-2 diagnostic test and who have at least one risk factor for developing severe illness. Molnupiravir also shows potential antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, respiratory syncytial virus (RSV), bovine viral diarrhea virus (BVDV), hepatitis C virus (HCV), Ebola virus (EBOV), feline coronavirus (FCoV) and enteroviruses. == Contraindications ==

Use during 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. == 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. The US FDA prescription label contains a boxed warning. In rats, bone and cartilage toxicity was observed after repeated dosing. == Overdose ==

The effects of overdose are unknown, treatment consists of general supportive measures such as monitoring of clinical status. == Drug interactions ==

Based on limited available data, there are no drug interactions. == Mechanism of action ==

Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase. 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). During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine. NHC-TP is not recognized as an error by the virus's proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions. When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U. This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis. ==Chemistry==

The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018. 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. : == History ==

Molnupiravir was developed at Emory University by its drug innovation company, Drug Innovation Ventures at Emory (DRIVE). 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. 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. 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 COVID19 vaccine. == 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 COVID19 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. Sales of molnupiravir were $952 million in the fourth quarter of 2021. 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 Center for Drug Evaluation and Research met to discuss the application. 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 COVID19. 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. In February 2023, the EMA recommended the refusal of the marketing authorization for molnupiravir. In June 2023, Merck Sharp & Dohme withdrew its application for a marketing authorization of molnupiravir. 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 COVID19. In November 2021, the Bangladesh Directorate General of Drug Administration (DGDA) authorized emergency use of molnupiravir. In January 2022, molnupiravir was approved for medical use in Israel and in February 2022 in Russia. Brand names Molnupiravir is the international nonproprietary name. Generic versions are available under the brand names Molulife (Mankind), Molena (Emcure), and Esplevir (Promomed). Other scientists raised similar concerns both before and after the meeting. == Research ==

Alternative patented routes to molnupiravir have been reviewed. Clinical findings vary on the efficacy of molnupiravir in reducing COVID-19 severity. Some studies indicate a reduction in hospitalizations, deaths, and viral load, while others show no significant benefit, particularly in vaccinated populations. == References ==