Sahana S
10-01-2022
What is Molnupiravir?
Molnupiravir (MK-4482, EIDD-2801), was initially developed by the Drug Innovation ventures at Emory University. This was later licensed by the Ridgeback therapeutics in partnership with Merck & Co, USA. Molnupiravir’s active compound, N4-hydroxycytidine (NHC) has been known and studied for decades. The antiviral drug was first developed to treat influenza and is now being repurposed to treat COVID-19. The drug was approved for emergency use authorization (EUA) by the Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom on November 4, 2021 for treating COVID19 patients. On 23rd December 2021, US-Food and Drug administration (FDA) approved EUA for molnupiravir. In continuation to that, India has also approved the drug for treating the adults who have a high progression of COVID-19 infection.
What is an Emergency use Authorization (EUA)?
Emergency Use Authorization (EUA) is an authority given to US-FDA which allows them to authorise medical countermeasures (MCMs) to be used in a public health emergency situation to diagnose or treat life-threatening diseases or conditions when certain criterias are met. The MCMs can include vaccines, blood products, antibodies, antimicrobial or antiviral drugs and biologic devices. This is generally authorised to help protect the public health against chemical, biological, radiological and nuclear (CBRN) threats which also includes infectious diseases. Emergency Use Authorization is NOT the same as FDA- approved or authorized.
How does the Molnupiravir work?
The antiviral pill molnupiravir is a prodrug of N4-hydroxycytidine (NHC) that works by introducing mutations or changes in the genetic material of the SARS CoV-2 virus and stops or prevents the virus from further replicating in the host.
Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) which is the key enzyme for the process of replication in the SARS-CoV-2 which also plays a major role in the pathophysiology of the COVID19 infection.
When orally absorbed, molnupiravir hydrolyzes or breaks down into NHC, which then enters the tissues in the form of active triphosphates. The RNA-dependent RNA polymerase (RdRp) uses the NHC triphosphate instead of cytidine and uridine triphosphate in the replication process which leads to several errors or mutations in the replicated viral RNA. This leads to the reduction in the replication of the viruses which will eventually stop the virus from replicating in the host.
As per US-FDA EUA, Molnupiravir should be prescribed only when other FDA-authorised treatments for COVID-19 are inaccessible or are not clinically appropriate and for the patients with COVID-19 at high risk of hospitalisation or death. Also, the FDA has not authorised the use of the drug for longer than five consecutive days. The EUA has been issued to the drug based on the fact that the known and potential benefits of the molnupiravir when used under the terms and conditions of the authorization outweigh the known and potential risks of the product.
What is the benefit for the drug?
Molnupiravir has been shown in clinical trial in educing the risk of hospitalization and death by half the rate. However the Number needed to treat, the number of patients to be treated to prevent one additional bad outcome (in this case, it can be hospitalization or death) is very large. Molnupiravir has an NNT of 34.5 i.e., 34.5 people needed to be treated with molnupiravir to prevent one bad outcome.
Does molnupiravir cause mutations in the virus ?
The mechanism of action of molnupiravir is by creating mutations in the viral genome during replication. The active compound N4-hydroxycytidine, introduces mutations/changes in the genetic material of SARS-COV2 virus which limits the virus from replicating in the host environment.
The study conducted on hamster models revealed that all the animals treated with molnupiravir had a significant number of mutations in the viral genomes with an increased number of adenine-to-guanine and cytosine-to-uracil changes[6].
Can Molnupiravir lead to new mutations / variants ?
While there is a high probability that the viruses can accumulate new mutations on treatment with molnupiravir, as evidenced from studies in animal models, there is no conclusive evidence that this leads to new virus variants. Data is lacking in this regard to rule out this possibility.
There is no conclusive evidence and clinical reports of the drug's potential to introduce DNA changes in humans. A study involving animal cell culture assay has displayed that NHC has the potential to cause host mutational activity [7]. This is inferred based on the mutated ribonucleoside diphosphate generated by the drug is a common intermediate in the synthesis of both RNA precursors in the virus and DNA precursors in the host. These results have indicated that the active mutagenic ribonucleoside holds a high risk factor for the host as well.
Who should not get the medicine?
Molnupiravir is not authorised to be used for individuals under the age of 18 as it may affect bone and cartilage growth. Molnupiravir is not recommended for pregnant individuals, as it might affect the unborn child. Patients requiring hospitalisation due to COVID19 are not authorised to take molnupiravir. The drug should never be taken as a prevention for COVID19 infection. Also, the drug is not authorised for usage for more than 5 days.
What precautions should one take?
Pregnancy
Molnupiravir can potentially cause harm to the unborn child when administered to pregnant individuals. Hence, molnupiravir is not recommended for use in pregnant individuals. If clinically required, pregnancy tests should be assessed in individuals before initiating the molnupiravir treatment.
Also, breastfeeding is not recommended by the FDA during the treatment with molnupiravir and a few days after the treatment.
Birth control
Individuals are advised to take safe methods of contraceptives during the period of treatment of molnupiravir. Females are advised to continue the contraceptives for four days after the treatment. Studies have estimated the potential for molnupiravir to affect the unborn child of the treated males and so it is highly advised to continue usage of relevant contraceptives correctly and consistently for at least three months after the last dose of molnupiravir.
What are the risks?
There are three most common adverse effects associated with molnupiravir and have also been reported during the clinical trial: headache, nausea and diarrhoea.
Other less common adverse effects reported includes influenza-like syndrome, back pain, rhinorrhea, hot flashes and pain in extremity.
Drug-drug interactions are not studied which leads to the question of not knowing the effect of molnupiravir taken with other metabolic disorder drugs.
Mutagenic power of NHC might create changes/mutations among the other enzymes in the body, including the DNA and possibly lead to birth defects or cancer.
The changes caused by NHC in the viral genome might lead to more virulent SARS-CoV2 mutations in the world.
References
- https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain
- https://clinicaltrials.gov/ct2/show/study/NCT04575597
- Singh, Awadhesh Kumar, Akriti Singh, Ritu Singh, and Anoop Misra. "Molnupiravir in COVID-19: a systematic review of literature." Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15, no. 6 (2021): 102329.
- Pourkarim, Fariba, Samira Pourtaghi‐Anvarian, and Haleh Rezaee. "Molnupiravir: A new candidate for COVID‐19 treatment." Pharmacology Research & Perspectives 10, no. 1 (2022): e00909.
- Jayk Bernal, Angélica, Monica M. Gomes da Silva, Dany B. Musungaie, Evgeniy Kovalchuk, Antonio Gonzalez, Virginia Delos Reyes, Alejandro Martín-Quirós et al. "Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients." New England Journal of Medicine (2021).
- Rosenke, Kyle, Frederick Hansen, Benjamin Schwarz, Friederike Feldmann, Elaine Haddock, Rebecca Rosenke, Kent Barbian et al. "Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model." Nature communications 12, no. 1 (2021): 1-8.
- Zhou, Shuntai, Collin S. Hill, Sanjay Sarkar, Longping V. Tse, Blaide Woodburn, Raymond F. Schinazi, Timothy P. Sheahan, Ralph S. Baric, Mark T. Heise, and Ronald Swanstrom. "β-DN 4-hydroxycytidine (NHC) Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells." The Journal of Infectious Diseases (2021).
About the author
Sahana S is a PhD candidate at the CSIR Institute of Genomics and Integrative Biology. She can be reached at @S__Sahana on twitter. All opinions expressed are personal.
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