Covid-19Drugs & Updates

Molnupiravir: Authorised for emergency use, but serious concerns raised

Molnupiravir also known as Lagevrio or Molulife (MK-4482, EIDD-2801) is an investigational oral antiviral medicine from Merck and Ridgeback Therapeutics. In an interim analysis, the drug significantly reduced the risk of hospitalisation or death in its Phase 3 trials by approximately 50% in at-risk, non-hospitalized adult patients with mild-to-moderate COVID-19 infections (7.3% of patients who received molnupiravir were either hospitalized or died compared with 14.1% of placebo-treated patients). The trial was conducted globally and demonstrated the drug’s consistent antiviral efficacy against the Delta, Gamma and Mu variants of the virus. 

On December 23rd, 2021, the FDA authorised an emergency use authorisation (EUA) for molnupiravir to treat mild to moderate confirmed COVID-19 infections. Treatment with Merck’s coronavirus drug is limited to situations where other FDA-authorized treatments for COVID-19 are inaccessible or are not clinically appropriate. Molnupiravir is to be administered as four 200 milligram capsules taken orally every 12 hours for five days, for a total of 40 capsules. The FDA has not authorized the drug for pre or post exposure prevention of COVID-19 and states that it is not an alternative to the vaccines. 

Molnupiravir is a prodrug first developed in 2013 at the Drug Innovations at the Emory University (DRIVE) to treat Venezuelean equine encephalitis virus. The drug is a broad-acting antiviral as it targets RNA dependent RNA polymerase (Rdrp) and was considered as a possible treatment strategy in the wake of the COVID-19 pandemic to cease the growth of the SARS-CoV-2 virus. Molnupiravir was the second oral drug to be given an EUA along with Pfizer’s Paxlovid to treat COVID-19 infections. 

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Molnupiravir aims to kill the virus by inducing mutations. The drug is a ribonucleoside analog that can shift its configuration, acting as either a cytidine or a uridine mimetic. The Rdrp enzyme will incorporate the drug instead of the actual nucleosides onto the growing RNA strands. The faulty nucleosides are not captured by the virus’s inbuilt proofreading mechanism either. 

The RNA produced has several point mutations that continue to accumulate as newer viral RNA strands are made. This causes more mutations in all downstream copies which causes the viral population to collapse. This effect is called viral ‘error catastrophe’ or lethal mutagenesis. The mutations also accumulate randomly thus making it difficult for the viruses to develop resistance to molnupiravir. 

However, the drug is capable of inducing mutations in human cells. During organogenesis (organ development), embryo fetal lethality, teratogenicity (ability to cause defects in infants) and reduced fetal weight were observed in rats, making it unsafe for pregnant women to consume. The drug is also not recommended for patients under 18 years of age as it was found to affect bone and cartilage growth in rats, after repeated dosing. 

Females of childbearing potential are advised to use reliable birth control methods consistently during treatment with molnupiravir and for four days after the final dose. Breastfeeding is not recommended during treatment due to potential adverse reactions in the infant. Molnupiravir can also affect sperm growth and maturity. Hence, males of reproductive potential are advised to use reliable birth control methods during treatment with molnupiravir and for at least three months after the final dose. Some of the other side effects of the drug include diarrhea, nausea and dizziness. 

ICMR Chief Dr. Balram Bhargava, on January 5th, 2022, said that Merck’s coronavirus pill has not been added to the national treatment protocol due to these concerns. He also stated that the drug was approved based on a study conducted only in a small cohort of 1433 individuals who showed a 3% reduction and hence the results were not convincing enough. The World Health Organisation and the United Kingdom have not included molnupiravir to their treatment protocols either.

India’s Drug Regulator Central Drugs Standard Control Organisation on December 28, 2021 had approved molnupiravir for restricted use in emergency situations. “Molnupiravir will now be manufactured in the country by 13 companies for restricted use under emergency situations for treatment of adult patients with COVID-19 and who have high risk of progression of the disease,” says Mansukh Mandaviya, the Union Health Minister. 

According to the Drug Controller General of India (DCGI), molnupiravir is to be given for the treatment of adult patients with COVID-19, with oxygen saturation of >93% and who have high risk of progression of the disease, including hospitalisation or death.

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