Molnupiravir, hailed as a breakthrough oral drug for treating COVID-19, received approval from the UK Medicines and Healthcare products Regulatory Agency on November 4, 2021. However, just before the approval, renowned scientist Dr William Haseltine, on November 1, 2021, raised major concerns regarding the basic mechanism of the drug in an article for Forbes, titled 'Supercharging New Viral Variants: The Dangers Of Molnupiravir (Part 1)', adding that the drug should include a "black box warning" to emphasize its potential danger if given to a large population.

In fact, this comes months after Haseltine had written highly about the drug on March 16, 2021 in an article titled, "Molnupiravir: A New Hope For Prevention And Treatment Of Covid-19 And Other Dangerous Viruses".

Earlier, on October 1, 2021, Merck & Co and Ridgeback Biotherapeutics' officials, after the Phase 3 study, announced that their antiviral drug reduced the risk of hospitalisation or death by approximately 50% compared to placebo for patients with mild or moderate COVID-19. Haseltine, a virologist, formerly with Harvard Medical School and known for his work on HIV and cancer, raised concerns on the drug's ability to induce mutations or damage a patient's DNA (deoxyribonucleic acid) leading to cancerous tumours and birth defects.

Health experts FactChecker spoke to said although Haseltine's concerns are theoretically possible, they cannot be established without conclusive evidence. Meanwhile, the FDA has decided to convene an advisory committee on November 30, 2021 for an emergency authorisation of Molnupiravir.

To further understand the basic mechanism of the drug, FactChecker spoke to Dr T Jacob John, virologist and professor emeritus of Christian Medical College (CMC), Vellore, Dr. Shahid Jameel, virologist and director of Trivedi School of Biosciences at Ashoka University and Dr Satyajith Rath, immunologist, formerly with the Delhi-based National Institute of Immunology. Here's what we found:

What is Molnupiravir and how does it work?

Molnupiravir is an orally administered antiviral drug that inhibits or stops the replication of SARS-CoV-2. Initially called EIDD-2801, the drug was invented by scientists at Emory University to treat the influenza virus. Before releasing its antiviral effect, the drug must undergo conversion to its drug form called N4-hydroxycytidine (NHC). This product has shown to be effective against Ebola virus, Venezuelan equine encephalitis virus and other coronaviruses.

According to Dr John of CMC, Molnupiravir works as a trick agent. But before this, it's important to see what goes on in the body before consuming the drug. When Sars-CoV-2 enters the cells, they multiply furiously, infecting more cells, leading to pathology. Virus populations grow when individual virus particles make copies of themselves. In the core of each copy is the genetic code of the virus, which contains all the information to make virus copies. This genetic code comes in two major chemical types, DNA and RNA (ribonucleic acid).

"Human cells usually make DNA or RNA copies from DNA originals, but cannot make copies directly from RNA," said Dr Rath of National Institute of Immunology. "However, viruses like SARS-CoV-2 have enzymes which humans do not have, enzymes that can directly make RNA copies of an RNA original, chemical letter by chemical letter." he said.

Now, Molnupiravir looks somewhat like these chemical letters, so the viral enzyme uses them as letters. But Molnupiravir is similar enough to the natural chemical letters for the copies to be accurate. These inaccurate copies then begin to be further copied inaccurately. This means that, while SARS-CoV-2 goes on to make virus copies, the Molnupiravir treatment leads to extremely high frequencies of error-filled virus copies and increases the frequency of viral RNA mutations. These error-filled copies will, quite commonly, be unable to grow further which results in the impairment of SARS-CoV-2 replication, explained Dr Rath.

"Molnupiravir is what we call a nucleoside analog (a class of antiviral agent). DNA is made up of repeat units of 4 bases - Adenine, Cytosine, Guanine and Thymine; in RNA, Thymine is replaced by Uracil," said Dr Jameel from Ashoka University. Further, two studies published in July and August, 2021 have shown that increase in mutation frequencies can be linked to increase in antiviral effects, thus stating that the drug works against COVID-19.

In other words, once Molnupiravir enters the body, it tricks the virus during multiplication by mimicking mutated RNA. "The drug is metabolised by the body to produce a chemical entity that looks very much like Cytosine and Uracil. It gets incorporated into a growing RNA chain, can bypass the proofreading system and is sometimes interpreted by the viral replication enzyme as Cytosine and at other times as Uracil," said Jameel.

Since Molnupiravir increases the frequency of viral RNA mutations, the accumulation of these mutations causes the mutants to lose fitness which in turn makes it unable to replicate, hence protecting the host cells from getting infected, experts said.

Can the Drug Cause Cancer or Birth Defects?

Haseltine claimed that Molnupiravir can induce mutational errors in the DNA. If this causes damage in cells it could lead to cancer and birth defects. But experts said that the drug does not affect DNA synthesis but only RNA synthesis. Moreover, there are basic differences in DNA and RNA physiology in our cells. "As this drug tricks only mRNA synthesis and such RNA synthesis is not physiological, cancer or birth defects are not likely or even possible.," said John.

Similarly, Dr Rath said, "Molnupiravir (and similar drugs) can 'induce mutational errors' in viral RNA which is being copied, but not in human RNA since that is usually not being copied." Different copying enzymes are involved in human DNA, he added.

But all three experts warned that human biology is complex and we need long term data to be sure about safety. "This is theoretically possible. Though long-term use of similar nucleoside analogs as RT inhibitors in the treatment of HIV/AIDS has not shown this concern. Further, SARS-V-2 treatment would be short term as opposed to HIV/AIDS treatment, which is for life," said Dr Jameel. Further, Jameel said the safety concerns will be two-fold:

- How efficiently it gets into DNA when it is copied? If these errors are not corrected very efficiently, it could lead to accumulation of mutations with a potential for cancer development.

- Some of the mutant viruses may escape immunity but still infect and cause disease.

Additionally, In May 2020 and January 2021, concerns were raised on the mutagenicity and genotoxicity of Molnupiravir. It was said that the drug belongs to a class of compounds known to cause serious birth defects in animal experiments. However, in April 2021, Merck clarified Molnupiravir did not pose an increased risk of genotoxicity in clinical use. But it is still unclear whether the pharma company carried out experiments with pregnant animals to rule out possible birth defects.

Further, when it comes to long-term safety and effects of the drug, Merck said groups in the phase 3 trial experienced similar and mild side effects. Although evidence in the clinical trial of Molnupiravir has not so far found them, Haseltine's ideas could be possible in theory. "But how much of that would happen in practice can only be established with preclinical and clinical data," Jameel added.

Can Virus Develop Resistance to Drug?

Research in this area is acutely scarce. A 2019 study, published in American Society for Microbiology's Journal of Virology, concluded that low-level resistance to NHC (drug form of Molnupiravir) could be seen in viruses after continuous exposure. However, experts said without strong evidence, this remains to be a theoretical possibility. "But if an appropriate dose is given, this should not be the case," said Jameel. He said antiviral resistance is reduced further by combining two or more drugs with different modes of action.

"For a virus to develop resistance to a combination is very rare. The use of HIV/AIDS drugs has shown this. COVID-19 is an acute infection so its treatment is short term, unlike HIV/AIDS that is chronic with lifelong treatment," said Jameel.

"We need data and data takes time and meanwhile we must use the drug for the immediate benefits," John added.

The positive interim analysis of Merck's Phase 3 study shows that 14.1% or 53 of 377 participants in the placebo group developed severe COVID-19, required hospitalisation, and eight died. Whereas, 7.3% or 28 of 385 participants in the Molnupiravir-treated group developed severe COVID-19 leading to hospitalisation and reported zero deaths.

Lastly, when asked about the effectiveness of the drug, experts said 50% efficacy for a drug is neither great nor inadequate. They continued to say that proof of safety would be evident only after the actual roll out and wider use of the antiviral. "It is meant as an oral pill and a short-term treatment. As with any drug, longer term effects have to be studied in animal models," said Jameel.

"In vulnerable persons with proven Sars-CoV-2 infection, 50% reduction of severe disease, thus averting hospitalisation, is a great boon. Molnupiravir cannot stay around for long periods and so long-term side effects are unlikely, but that remains to be proven," concluded John.

FactChecker tried contacting Merck & Co and Haseltine for their clarifications via email but had not received a response by the time this article was published.