Coronavirus less likely to develop resistance to molnupiravir: Gagandeep Kang

Gagandeep Kang. File   | Photo Credit: C. Venkatachalapathy

On October 11, just 10 days after Merck announced via a press release the highly encouraging news of an interim analysis of a phase-3 trial using the antiviral drug molnupiravir, the company has submitted an emergency use authorisation application to the FDA. Preliminary data, which is yet to be peer-reviewed, shows molnupiravir can reduce risk of hospitalisation or death by 50% in non-hospitalised adult patients with mild-to-moderate COVID-19 disease. That molnupiravir is an oral drug is a major advantage in treating patients as it would not require hospitalisation. In an email, Dr. Gagandeep Kang, Professor of Microbiology at CMC, Vellore, explains the other advantages that the drug will have, if granted an EUA.

Since it is an oral drug unlike Remdesivir, can molnupiravir (if given an EUA) substantially change the way COVID-19 disease is managed?

Yes, molnupiravir has significant promise. But there are some concerns about how early and how mild the disease has to be for molnupiravir to work. It seems important to treat within the first few days of diagnosis or symptoms and the drug does not work towards the more severe end of the spectrum, including what is considered moderate disease.

Why was the drug tested only in people older than 60 years and those with at least one risk factor associated with poor outcomes?

The study was designed to include people with at least one risk factor for severe disease, because the goal was to study progression to severe disease. Had completely healthy people been included the study size would have needed to be much larger to get clear outcomes. Merck’s selection strategy of people at risk of severe disease led to a clear answer on efficacy in mild disease, such that the study was stopped for efficacy with data on 775 people.

What is the precise mechanism by which the drug prevents the SARS-CoV-2 virus RNA replication process through “error catastrophe”? Besides blocking replication, can the drug also reduce the viral load in humans? Like in ferrets, can the drug also block virus transmission in humans?

Molnupiravir is a pro-drug, which means that it needs to undergo processing in the body to become active. It is metabolised to a ribonucleoside analog, which is essentially a sugar molecule linked to a molecule that resembles a nucleic acid. Nucleic acids are needed to make RNA, and if molnupiravir is used, the viral enzyme instead of using real cytidine or uridine uses a molecule that is generated by metabolism of molnupiravir called NHC-TP. The virus has a proof-reading mechanism but the viral exnuclease which is responsible for removing mistakes does not recognize NHC-TP as an error, so that when the viral RNA polymerase is making copies of RNA that contains molnupiravir, then it randomly replaces cytidine or uridine. This causes more mutations that can be survived by the virus or it becomes unable to replicate — this is called lethal mutagenesis or error catastrophe. A Phase IIa study conducted earlier this year showed a reduction in viral load in the upper respiratory tract, which will indirectly reduce transmission.

How has the drug performed against other viruses, including influenza, tested in the past?

The drug has performed well against influenza in animal studies and was set to go into phase-1 trials in 2020. It has also worked well against Ebola and Chikungunya.

Can the virus develop resistance to molnupiravir considering that the drug can induce several point mutations in the virus at random locations?

It is always possible for a virus to develop mutations that will render an antiviral ineffective, but molnupiravir’s mode of action makes it a little less likely than for many other antivirals. If multiple antivirals are available then using a combination that targets different steps in the replication of the virus is the best way to delay the development of resistance. Both remdesivir and molnupiravir target the same enzyme but in different ways, so while ideal to have the same target, it may be worthwhile to test a combination therapy, with the caveat that giving IV infusions as required for remdesivir negates the ease and reach of an oral drug such as molnupiravir.

Is there a possibility that the nucleoside analog can turn out to be mutagenic? Though none were seen in the trial, what are the chances that the drug might cause serious adverse events?

There are opinions that molnupiravir may potentially drive mutagenesis in viral RNA and mammalian DNA. Scientists from Emory who developed the drug say they have not seen any evidence of mutagenicity. In April 2021, Merck reported results of preclinical research using assays that should identify the ability of drugs to induce mutations — animals were given molnupiravir at high doses and for longer times than in human clinical trials, and no evidence of mutagenicity or genotoxicity was found. But the clinical trials excluded pregnant and breastfeeding women and required men to not donate sperm and required either abstinence or contraception for all genders.

Since Merck has signed non-exclusive agreements with generic manufacturers in India to produce the drug for low- and middle-income countries, will we see the drug becoming accessible to people in these countries unlike the vaccines?

With eight Indian companies manufacturing the drug, I assume it will become accessible, but indiscriminate use should be prevented. The last thing we want is for a promising drug to become useless if it is inappropriately used, as happens all too often with antibiotics in India.

Since the virus replication blocking mechanism may not be affected by variants that might emerge in future, can the drug be seen as a substitute for vaccines especially in countries deprived of vaccines?

The drug is not yet in the market and vaccine supply is increasing so this is not an either/or situation. An antiviral to be used in early treatment of an infected person with 50% efficacy in those with conditions predisposing to severity has a role that is very different from vaccines that are intended to protect prior to exposure.

As in the trial, will the drug be restricted for use only in unvaccinated people belonging to the approved categories?

Restricting the drug to unvaccinated individuals makes no sense whatsoever, but using it for people at risk does. The reason for not giving it to vaccinated individuals in the trial was because vaccination reduces the risk of progression to severe disease, which is what the trial wanted to measure. But once the trial is done, we want to prevent progression to severe disease in all infected individuals, vaccinated or unvaccinated. Vaccinated individuals who are older and have co-morbidities continue to have a higher risk of severe disease and certainly should be given the drug if they develop symptoms,

A Merck spokesperson has said what is regarded as a “moderate” case in India is considered severe in the U.S. How does one define “moderate” disease?

The Indian definition was 90-93% oxygen saturation for moderate disease, while anything lower than 93% would be considered severe in the US. The important thing about definitions in trials is that they should be the same measured using the same protocol.

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Printable version | Dec 6, 2021 5:01:24 AM |

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