Analysis: new antiviral drugs represent a significant advance in our ability to quell the global pandemic

By Tim O'Sullivan and J.J. Keating, UCC

In light of mounting evidence of waning protection against Covid-19 several months following vaccination, and the pressure placed on our hospital system as yet another coronavirus wave hits Europe, access to effective antiviral drugs is becoming increasingly important. Two new medicines with significant potential as effective weapons against COVID-19 are Lagevrio® and Paxlovid®.

The European Medicines Agency (EMA) recently approved Lagevrio® as a novel Covid-19 antiviral agent. Lagevrio® contains the drug molnupiravir which is available in capsule form and taken by mouth. Molnupiravir is manufactured by the US pharmaceutical company Merck, Sharp and Dohme, which has several sites in Ireland including Clonmel, Cork and Dublin.

As is often the case in drug discovery, molnupiravir was originally developed as a treatment for a different disease, namely viral Venezuelan equine encephalitis, which is spread by mosquitoes in Central and South America. It was subsequently tested for its activity against coronaviruses and was found to be highly effective against Middle East Respiratory Syndrome (MERS), the result of a respiratory coronavirus which first emerged in the Middle East in 2012. At the start of the recent pandemic, molnupiravir was again investigated as a possible treatment for Covid-19 which is caused by a related coronavirus.

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From CNBC, US White House Chief Medical Advisor Anthony Fauci on Merck's Covid-19 antiviral drug

Molnupiravir targets a viral enzyme known as ribonucleic acid (RNA) polymerase. RNA is the genetic code contained within every coronavirus which acts as a genetic blueprint for creating new copies of the virus. RNA polymerase functions as a cellular photocopier by generating new copies of the viral genetic code which, when combined with a protein coat, creates new viral particles. These virions can then go on to infect other cells in the body and the life cycle of the virus starts all over again.

A key function of RNA polymerase in the viral replication process is to stitch together a series of four chemical building blocks that are found in the RNA genetic code of the virus. Molnupiravir closely mimics the chemical structure of one of these building blocks and is mistakenly incorporated by RNA polymerase into the new copies of RNA. This introduces fatal errors into the new viral genetic code, and, in the words of one virologist, causes the virus to "mutate itself to death".

Molnupiravir reduced the risk of hospitalisation or death by nearly 50% in clinical trials, although this number has been revised down to 30% based on a more recent analysis. These antiviral drugs are usually most effective when administered to patients as early as possible, thereby preventing the virus from gaining a significant foothold in the body. Importantly, molnupiravir is effective against both the dominant Covid-19 Delta variant, as well as the Beta variant first identified in South Africa. Merck have also claimed that their drug will likely be useful against the new Omicron variant.

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From RTÉ 1's Six One News, Pfizer says antiviral pill cuts risk of severe Covid by 89%

A second promising treatment for Covid-19 is Paxlovid® and this has been developed by Pfizer, who are currently seeking emergency approval for its use from the US Food and Drug Administration (FDA). This orally active medicine, known as Paxlovid®, is actually a combination of two different drug molecules. As we have previously explained, the use of combination therapies is quite common in the treatment of viral infections.

The first component of Paxlovid® is a wholly novel antiviral agent (with the temporary name of PF-07321332) which is a powerful protease inhibitor. The main effect of this molecule is to disrupt the viral replication process, but through exploiting a different mechanism to molnupiravir. During replication of the coronavirus genome, the RNA blueprint is transcribed (i.e. converted) into long strings of amino acids. These chains are next chopped up by viral protease enzymes into smaller pieces which make up the proteins of the new viral particles. PF-07321332 prevents the generation of new Covid-19 virions by blocking the cutting action of the proteases.

The second drug component of Paxlovid® is called ritonavir, an anti-retroviral medication, typically used to treat Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immunodeficiency Syndrome (AIDS). The role of ritonavir is to increase the lifetime of PF-07321332 in the body. Ritonavir essentially acts as a 'sacrificial lamb' which prevents the liver from degrading PF-07321332 before it can stop the virus from replicating.

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From DW News, could antiviral drugs mean an end to Covid-19?

Care has to be taken in administering ritonavir to patients who are taking other medications, as ritonavir can also slow down the natural breakdown of other drugs in the body. This can have the effect of prolonging their duration of action which may result in significant side-effects. An example might include someone taking a sleeping pill at night, but still feeling quite drowsy next day.

Treatment of patients with Paxlovid® within three days of displaying Covid symptoms was associated with an 89% reduction in hospitalisation or death. Pfizer has already announced that it will allow generic manufacturers to produce Paxlovid® in 95 low- and middle-income countries. Ireland will also play a key role, with the Pfizer plant in Ringaskiddy, Co Cork supporting production of the drug.

While Lagevrio® and Paxlovid® have demonstrated particularly promising results in clinical trials, they are not the only medicines available for use against Covid-19. In 2020, Gilead Sciences’ product remdesivir, known by the brand name Veklury®, was the first Covid-19 antiviral authorised for emergency use in the European Union. Remdesivir had previously shown some success against the Ebola virus and it can aid recovery from COVID-19 infection.

Dexamethasone, a steroid which has been used in the clinic for many years for the treatment of inflammatory conditions, has shown some efficacy in reducing mortality in hospitalised patients requiring supplemental oxygen therapy. Additionally, several antibody-based medicines are also undergoing clinical trials. While the Covid-19 drugs pipeline is still in its infancy, these new medicines represent a significant advance in our ability to quell this global pandemic.

Dr Tim O’Sullivan and Dr J.J. Keating are Lecturers in Pharmaceutical Chemistry at the School of Pharmacy and School of Chemistry at UCC.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ