In November, 2021 the US-based multinational pharmaceutical company, Pfizer announced their interim analysis of a phase-2/3 trial to analyse the efficacy of their newly developed oral antiviral drug, paxlovid which is approved by the UK drug regulator, Medicines and Healthcare products Regulatory Agency (MHRA).
In the trial phase these two oral drugs will enhance the COVID-19 treatment process through an easy process. Paxlovid exhibited an efficacy of about 89 per cent in preventing hospitalisation and death in certain high-risk groups within five days of treatment after the symptoms had occurred. Pfizer made the announcement for paxlovid about a month after US-based multinational pharmaceutical company, Merck&Co, had launched its first ever oral antiviral drug for the treatment of COVID-19, molnupiravir. This drug showed an efficacy of about 50 per cent in preventing deaths and hospitalisation due to COVID-19.
Pfizer was initially working towards tackling SARS-CoV-2 through synthesising and pre-clinically analysing protease inhibitors. These tests were being conducted years ago as a possible treatment. The clinical data shared by Pfizer showed that the paxlovid’s Mpro inhibitor had effectively performed on minimising the SARS-CoV-2 and all the human coronaviruses. Additionally, tests performed on human cells and mouse models containing SARS-CoV-2 showed that this form of treatment could also reduce damage to lung tissue. Therefore, this is considered as a significant advancement in the treatment of SARS-CoV-2 and all the other coronaviruses.
Molnupiravir had been originally developed for the treatment of influenza. It now been repurposed for treating COVID patients. It hinders the replication of SARS-CoV-2, which results in reducing the severity of the disease.
Comparisons between Paxlovid and Molnupiravir
Both, paxlovid and molnupiravir, have shown promising results by preventing deaths and hospitalisation of the COVID-19 patients. However, the interim data for these drugs, only belong to the early stages, based on tests performed on about a few hundred people. The analysis showed that the drug minimised the chances of progression to severe disease condition.
For both the trials, patients with at least one risk factor (leading to severe disease) were chosen, that is, the emphasis was on individuals, who required more intense care.
The efficacy of these drugs would mainly depend on the following factors:
- whether the patient’s immune response to infection or vaccination is not mounted due to immunocompromise, and
- for any infections in the unvaccinated people, or breakthrough infections among the vaccinated ones.
The point estimates for paxlovid are greater than those for molnupiravir. However, the two drugs have not been directly compared in the clinical trials. Hence, no certain statement can be made that one of the drugs has an added advantage over the other, based on headline numbers, at such an early stage. However, with the help of further independent clinical trials, the performances of these drugs can be effectively compared. Additionally, there is no evidence that molnupiravir has any noticeable side-effects. However, safety monitoring would be an essential process throughout the life cycle of the drugs.
Working Mechanism of Paxlovid and Molnupiravir
Paxlovid is a ‘protease inhibitor’, originally known as PF-07321332 (in short, 332), given in combination with ritonavir. (‘Protease inhibitors’ are synthetic drugs, used to inhibit the action of HIV-I protease.) Protease is an enzyme, that cuts the protein at a specific sequence of amino acids. The SARS-CoV-2 virus has a protease through which, it cuts one polyprotein into smaller segments, that it requires for its life cycle. This protease, termed ‘Mpro’ or the ‘3CL’ protease, is targeted by 332, which is Pfizer’s protein inhibitor. This stops the cleavage of the SARS-CoV-2 virus. Once the viral protease is unable to function, the SARS-CoV-2 virus would not be able to replicate itself to infect other cells.
On the other hand, the molnupiravir functions by causing many point mutations that prevent the virus from replicating. The two drugs could, however, not be compared based on how they act on the SARS-CoV-2 virus, unless a direct head-to-head clinical trial is conducted.
Impact of Ritonavir Combination on the Efficacy of Paxlovid
Ritonavir, present in the drug, slows down the metabolism of paxlovid, allowing the drug to function for a longer period of time. Ritonavir and lopinavir, used in the combination for the HIV, were analysed for treatment of SARS-CoV-2 in several large and small clinical trials in their early stages. However, they proved to be ineffective.
For any enzymatic activity, the main principle would be to extend the duration for which the drug functions to help reduce the number of doses required. Paxlovid is administered twice a day, but without ritonavir paxlovid needs to be given much more frequently.
Combination of Paxlovid and Molnupiravir
Usually in the case of antivirals, it is sensible to combine their usage to minimise the chances of resistance developing.
However, in case of COVID-19 molnupiravir and paxlovid function differently. One drug causes point mutations on the virus, whereas, another one hinders the replication of the virus. Therefore, combination of paxlovid and molnupiravir should be avoided.
Efficacy of Molnupiravir
The Medicines and Healthcare products Regulatory Agency (MHRA) states that molnupiravir has been authorised for the treatment of patients, who have mild to moderate Covid-19 and at least one risk factor for developing severe illness. The risk factors include obesity, older age diabetes, and heart disease. The MHRA had stated that molnupiravir has been found to be ‘safe and effective’ following a ‘stringent review of the available evidence’.
Molnupiravir has been recommended by a panel of experts as the first at-home treatment for COVID-19. If the US Food and Drugs Administration (USFDA) approves it, the emergency use authorisation (EUA) can be given in different countries including India as well.
Pfizer is also preparing to submit its trial data for paxlovid to the USFDA for getting permission for emergency use authorisation of the oral drug.
Production Estimate of Molnupiravir
Merck has provided a production estimate of about 10 million courses for molnupiravir by the end of 2021. Some of the countries including the USA, Australia, the Philippines, Britain, Japan, Indonesia, Malaysia, Thailand, Vietnam, and New Zealand have already secured deals for purchasing this oral antiviral drug, or are currently in the process of finalising the deals. The company would be supplying around 1.7 million courses to the US government, and about 4,80,000 courses to the UK government. An article published in the Nature magazine stated that based on the current US purchase, a five-day course of molnupiravir would cost about US $ 700.
Pfizer’s New Drug Molecule for Low-Risk Patients
Pfizer is also testing another drug molecule, that could be used by patients belonging to low-risk categories and would ease out the process for treating COVID-19 patients.
However, no drug is 100 per cent safe or 100 per cent efficacious. The more drugs that are available, the more tools one could use for treatment of the infected.
The trials of the two oral drugs have shown promising results and have performed well on patients with risk factors involved. They also work on low-risk individuals as well. However, this needs further evaluation.
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