Paxlovid may be huge advancement for all coronaviruses: Gagandeep Kang

Treatment of people infected with SARS-CoV-2 virus to prevent death and hospitalisation got a shot in the arm when Pfizer announced via press release encouraging results of an interim analysis of a phase-2/3 trial of the antiviral drug paxlovid. The drug showed 89% efficacy in preventing hospitalisation and death in certain high-risk groups when treatment was started within five days of symptom onset. The announcement comes about a month after Merck’s antiviral was found to have 50% efficacy in preventing COVID-19 death and hospitalisation.

November 20, 2021 08:26 pm | Updated 09:35 pm IST

Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore. File

Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore. File

In an email, Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore explains the significance of paxlovid antiviral for treatment, its mode of action, and the need for a combination therapy to reduce the chances of the virus developing resistance.

Compared with Merck’s molnupiravir, will Pfizer’s antiviral oral drug paxlovid be better at sharply reducing the death toll and strain on the health-care system?

Both molnupiravir and paxlovid are likely to have a role to play in prevention of hospitalisations and deaths. What we have at the moment are very early data in a few hundred people with each drug showing that the drugs reduce the chances of progression to severe disease. Both trials chose people with at least one risk factor for progression to severe disease which means that they were focused on individuals most likely to need higher levels of care. The fact that both drugs worked well is an advantage to the health-care system, of course, but is a complement to vaccines, which also play a critically important role in protecting the health-care system.

Where these drugs will especially matter is for those people in whom (i) an immune response to infection or vaccination is not mounted because of immunocompromise and (ii) for infection in the unvaccinated or breakthrough infection in the vaccinated.

Pfizer is currently testing another drug molecule that can be used by people belonging to low-risk groups (without comorbidities). If this candidate drug too shows similar efficacy, can we positively say that COVID-19 is a completely treatable disease for all categories of people?

No drug is 100% safe or 100% efficacious. Therefore, to say any disease is completely treatable in every case is a fallacy. The more drugs we have, the more tools we can use to treat those who acquire infection.

Since both clinical trials were in individuals with risk factors and the drugs worked well, it is likely that they will also work well in people without risk factors, but this will need to be evaluated.

Besides higher efficacy, is there any major advantage of using paxlovid than molnupiravir? Will molnupiravir with a possibility, even if slim, of causing mutagenesis be a differentiating factor?

The point estimates for paxlovid are higher than for molnupiravir, but the two drugs have not been directly compared in a clinical trial, so stating that one has an advantage over the other based on two headline numbers is inappropriate at this early stage. With more independent trials we will be better able to compare performance. So far, we have no evidence that molnupiravir has significant side-effects, but as with all drugs, safety monitoring will be critical throughout the lifecycle.

What is the precise mechanism by which paxlovid prevents viral replication? How is inhibiting a particular protease better than molnupiravir that causes many point mutations that prevent the virus from replicating?

Pfizer’s oral antiviral is a protease inhibitor, originally called PF-07321332, or just 332 for short, given in combination with ritonavir. A protease is an enzyme that cuts a protein at a specific sequence of amino acids. The SARS-CoV-2 virus has a protease which allows it to cut one polyprotein into smaller segments that it needs for its life cycle. This protease called Mpro or the 3CL protease is targeted by 332, Pfizer’s protease inhibitor, which can stop that cleavage, as was shown in Pfizer’s initial publication in Science . With the viral protease out of action, SARS-CoV-2 cannot make more of itself to infect other cells.

You cannot compare two drugs that have different mechanisms of action as being better or worse except in a direct head-to-head clinical trial with the same outcome.

How does the use of an HIV drug ritonavir, which is also a protease inhibitor, improve the efficacy of paxlovid? Since ritonavir is generally used in combination with other HIV protease inhibitor drugs, was it natural to test it in combination with paxlovid to increase efficacy?

Ritonavir extends the duration for which 332 [paxlovid] can act on the 3CL protease. Essentially, ritonavir slows down the metabolism of 332 [paxlovid]. Ritonavir and lopinavir, which are used in combination for HIV, were evaluated for treatment of SARS-CoV-2 in several large and small early clinical trials and shown to be ineffective.

For any evaluation of enzymatic activity, the general principle is to prolong the duration of action so that the number of doses that need to be given can be reduced. Paxlovid is given twice a day, but without ritonavir’s inclusion, 322 [paxlovid] would have needed to be given much more frequently, which is a key factor in reducing compliance with any treatment.

Since paxlovid is a protease inhibitor, can the virus develop resistance faster than when molnupiravir is used? Would it be prudent to use both drugs together to achieve better outcomes and reduce the chances of drug resistance?

With most antivirals it makes sense to combine them to reduce the chances of resistance developing. However, with molnupiravir’s mode of action being the induction of mutations through the random replacement of cytidine or uridine with NHC-TP, a molecule generated by metabolism of molnupiravir, resulting in lethal mutagenesis or error catastrophe, the chances of development of resistance are believed to be low. With paxlovid, it targets an essential protease, so if the virus mutates the protease in order to escape the antiviral drug it is likely to have a fitness cost to the virus. One of the advantages of an oral antiviral that targets viral replication is that the spike protein mutations that we worry about with vaccine induced immunity or with monoclonal antibody therapy will not matter, because the drug has a different target.

Though Pfizer has been developing and testing protease inhibitors against SARS virus, is the development of a novel drug molecule in a short time to specifically treat COVID-19 be seen as a major advancement?

Pfizer originally started its work on SARS-CoV-2 by synthesising and pre-clinically evaluating protease inhibitors years ago as a potential treatment. The data published by the Pfizer team reported that the Mpro inhibitor showed potent antiviral activity against SARS-CoV-2 and all the human coronaviruses.

Testing in human cells and mouse models of SARS-CoV-2 suggest that the treatment could limit damage to lung tissue. The first trial in six individuals was published and the recent announcement, not yet published, showed that paxlovid resulted in an 89% protection against progression to severe disease and no patients treated with the drug died, as compared to 10 deaths in the placebo recipients. This is a major advancement for SARS-CoV-2 and potentially for all coronaviruses.

Even if paxlovid is approved by the FDA, should the drug be tested in India for safety and immunogenicity or efficacy too for approval? Or will it be just a safety and bioequivalence study?

Drugs do not need immunogenicity studies. A small safety and bioequivalence study may be required for the drug to be manufactured in India.

Since Indian generic manufacturers have been producing HIV drugs, will it be difficult for them to manufacture paxlovid?

Pfizer has committed a billion dollars to supporting technology transfer and supporting manufacturing capacity to be established through the Medicines Patents Pool (MPP). Given the experience of the Indian Pharma industry, I see no reason why they should not be able to rapidly ramp up manufacturing, not just for India, but for the 95 countries eligible to receive these drugs under the MPP mechanisms.

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