Virus World

The first crop of antivirals against SARS-CoV-2 is promising. But new drugs will be needed to counter the looming threat of resistance.  The roll-out of COVID-19 vaccines at the beginning of 2021 marked a key turning point in the fight against the global pandemic. Another major milestone arrived at the end of the year, with the approval of two oral antiviral treatments — molnupiravir and Paxlovid — that promise to reduce the number of COVID-19 hospitalizations and deaths. But as these pills slowly make their way into pharmacies worldwide, researchers are already looking ahead to the drugs that could supersede them. “These are our first-generation antivirals against coronaviruses,” says Sara Cherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Our experience with antivirals against other diseases, like hepatitis C and HIV, proves that “we can do better and better over time”, she adds.  Clinical-trial data showed that molnupiravir, developed by the pharmaceutical firm Merck, based in Kenilworth, New Jersey, and the biotechnology company Ridgeback Biotherapeutics in Miami, Florida, cut hospitalizations and deaths by 30%, compared with people who took placebos. Meanwhile, Paxlovid (nirmatrelvir and ritonavir), made by Pfizer, based in New York City, cut hospitalizations and deaths by 89%. UK regulators approved molnupiravir in November and Paxlovid in December, and US regulators granted emergency authorizations for both drugs in December. Other countries have followed suit with their own approvals, and many are negotiating with the drug makers to buy courses of the drugs or to manufacture their own generic versions. For now, the pills are in short supply. Drug makers are still scaling up production of the antivirals, which are in huge demand to treat the highly transmissible Omicron variant. But when they become more widely available — and if their clinical-trial data is borne out in the real world — the pills will become vital tools to prevent people from becoming seriously ill with COVID-19, says Cherry. It’s too soon to tell whether SARS-CoV-2 is likely to develop any resistance to these first-generation antivirals, says Tim Sheahan, a coronavirologist at the University of North Carolina at Chapel Hill. Although its sky-high rate of replication is a breeding ground for mutations, he says, the virus also causes acute infections that offer relatively little time for resistance-causing mutations to accumulate. But the threat of resistance is particularly severe for ‘monotherapies’ such as molnupiravir and Paxlovid that each target only one part of the virus. That’s why it’s imperative to develop new antivirals aimed at different targets, or ones that can be combined into a single treatment to attack the virus on multiple fronts, says Sheahan. 

A race against resistance

Successful antivirals have typically targeted two key pieces of a virus’s biological machinery, a polymerase and a protease, both of which are essential for viral replication. The current COVID pills are no exception: Paxlovid inhibits SARS-CoV-2’s main protease, whereas molnupiravir tricks its RNA polymerase into incorporating part of the drug into the virus’s RNA, creating so many errors that it cannot survive. A third drug — remdesivir, developed by Gilead, based in Foster City, California — inhibits RNA polymerase, but treatment is expensive and currently requires intravenous infusions over three consecutive days, making it inaccessible to many people.  Unfortunately, molnupiravir’s mode of attack means that it might not be wise to include it in a combination therapy, says Luis Schang, a virologist at Cornell University in Ithaca, New York. If the treatment does not completely wipe out the virus in a patient, some of the RNA errors it creates might inadvertently give the virus resistance against the other drug in the combination. That’s why it’s a key priority for researchers to find an accessible drug that effectively blocks the virus’s RNA polymerase, he says, which could be used in partnership with a protease inhibitor such as Paxlovid. One option may be an oral version of remdesivir, which Gilead is currently testing. Other antiviral drug candidates are slowly working their way through the clinical-trial pipeline, says Carl Dieffenbach, director of the division of AIDS at the US National Institute of Allergy and Infectious Diseases (NIAID). He says that one promising candidate is a protease inhibitor, developed by Shionogi & Company, based in Osaka, Japan, and Hokkaido University in Japan, that is currently in phase II/III clinical trials in Asia. The candidate targets the same protease as Paxlovid but would only require patients to take a single pill each day.  That simpler regimen could help to avert the rise of resistance, Cherry says. Unfinished treatments can hasten drug resistance by allowing the virus to develop defences against the drug while it continues multiplying and wreaking havoc in the body. Both molnupiravir and Paxlovid consist of several pills that must be taken twice a day for five consecutive days. “The second you have people taking something multiple times a day when they’re sick is when you have issues with compliance,” Cherry says.

Target practice

Researchers should also develop treatments that target other parts of the virus, Schang says. “This time we got lucky with a virus that encodes both a polymerase and a protease, and here we are two years later with only a suboptimal arsenal,” he says. “We really have to identify and validate new targets for antivirals so that when the next [pandemic] happens, we have a much broader pipeline to choose from.”  Other potential targets include a different protease in SARS-CoV-2 called PLpro, and an enzyme called methyltransferase that stabilizes the virus’s RNA, says Matt Hall, the director of the early translation branch at the US National Center for Advancing Translational Sciences (NCATS). Clear Creek Bio, a biotechnology firm based in Cambridge, Massachusetts, announced on 6 January that it will collaborate with NCATS to develop an oral drug targeting the PLpro enzyme. Dieffenbach says that researchers would ideally like to identify targets that are common to entire families of viruses and inhibit them with a single drug. That would potentially allow public-health officials to rapidly deploy an effective antiviral the next time a novel virus with pandemic potential emerges. Developing such broad-spectrum drugs will take significant public and private investment, and the cooperation of pharmaceutical companies, says Hall. Calls for such efforts were not heeded in the wake of the 2003 SARS-CoV outbreak, he adds, but the latest pandemic has underlined the need for action. Last year, the United States appropriated US$1.2 billion to NIAID to launch the Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern, which will fund basic research on developing antivirals for seven virus families. Hall says this gives him hope that antiviral research will continue even as the COVID-19 pandemic wanes. But all antivirals face an inherent limitation, says Dieffenbach: they must be taken within days of infection to stop a virus from proliferating. Antivirals are only effective if people acknowledge that they might be ill, and can access tests that provide a timely diagnosis. “We can build the best drugs in the world, but if people don’t understand that they have to get on board quickly, they’re not going to do any good,” says Dieffenbach. “Pills do not take themselves.”

Published in Nature (Jan. 22, 2022):

https://doi.org/10.1038/d41586-022-00112-8 

European Union countries can use Pfizer's antiviral COVID-19 pill Paxlovid early after diagnosis of an infection even though its full review for regulatory approval has not been completed, the bloc's drugs regulator said on Thursday. Patients at risk of suffering severe forms of the infection should start the five-day course of Paxlovid as soon as possible after diagnosis or within 5 days of symptom onset but not when supplemental oxygen is already required. "The Agency's advice can now be used to support national recommendations on the possible use of the medicine before marketing authorisation," the European Medicines Agency (EMA) said in a statement.  EMA has given such clearances before for some antibody-based injectable drugs as governments scramble to boost their arsenal to fight the new Omicron variant. Omicron has likely grown resistant to some of those antibody drugs already. read more

Faced with rising coronavirus cases in the region, the EU regulator took similar action with Merck's molnupiravir pill in November. It advised it should be given within five days of first symptoms to treat adults who do not need oxygen support and are at risk of their disease worsening. read more  Data released this week showed Pfizer's pill was nearly 90% effective in preventing hospitalisations and deaths in high-risk patients, and recent lab data suggests the drug retains its effectiveness against the fast spreading Omicron. read more  The EU is still in talks to buy the Merck and Pfizer drugs. It is not clear when, or if, the European Commission will launch joint procurements for these drugs and how many states will buy supplies through the EU scheme or individually. Pfizer said on Tuesday it expected authorisation from the U.S. Food and Drug Administration and other regulatory agencies soon. read more  The decisions come as the region struggles to tame a spike in infections, which threatens to overwhelm healthcare systems and as the rapid spread of Omicron has prompted some governments to reimpose restrictions ahead of the Christmas holidays. read more

EMA Press Release (Dec. 16, 2021) available here  :

https://www.ema.europa.eu/en/news/ema-issues-advice-use-paxlovid-pf-07321332-ritonavir-treatment-covid-19 

Drugmaker Pfizer said Friday its experimental pill designed to fight coronavirus reduced the risk of hospitalization and death for high-risk patients taking part in a trial of the drug.  The company hopes it can eventually offer the pill, given in combination with an older antiviral drug called ritonavir, to people to take at home before they get sick enough to go to the hospital. A so-called interim analysis -- done before the trial was scheduled to end -- showed an 89% reduction in the risk of hospitalization or death from Covid-19 if patients got it soon enough, the company said.  Pfizer released the results in a news release and did not provide scientists to discuss the data ahead of release. The data has not been peer reviewed or published. The company says it will share more specifics in a peer-reviewed paper and in its submission to the US Food and Drug Administration.  On CNN New Day on Friday, Pfizer CEO Albert Bourla said the company planned to submit data to regulators as soon as possible, maybe before Thanksgiving. The company has been testing the drug in adults with Covid-19 who are considered at high risk of progressing to severe illness. The volunteers have been randomly given either the pill combination or a placebo within three days or five days of their symptoms starting. The pill, called Paxlovid and its experimental name, PF-07321332, is what's known as a protease inhibitor. It's designed to stop the virus from multiplying. Giving it along with ritonavir slows its breakdown in the body, the company said. Pfizer said 0.8% of patients who got the drug combination within three days were hospitalized within four weeks -- three out of 389 patients -- compared to 7% of patients who got placebos, or 27 out of 385. And seven of those who got placebos died, Pfizer said. No one who got the treatment died within a month.

Background

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Findings

Interpretation

The first-of-its-kind treatment, Paxlovid, has been found to be highly protective against severe illness. It could be available within a few days.  The Food and Drug Administration on Wednesday authorized the first pill for Covid-19, offering a highly effective defense against severe illness that will arrive as the country endures another major surge of the pandemic. The drug, developed by Pfizer and known as Paxlovid, is authorized for Covid patients age 12 and over who are vulnerable to becoming severely ill because they are older or have medical conditions such as obesity or diabetes. Tens of millions of Americans — including both vaccinated and unvaccinated people — will be eligible if they get infected with the virus. The treatment could be available within a few days. Pfizer’s laboratory studies indicate that its pills are likely to work against the Omicron variant, which has rapidly become the dominant form of new cases in the United States. A clinical trial indicated that Paxlovid is highly effective when taken soon after people start feeling sick. In a final analysis of a key study conducted while the Delta variant was surging, Pfizer’s drug reduced the risk of hospitalization or death by 88 percent when given to high-risk unvaccinated adults within five days of the start of their symptoms. Paxlovid appears to be substantially more effective than a similar antiviral pill from Merck, known as molnupiravir, that is still awaiting authorization by the F.D.A. In a clinical trial, Merck’s drug reduced risk of hospitalization and death for high-risk patients by 30 percent.

Pfizer said Tuesday it signed a licensing agreement to allow broader global access to its experimental Covid-19 pill.  The agreement with the Medicines Patent Pool, a United Nations-backed public health organization, would allow generic manufacturers to make the pill widely available in 95 low- and middle-income countries covering 53% of the world's population, the company said. The pill, known as PF-07321332 or Paxlovid, is to be given in combination with an older antiviral drug called ritonavir.  Earlier this month Pfizer announced topline results from its trial saying that an interim analysis -- done before the trial was scheduled to end -- showed an 89% reduction in the risk of hospitalization or death from Covid-19 among people given the drug within the first three days of symptom onset.  "Pfizer will not receive royalties on sales in low-income countries and will further waive royalties on sales in all countries covered by the agreement while COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization," Pfizer said in the statement. The Medicines Patent Pool, founded by Unitaid 10 years ago, facilitates rapid access to medicines for people in low- and middle-income-countries.