As Covid-19 Pills rolls in, worry mounts that resistance could develop

US researchers and health regulators worry Covid-19 will find a way to avoid key new drugs, prompting efforts to look for signs of that resistance and find ways to combine it. to prevent it.

Treatments — Paxlovid from

Pfizer Inc.

and molnupiravir from

Merck

& Have. and Ridgeback Biotherapeutics LP — is the first drugs authorized by federal health regulators that people who develop an early infection can easily do it at home to avoid becoming seriously ill.

However, viruses are notorious for mutating in ways that allow them to outmaneuver antiretroviral drugs, especially when the drugs are used alone as is the case with the new Covid-19 pills.

That’s why other viral treatments like HIV and hepatitis C include multiple medications. The combination reduces the risk of drug resistance due to mutation because the virus is forced to work harder to survive.

Merck and Ridgeback Biotherapeutics developed molnupiravir, its chemical name.


Photo:

Kobi Wolf / Bloomberg News

The Covid-19 medicine promises to keep people out of hospitals and slow the spread of coronavirus, but drug resistance could jeopardize the usefulness of medicine and dealing with an obstacle as businesses and schools are forced to stay afloat.

“We knew this was likely to happen at some point, so we needed to beat it and smother it in its infancy before it could happen,” said Katherine Seley-Radtke, a pharmacological chemist. it got out of hand and started to take over. professor at the University of Maryland, Baltimore County, where the laboratory is working on antiviral combination therapies.

However, some researchers and drug manufacturers say the risk that resistance could develop to the new Covid-19 pills is very low because they are only used for 5 days, a period too long. short for the virus to mutate meaningfully.

The FDA has approved Merck’s new Covid-19 therapy, molnupiravir, the newest antiviral that adults can take at home to ward off serious illness. WSJ’s Daniela Hernandez explains the science behind the new drug. Photo: Merck

HIV is more likely to develop resistance against treatment with a single drug, researchers say, because it is more susceptible to mutating as it multiplies than the pandemic coronavirus. Another factor: the course of treatment for a chronic illness takes much longer than for an acute infection.

The Pfizer and Merck researchers said they did not see resistance develop during clinical trials evaluating the pills. The company’s researchers also say each pill has characteristics that help reduce the risk of drug resistance, although they’re looking for any markers.

Viruses are pieces of genetic code encased in protein envelopes. They can survive and grow only by infecting cells that they have acquired the machinery to reproduce and spread.

As the virus makes copies of itself, it can mutate to evade treatments that aim to get rid of it. Genetic changes tend to occur while the virus is replicating early in the course of the disease, when antiviral drugs are usually most effective.

The Food and Drug Administration has required Pfizer and Merck-Ridgeback to monitor drug resistance and submit a monthly report on their findings as a condition of allowing the new pills.

The FDA also said it may require drug manufacturers to assess whether their drugs are suitable for any of the variants of interest and must provide drug samples to the government for review.

“As with any virus, SARS-CoV-2 is no exception, with the potential for emerging drug resistance that could affect existing therapies,” the agency said. “Therefore, the FDA introduced mechanisms as part of the authorization to help the agency understand the potential impact of variations on these products.”

Pfizer researchers say they found no resistance to the drug during clinical trials of Paxlovid, known by its brand name.


Photo:

Kobi Wolf / Bloomberg News

The pandemic virus may develop more resistance to Paxlovid than to molnupiravir, the independent researchers say, because the pills work in different ways to prevent the virus from replicating.

Paxlovid, known by its brand name, blocks the virus by blocking an enzyme – called protease – that is involved in the replication process.

Molnupiravir, which belongs to another class of antiviral drugs, prevents the virus from replicating by tricking an enzyme it needs to replicate, called polymerase, to insert the error into the coronavirus genome, thereby shorting the circuit. progress.

Dr Seley-Radtke said the structure of Molnupiravir, which resembles the genetic molecule, makes it harder for the virus to function.

The independent researchers say the virus has developed resistance to both drugs, although it may take longer to emerge for the class of molnupiravir.

“I’ve been in antivirals for 35 years and there’s no drug that I know of that is resistant,” said John Mellors, an infectious disease expert at the University of Pittsburgh.

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Using a combination of drugs can help block the virus’s attempts to bypass and evade treatment, by attacking the virus at different steps in its attempt to replicate.

“Think of it like Swiss cheese,” said Carl Dieffenbach, director of the AIDS division at the National Institute of Allergy and Infectious Diseases, who studies the development of Covid-19 antiviral drugs. “Swiss cheese has holes in it, and if you have slices of Swiss cheese on top of each other, nothing can get through.”

The National Institutes of Health wants to test Covid-19 combination therapies when several drug options are available, Dr. Dieffenbach said.

Pfizer is working on potential new Covid-19 antivirals and trying to see what combinations might work, if needed, said Annaliesa Anderson, Pfizer’s head of research on Paxlovid.

Research from the company published last year in the journal Nature found that the infusion version of Paxlovid works well with remdesivir, an antiviral drug from

Gilead Science Inc.

currently used for hospitalized patients.

Dr Anderson said: “So far we haven’t seen anything that interests us, but we are continuing to look to see if there is an Achilles heel in the strategy we are in.

blank

A technician oversaw the production of remdesivir last year in Cairo. Gilead is allowed to be used for hospitalized and non-hospitalized Covid-19 patients.


Photo:

Mohamed Abd El Ghany / Reuters

Merck is considering a merger molnupiravir with other drugs, including remdesivir, also known as Veklury, said Daria Hazuda, Merck’s vice president of infectious disease detection.

Dr. Hazuda says that combination would be interesting because Veklury-related resistance mutations are more susceptible to molnupiravir infection, making it more effective.

Veklury has just been authorized for use in non-hospitalized patients. However, it will be difficult for people to use at home with molnupiravir because it is given as a three-day infusion.

An oral version of Veklury will begin early-stage testing this quarter, but even if the trials prove successful, it won’t be available until next year at the earliest, Gilead CEO Daniel O’ Day said.

Merck scientists have not yet looked at whether molnupiravir can work safely with Paxlovid, although the drugmaker is also developing its own protease inhibitor, Dr. Hazuda said.

“I always say we should never bet against the virus,” she said.

Finally, there may be more antiviral drugs that can be tested in combination with Paxlovid or molnupiravir, including one from

Shionogi

& Co, which the Japanese company said could soon begin a late-stage trial with results by the end of the year.

The Biden administration is investing $3 billion in the development and production of a Covid-19 antiviral drug.

7 analysis from Airfinity in London, there are 18 Covid-19 trials aimed at attracting more than 100 people to test antiviral drug combinations, not involving Paxlovid or molnupiravir.

Write letter for Jared S. Hopkins at jared.hopkins@wsj.com and Felicia Schwartz at felicia.schwartz@wsj.com

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https://www.wsj.com/articles/as-covid-19-pills-roll-out-worry-mounts-that-resistance-could-develop-11642847405?mod=pls_whats_news_us_business_f As Covid-19 Pills rolls in, worry mounts that resistance could develop

Ian Walker

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