As Omicron approaches, new COVID tablets offer hope

While the world is concerned that the omicron coronavirus variety could lead to an increase in cases and weaken vaccinations, medication makers have some good news: Two new COVID-19 tablets are on their way, and they should work against all variants of the virus.

The Food and Drug Administration is anticipated to approve molnupiravir, a tablet developed by Merck and Ridgeback Biotherapeutics that decreases the risk of COVID-19-related hospitalisation and mortality by 30% when given within five days after beginning of symptoms.

Another antiviral pill, developed by Pfizer, may perform even better. An interim analysis showed that the drug was 85% effective when taken within five days of the start of symptoms. The FDA could authorize it by year’s end.

Since the start of the pandemic, scientists have hoped for convenient options like these: pills that could be prescribed by any doctor and picked up at a local drugstore.

And these two pills may be just the beginning. With the threat of omicron and other variants looming, scientists say we will need an arsenal of drugs to deploy against new foes — especially if those variants erode the protection of existing vaccines.

Researchers across the world are designing new drugs from scratch, precisely targeting weak points in the molecular structure of the coronavirus. And others are testing whether pills work better in combination than when taken on their own.

“Viruses are wily creatures, and you’ve got to stay ahead of them,” said Dr. Anthony Fauci, the government’s top infectious disease expert. “I think it would be naive to think that if you get one or two good drugs, you don’t need any more — not when you have a virus that has already killed 760,000 Americans.”

Early Efforts

The scramble for COVID-19 pills started last year in the early days of the pandemic. At pharmaceutical companies and academic labs, researchers screened thousands of existing drugs to see if any worked against SARS-CoV-2, the virus that causes COVID-19.

This strategy was a long shot, but a success would have led to an antiviral pill more quickly than trying to make an entirely new drug. What followed was a brutal wave of failures.

Antivirals that worked in Petri dishes failed when tested in animals, and those that worked in animals failed in clinical trials.

Even drugs that made it into trials often proved disappointing. A flu drug called favipiravir delivered promising results in early trials, leading Canada-based Appili Therapeutics to begin a late-stage trial on more than 1,200 volunteers. But on Nov. 12, the company announced that the pill did not speed up recovery from the disease.

“Not everything in research is a big success,” Fauci said.

Merck’s new drug, molnupiravir, was studied in 2019 by a nonprofit company linked with Emory University as a treatment for Venezuelan equine encephalitis virus — a little-known virus feared as a potential bioweapon. When molnupiravir encounters a virus’s genes, it wreaks havoc, leading to a batch of new mutations. New viruses are often left unable to replicate.

In October, Merck announced the initial results of its molnupiravir trial: The drug reduced the risk of hospitalization and death by about 50%. Eager to curb the toll of COVID-19, the U.S. government has bought approximately 3.1 million courses of molnupiravir for about $2.2 billion.

But in the final analysis of the trial, the drug’s effectiveness dropped to 30%.

At a Nov. 30 meeting of an FDA advisory committee, experts discussed the potential for the drug to cause mutations not just in viruses, but in people’s own DNA. The committee voted to recommend authorizing molnupiravir, but only by a slim majority. And even the committee members who voted in favor of the drug expressed reservations, given the potential side effects.

Pfizer’s drug is next to enter the spotlight. Its origins reach back nearly two decades, to when Pfizer researchers were searching for a drug that could fight the coronavirus that caused SARS. They decided to build a molecule that could block an essential viral protein, known as a protease. Proteases act like molecular scissors, cutting long molecules into pieces that help build new viruses.

The drug, originally called PF-00835231, lodged in the protease like a piece of gum crammed between scissor blades. PF-00835231 proved effective against SARS when given intravenously to rats.

The SARS epidemic ended before the Pfizer could launch a clinical trial. But after the COVID-19 pandemic hit last year, researchers at the company pulled the drug off the shelf to try against SARS-CoV-2.

They modified it to work against the protease of the new coronavirus and tinkered with the molecule so it would work as a pill. Paxlovid, as Pfizer has branded the drug, came out of clinical trials last month with terrific initial results: 85% effectiveness if taken within five days of the onset of symptoms. It remains to be seen if the number stays that high in the final analysis.

Shortly after announcing the interim results, Pfizer applied for FDA authorization of Paxlovid and reached a deal with the U.S. government to provide up to 10 million courses of the drug for $5.3 billion.

As the FDA reviews the company’s application, it will consider not just the effectiveness of Paxlovid, but also its potential side effects. Unlike molnupiravir, Paxlovid does not introduce mutations, so it probably won’t raise the same red flags.

“Given that it works through a different mechanism unrelated to our genetic material, it is less likely to cause changes in our DNA,” said Sara Cherry, a virus expert at the Perelman School of Medicine at the University of Pennsylvania. But, she added, “protease inhibitors have different liabilities.”

Our own cells make proteases, which we use to whittle down our own proteins, enabling them to perform new jobs. Although many protease-inhibitor drugs have proved safe, some of them can also lock onto our proteases instead of the proteases made by viruses. Still, the short course of pills needed to stop COVID-19 may reduce any such risk from a drug such as Paxlovid

Cherry said the advent of two antiviral drugs for COVID was “super exciting,” especially as omicron spreads across the world. The pills will be particularly welcome, she said, if omicron — or another new variant — turns out to reduce the effectiveness of vaccines. The worrisome mutations in omicron are in the virus’s outer spike protein, which has nothing to do with the pills’ viral targets.

“That will definitely help us as a stopgap, if we really do need to change the vaccines,” Cherry said.

Winning Combinations

If history is any guide, the first antiviral pills to show promise won’t be the best. The first pill for HIV, a cancer drug called AZT, caused serious side effects and led to the evolution of AZT-resistant versions of the virus.

Years later, pills that target HIV’s proteases proved to be less toxic and more effective than AZT. Scientists also found that combining the pills could make them more effective. It was also harder for viruses to evolve resistance to the drug cocktails.

Cherry and her colleagues are mixing antiviral drugs to see how well they work. In tests on infected human cells, they have found that combining molnupiravir and Paxlovid creates a more powerful impact than either drug has on its own.

This combined effect is known as additivity. But researchers are also searching for combinations that create “synergy”: an effect that is bigger than just adding the effects of two drugs together.

“Additivity means one plus one equals two, and synergy means one plus one equals four,” said Dr. Mark Denison, a virus expert at Vanderbilt University Medical Center. “And those are possible.”

Fauci, who oversaw the development of combination therapy for HIV 30 years ago, said that the National Institutes of Health would be able to quickly test combinations of pills for COVID-19 in clinical trials.

And through the newly formed Antiviral Program for Pandemics, Fauci’s agency will have $3 billion to fund academic research centers developing new drugs. The first results from those studies, he said, could arrive in about a year.

Coronaviruses produce a host of proteins essential for their replication, and each could be a target of a new drug. When an infected cell makes a new piece of the virus’s RNA, for example, a viral protein called a helicase has to unwind it before it can be packaged into a new virus shell. Researchers are investigating drugs that block the coronavirus helicase, leaving the virus’s genes in a tangled mess.

Other researchers are aiming to attack not viral proteins, but the genetic material of the viruses. When a coronavirus injects its RNA into a human cell, the molecule squirms into loops and kinks. These structures can then manipulate the human cell and are crucial for the virus’s survival.

In recent years, a handful of drug developers have gone after these tangles of RNA. “It’s a pretty small club,” said Amanda Hargrove, a chemist at Duke University.

Hargrove and her colleagues have modified various versions of a blood-pressure drug called amiloride so that they can latch onto viral RNA. In a study published Nov. 26, the researchers found three amilorides that grab the RNA of SARS-CoV-2. In a laboratory experiment using infected monkey cells, they found that the amilorides could reduce the production of viruses thirtyfold.

If any of these experimental drugs prove effective, they could open the way for even more potent cocktails.

“You want to hit the virus from every single side,” Denison said. “You want to slash the tires and foul up the engine and screw up the brakes.”

At the Walter Reed Army Institute of Research, researchers are trying to build a pill that will work against all coronaviruses. They are looking for targets common to all coronavirus proteases. At the start of the pandemic last year, they screened 41 million compounds with the help of a computer trained to recognize potential drugs.

They ran experiments on the 800 best candidates and found just a few top contenders, which they are now testing in mice.

Lt. Col. Brandon Pybus, one of the Walter Reed researchers, said using artificial intelligence shaved many years off the project. But because they are making a drug from scratch, they will not be able to move as fast as Merck or Pfizer toward an authorized pill. “It could be a matter of a few years, if resources permit,” he said.

Fauci and his colleagues intend to use the same strategy to search for antiviral pills that work on other viral families, such as flaviviruses, which cause diseases such as dengue fever and West Nile fever, and togaviruses, which cause mosquito-borne diseases such as chikungunya and eastern equine encephalitis.

“I have a great deal of confidence,” Fauci said, “in the creative ability of the investigators that are out there, some with crazy ideas, and some with ideas that look crazy that turn out to be really, really good.”