New COVID pills offer hope as omicron looms
By Carl Zimmer
As the world worries that the omicron coronavirus variant may cause a surge of cases and weaken vaccines, drug developers have some encouraging news: Two new COVID-19 pills are coming soon, and are expected to work against all versions of the virus.
The Food and Drug Administration is expected to soon authorize a pill made by Merck and Ridgeback Biotherapeutics, called molnupiravir, which reduces the risk of hospitalization and death from COVID-19 by 30% if taken within five days of the onset 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.
“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.”
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.
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%.
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.”
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.
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.