Before this pandemic is over, scientists are preparing to fight the next one.
Anthony S. Fauci, chief medical adviser to the administration, and David Kessler, chief science officer for the covid-19 response, began brainstorming the idea late last year. With remarkably effective vaccines rolling out, their initial focus was on drugs that could make the next pandemic less devastating. But as virus variants emerged and it became clear that even a historic vaccination campaign wasn’t likely to eradicate the coronavirus, they accelerated the deadline.
“The focus was to reinvigorate the nation’s antiviral program over the next three to five years. What’s become more clear, as the pandemic has come into focus, is we have to do it this fall,” Kessler said. “We need this set of tools to close out this pandemic. … The hard thing is to recognize with all the success, there’s still several hundred deaths a day.”
The $3.2 billion represents a multiyear investment to jump-start basic science research to develop new drugs and test whether existing drugs show promise. The funding will support clinical research and manufacturing. The focus initially is on this coronavirus but will expand into collaborative drug discovery programs focused on viruses that have the potential to spark a pandemic.
At the same time, the government has started placing preorders for antiviral drugs for this pandemic — before they have been shown to work. It’s a strategy similar to the one used to encourage vaccine development.
“The aim of the program is to catalyze the development of new medicines to combat covid-19, but also to provide a structure, a durable structure, to prepare from a therapeutic standpoint against any of the pandemic threats,” Fauci said.
Short memories, vanishing viruses
For months, scientists who work on therapies for viruses have debated whether the pandemic will be a wake-up call, an event that triggers sustained investment in an area increasingly neglected as drug companies seek more lucrative targets. Many have been skeptical much will change, aside from perhaps a temporary surge of drug development against coronaviruses.
“Investors are totally uninterested in antivirals. Even if you can demonstrate you can make a couple billion dollars, nobody cares,” said Ann Kwong, a virologist who played a leading role in developing an antiviral approved against hepatitis C at Vertex Pharmaceuticals, along with an influenza treatment. “What they really want is a chronic treatment. Nobody ever gets cured of high cholesterol.”
Scientists express hope tinged with doubt that the pandemic will trigger permanent change; among them are coronavirus researchers who learned firsthand how short attention spans can be. After severe acute respiratory syndrome emerged in 2003 and Middle East respiratory syndrome in 2012, scientists who study the viruses thought it was only a matter of time before another one threatened — but sometimes had trouble convincing funders of the urgency.
“The lack of antivirals on the shelf has been a really sad part of watching SARS-2 emerge,” said Matthew Frieman, a coronavirus expert at the University of Maryland School of Medicine. Frieman conducted experiments to sift through existing drugs to see whether any could be repurposed against Middle East respiratory syndrome.
“We had been working on developing this — antivirals for future pandemics. It was problematic to get funded,” Frieman said.
Even if money exists, the development path wasn’t always clear when targeting viruses that disappeared — or have yet to appear.
Norbert Bischofberger, one of the inventors of Tamiflu, an oral antiviral pill for influenza, said coronaviruses were on his radar in recent years when he worked at Gilead Sciences.
“We thought about corona, we knew about corona — we just found it almost impossible to do clinical studies. Let’s say you have a drug, and you want to do a clinical study to show it’s safe and effective. Safe, that’s the easy part,” said Bischofberger, who is now president of Kronos Bio, a company focused on cancer. But to show it works outside of lab experiments? “You need for corona to be around.”
Several scientists who have worked on developing antivirals said that appetite for the drug class had decreased, in part because there wasn’t a clear commercial model. The hope is the new government effort, if it succeeds in a way similar to the investment into HIV, could remove much of the uncertainty from the process.
Closing out the pandemic
So far, the quest for antivirals against covid-19, the illness caused by the virus, has been a list, mostly, of failures.
The anti-malarial drug hydroxychloroquine, the HIV drugs lopinavir and ritonavir, and the anti-parasitic drug ivermectin all showed hints of promise and have been touted at various stages of the pandemic as antivirals. None are recommended for use, although trials continue.
Even remdesivir — the only approved covid-19 antiviral, which is delivered by IV — has been the subject of ongoing debate, with conflicting evidence on how well it works.
Beyond investing to produce drugs against future threats, the U.S. government is making bets on drugs that might, finally, help knock back covid-19. As it did with vaccines, the government has begun placing advanced purchase orders for antiviral drugs even before they are shown to work.
Last week, the administration committed $1.2 billion to buy 1.7 million doses of molnupiravir, an antiviral developed by Merck and Ridgeback Biotherapeutics, if it is authorized. The drug integrates itself into the virus’s genetic code and interferes with the ability of the coronavirus to multiply, leading to “error catastrophe.”
Daria Hazuda, Merck’s vice president of infectious-disease discovery and chief science officer, said data from the late-stage clinical trial of the drug should be available in the last half of the year.
Even with the success in vaccines, Hazuda said she sees a role for an oral antiviral pill in helping thwart the coronavirus: Many countries have low vaccination rates, and vaccines don’t work for everyone. In the United States, several drugs known as monoclonal antibodies are authorized, but they are clunky to implement, typically requiring a lengthy IV infusion early in people’s illness when they still don’t feel very sick.
In addition, variants have already posed a risk to some monoclonals. In May, government health officials paused shipments of a monoclonal antibody cocktail made by Eli Lilly to eight states because it does not work against virus variants spreading in those states. This week, Rhode Island was added to the list.
Antivirals, on the other hand, could offer a way to target multiple variants, or even an entire family of viruses.
“As we’re seeing, the virus can evolve, and with variants cropping up, how well the vaccines will work against variants in the future is, I think, still an open question,” Hazuda said. Antivirals could be variant-proof and even work broadly against multiple coronaviruses.
A tough scientific target
Developing antiviral drugs, particularly for acute viral infections, comes with challenges, researchers said. The window of opportunity to intervene is short — possibly when people barely realize they are sick. Testing antiviral drugs in hospitalized patients has been common during the pandemic because of the clear need. But by the time someone winds up in the hospital, their condition is driven as much by how their body is responding as it is by the virus itself. That limits the potential impact of an antiviral drug.
Bischofberger said one of the most powerful uses of Tamiflu was as a preventive measure — when flu hits a region or a nursing home, people could be given a prophylactic daily pill.
Identifying people early in their course of illness may not prove as hard with covid-19, because of awareness of testing. Still, Hazuda said that unlike flu, the precise trajectory of the disease and how it varies among people is still not well understood, and that poses another challenge.
Because viruses use the infected person’s cellular machinery to replicate, another approach involves developing antiviral therapies that aim at the host, not the virus. That could be a way to design a broad-acting drug against many viruses, but it adds a new wrinkle: the possibility of side effects.
In the end, the business proposition may be the fundamental problem with developing antivirals for acute diseases that often resolve on their own, said Kara Carter, president of the International Society for Antiviral Research and senior vice president of discovery biology at Dewpoint Therapeutics.
A chronic infection may have the same commercial potential as a drug for diabetes or rheumatoid arthritis. But an acute viral infection presents both a scientific challenge and a commercial one.
“You’re probably going to dose those patients for anywhere from five to 10 days, but you require the same amount of expense to develop and discover those drugs,” Carter said.
She and others pointed to the progress of the past year, with drugs in clinical development from Merck, Pfizer, Atea Pharmaceuticals and other companies. Carter cited a widely accepted formula for corralling a pathogen: at least one vaccine plus two antivirals that use different mechanisms to stop a virus.
“There’s going to be money to support it as long as the pain points are still there and being experienced and in people’s memory,” Carter said. “I hope I’m wrong, but as soon as this starts being less of a global health concern, it’s going to be, ‘We dealt with that, it’s done.’”