Even as vaccines roll out, the pandemic’s holy grail — a drug to successfully treat COVID-19 — continues to elude medicine.
On Monday, a World Health Organization panel called for scientists to quit researching hydroxychloroquine, the poster child for drugs that failed to work against the coronavirus. Meanwhile, more than 40,000 people are still hospitalized nationwide with COVID-19, and only a handful of mediocre therapies can help treat them. And with new variants threatening to thwart vaccines, finding drugs to fight SARS-CoV-2 is all the more urgent.
“The bottom line of what we need to do looking forward, and the clear need in this, is the development of potent antivirals directly acting on SARS-CoV-2,” Anthony Fauci, chief of the National Institute of Allergy and Infectious Diseases, said at a White House briefing last week. Antivirals would revolutionize the fight against SARS-CoV-2, since they block viruses from replicating and can stop people from getting very sick or dying.
But efforts to develop such drugs have languished because of a lack of funding and coordination: While Operation Warp Speed devoted nearly $18.75 billion to develop vaccines, it only set aside $6.34 billion for drugs. Instead, scientists tried to repurpose older drugs, including antivirals for other diseases, to see if they worked against COVID-19.
“Everyone was looking for a quick fix,” Fauci told BuzzFeed News. The FDA has so far only authorized one drug to treat COVID-19, remdesivir, initially developed against Ebola. But it is far from a perfect drug: Results on how it affects the length of hospital stays have been mixed, and it has not been shown to reduce deaths.
“There's nothing wrong with looking for quick fixes, but you'll also have to make the long-term investment,” Fauci said, noting the search for effective new drugs would take anywhere from months to a year. The goal would be to develop drugs that are explicitly designed and targeted to SARS-CoV-2 like the “spectacularly successful” ones made against HIV and hepatitis C, which made the deadly diseases treatable, he said.
But that’s not happening yet. After evaluating hundreds of older drugs, the National Institutes of Health has no new antivirals for COVID-19 in its public-private partnership of clinical trials, called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). There are no newly designed antivirals listed among the 160 NIH-supported clinical trials registered by the National Library of Medicine. Operation Warp Speed’s “medical countermeasures” effort also contains no new antivirals.
The only new treatments on the ACTIV list are monoclonal antibodies — like the ones former president Donald Trump took — which are difficult to give patients because they require hourlong transfusions near the start of an illness. ("HHS is working to increase awareness of the therapeutics and provide [monoclonal antibodies] to more types of sites," according to an agency statement. Agency figures suggest monoclonal antibody use for outpatients at high risk of developing severe COVID-19 has risen to approximately 34%, up from 20% in December.)
Scientists have tried to repurpose older drugs to help treat COVID-19 — without much success.
The most successful repurposed drug in the pandemic has been dexamethasone, a steroid invented in 1957 — so long ago that Fauci said he prescribed it in graduate school. Instead of attacking the coronavirus, dexamethasone suppresses the immune system, which can turn the body against itself and attack vital organs in the later stages of COVID-19. This cheap and safe drug lowered deaths among COVID-19 patients on ventilators by about a third, a compelling argument to look for another needle in the haystack of older drugs that could work directly against the virus.
“There’s a lot of reasons to use those FDA-approved medications, because they have already known properties in human patients,” said Texas A&M biochemist Wenshe Ray Liu, who is researching both new and repurposed drugs to fight the coronavirus. And testing them is relatively easy: Companies just have to dose infected cells in test tubes with their library of existing drugs and pull out the ones that seem to block SARS-CoV-2. Because they've already been vetted, the winners can go straight into clinical trials without extensive studies to show they are safe.
Clinical trials are expensive, Liu added, and pharmaceutical companies prefer to test drugs they’ve already spent money to develop. For both of those reasons, drug companies have largely pursued small clinical trials with too few patients to show that their own drugs worked, hoping to hit a home run. Those patients have little incentive to sign up to test the experimental drugs at the early stages of the disease when they aren’t terribly sick.
Molnupiravir, an antiviral designed to fight the flu, is an example of the challenges facing clinical trials to test promising drugs. Safety trials this summer looked promising for the drug, and the drug company Merck started a larger clinical trial of 1,300 patients in October to see if it will lower virus levels. It is expected to end in December 2021, taking three to four times longer than vaccine trials that enrolled tens of thousands of people. On top of other challenges, the study measures reduced viral loads rather than improved patients’ symptoms, which might not convince the FDA of its benefits.
These kinds of hurdles are one reason that repurposed drugs haven’t shown much benefit in patients. And while NIH-funded trials are studying more than a dozen old drugs for diseases such as arthritis, cancer, malaria, hepatitis, or gout to see if they can fight SARS-CoV-2, the only antiviral besides remdesivir in ACTIV's clinical trials is a Japanese pancreatitis drug developed in the 1980s. Results from that trial, which started last August, are projected for the end of this year.
Results from smaller trials for molnupiravir should come sooner, said University of North Carolina virologist Victor Garcia-Martinez, who led a February study showing the drug was very effective in mice equipped with human lung tissue. Ridgeback Biotherapeutics, which is developing the drug with Merck, presented some preliminary results from that trial in 202 hospitalized adults at a scientific conference on Saturday morning. Those showed a quicker decrease in virus levels on nasal swabs of patients who took the drug, compared to those who didn't. The firm hopes to present full results showing whether the drug completely eliminated the virus faster at an upcoming medical meeting.
If it eventually proves effective, Garcia-Martinez said, “This will be easy to manufacture and distribute. Particularly if there is an outbreak, say, in a nursing home, you can get it right away to people.”
The coronavirus has characteristics that make it hard to find an effective drug to fight it — but there is reason to be hopeful.
Many drugs regularly hobble viruses in test tubes, even other coronaviruses, said drug researcher Martin Michaelis of the University of Kent in the United Kingdom. Scientists were initially optimistic that these drugs would similarly work against SARS-CoV-2, but this virus is different enough that most of those drugs may not be effective.
In a recent study, Michaelis and colleagues laid out the differences between SARS-CoV-2 and its closest human-infecting relative, the SARS virus, which killed 774 people after the 2002 outbreak. While they are about 80% similar genetically, the two viruses differ in the biological machinery they use to replicate inside cells, Michaelis and his colleagues found. That’s important because interfering with this viral replication is a main task of antiviral drugs. If viruses can’t replicate, they can’t spread.
Although the spikes on the outside of the coronavirus are now mutating wildly to produce more contagious variants, the virus has less freedom to change its reproductive process, Michaelis said. That’s because the same machinery is also vital in other basic viral functions, making it a more reliable target for drugs taking aim at the virus.
“You can’t say these conserved regions will never mutate,” he said, “but it is a lower probability.”
Examples of new antivirals designed specifically against SARS-CoV-2 are now turning up in animal studies. A Feb. 18 report by Chinese researchers in the journal Science found that two drugs successfully reduced viral loads in the lungs of mice.
And there are other signs we may find helpful COVID-19 drugs. A year into the pandemic, scientists know much more about how SARS-CoV-2 works and may be better equipped to find existing drugs that could attack it, Texas A&M’s Liu said. His team recently found a high blood pressure drug that in a computer simulation fits like a key in a lock to the coronavirus. The drug may have been overlooked because it’s a generic and doesn’t have a corporate sponsor willing to invest in a clinical trial.
“We’ll try to start our own clinical trial if we can’t find a corporate sponsor,” Liu said.
More money is needed to push as hard on treatments as we did on vaccines.
On March 11, 2020, the day that the pandemic was first declared by the WHO, Fauci testified to Congress that there were two avenues for medicine to address the coronavirus: vaccines or drugs.
From a scientific perspective, there were a lot of reasons to have expected an effective antiviral drug to turn up sooner than a vaccine, Fauci told BuzzFeed News. “You generally know relatively quickly whether a [drug] treatment works or not because you're giving a treatment to somebody that's already sick,” he said.
A vaccine, meanwhile, requires giving real shots and placebos to tens of thousands of people and then waiting until natural infections cause enough infections to show it’s effective.
“We were fortunate in that we had a couple of vaccine candidates that were red-hot and really turned out to be good,” Fauci said. “And unfortunately for the country, but fortunately for the vaccine trials, we continued to have a high level of infection, which allowed us to get an answer pretty quickly.”
Vaccines trigger a well-understood natural immune reaction, making their design and safety testing more straightforward compared to new antivirals, Michaelis added. But the US vaccine trials also had significantly more funding than ones for treatments.
“There is not that much money in antiviral drugs for acute diseases that are only used for a week or so,” Michaelis said. The lack of a clear path means new antivirals designed explicitly against the coronavirus will likely require a big public investment, Fauci said. The NIH only recently started an initiative to research new antivirals, which would be “unlikely to provide therapeutics in 2021,” NIH chief Francis Collins told the New York Times.
In some ways, the lack of COVID-19 antivirals underscores just how lucky humanity is to have effective vaccines, Michaelis said.
“People tried many, many compounds against SARS-CoV-2, COVID-19, but they just haven’t had the big, big, successful candidate so far,” he said. Forging ahead to create new drugs, he added, “becomes tougher and harder work.”
This post has been updated with HHS figures on monoclonal antibody use.
This post has been updated with the preliminary results from the Ridgeback Biotherapeutics presentation on Saturday morning.