Even as vaccines are rolled out, the holy grail of the pandemic, a drug to successfully treat COVID-19, continues to elude medicine.
On Monday, a World Health Organization panel asked scientists to stop investigating hydroxychloroquine, the example of drugs that did not 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 even more urgent.
“The end result of what we have to do going forward, and the clear need for this, is the development of powerful antivirals that act directly on SARS-CoV-2,” Anthony Fauci, head of the National Institute of Allergies and Infectious Diseases, he said at a briefing at the White House last week. Antivirals would revolutionize the fight against SARS-CoV-2, as they block the replication of viruses and can prevent people from getting seriously ill or dying.
But efforts to develop such drugs have languished due to a lack of funding and coordination: While Operation Warp Speed dedicated nearly $ 18.75 billion to developing vaccines, it only set aside $ 6.34 billion for drugs. Instead, the 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. So far, the FDA has only licensed one drug to treat COVID-19, remdesivir, initially developed against Ebola. But it is far from a perfect drug: The results on how it affects the length of hospital stays have been mixed and it has not been shown to reduce deaths.
“There is nothing wrong with looking for quick fixes, but you will also have to make the investment in the long term,” Fauci said, noting that finding effective new drugs would take months to a year. The goal would be to develop drugs that are explicitly designed and targeted at SARS-CoV-2, such as the “spectacularly successful” anti-HIV and hepatitis C events that make deadly diseases treatable, he said.
But that is 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 clinical trial partnership, called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). There are no newly designed antivirals included 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 those taken by former President Donald Trump, which are difficult to administer to patients because they require hour-long transfusions near the onset of an illness.
Scientists have tried repurposing 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 reduced deaths among COVID-19 patients using ventilators by about a third, a compelling argument for looking for another needle in the haystack of older drugs that could work directly against the virus.
“There are many reasons to use these FDA-approved drugs, because they already have known properties in human patients,” said Texas A&M biochemist Wenshe Ray Liu, who is researching new and repurposed drugs to combat the coronavirus. And testing them is relatively easy: Companies just have to dose the infected cells into test tubes with their library of existing drugs and extract the ones that appear to block SARS-CoV-2. Because they have already been screened, winners can go straight to clinical trials without extensive studies to show they are safe.
Clinical trials are expensive, Liu added, and drug companies prefer to test drugs that they have already spent money developing. For both reasons, drug companies have largely conducted small clinical trials with very few patients to show that their own drugs worked, in the hope of success. Those patients have little incentive to sign up to try the experimental drugs in the early stages of the disease when they are not terribly ill.
Molnupiravir, an antiviral designed to fight the flu, is one example of the challenges clinical trials face in testing 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 would lower levels of the virus. It is expected to end in December 2021, which will take three to four times longer than vaccine trials that enrolled tens of thousands of people. In addition to other challenges, the study measures reducing viral loads rather than improving patients’ symptoms, which may not convince the FDA of its benefits.
These kinds of hurdles are one of the reasons why repurposed drugs haven’t shown many benefits for patients. And while NIH-funded scientists are studying more than a dozen old drugs for diseases like arthritis, cancer, malaria, hepatitis or gout to see if they can fight SARS-CoV-2, the only antiviral. In addition to remdesivir in clinical trials is a Japanese drug for pancreatitis developed in the 1980s. Results from that trial, which began last August, are projected for the end of this year.
Smaller trial results for molnupiravir could come as early as May, said University of North Carolina virologist Victor Garcia-Martinez, who led a study in February that showed the drug was very effective in mice equipped with human lung tissue. If it eventually turns out to be effective, García-Martínez said, “This will be easy to manufacture and distribute. In particular, if there is an outbreak, for example in a nursing home, it can immediately spread it to people. “
The coronavirus has characteristics that make it difficult to find an effective drug to combat it, but there is reason to be hopeful.
Many drugs regularly hamper viruses in test tubes, even other coronaviruses, said drug researcher Martin Michaelis from the University of Kent in the UK. Scientists were initially optimistic that these drugs would work similarly against SARS-CoV-2, but this virus is different enough that most of those drugs are ineffective.
In a recent study, Michaelis and his colleagues established the differences between SARS-CoV-2 and its closest relative that infects humans, the SARS virus, which killed 774 people after the 2002 outbreak. 80% genetically similar, the two viruses differ in the biological machinery they use to replicate within cells, Michaelis and his colleagues found. That’s important because interfering with this viral replication is a primary task of antiviral drugs. If viruses can’t replicate, they can’t spread.
Although the spikes on the outside of the coronavirus are now wildly mutating to produce more contagious variants, the virus has less freedom to change its reproductive process, Michaelis said. This is because the same machinery is vital in other basic viral functions as well, making it a more reliable target for drugs that target the virus.
“You can’t say that these conserved regions will never mutate,” he said, “but it’s a lower probability.”
Examples of new antivirals designed specifically against SARS-CoV-2 are emerging 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 that we may find useful such as COVID-19 medications. A year after the pandemic, scientists know much more about how SARS-CoV-2 works and may be better equipped to find existing drugs that can attack it, said Liu of Texas A&M. His team recently found a high blood pressure drug that in a computer simulation fits like a key in a lock for the coronavirus. The drug may have been overlooked because it is a generic and does not have a corporate sponsor willing to invest in a clinical trial.
“We will try to start our own clinical trial if we cannot find a corporate sponsor,” Liu said.
More money is needed to push treatments as much as we did vaccines.
On March 11, 2020, the day the WHO first declared the pandemic, Fauci testified before Congress that there were two avenues for medicine to address the coronavirus: vaccines or drugs.
From a scientific perspective, there were many reasons to expect an effective antiviral drug to appear before a vaccine, Fauci told BuzzFeed News. “In general, it is known relatively quickly if a [drug] the treatment works or not because you are treating someone who is already sick, “he said.
Meanwhile, a vaccine requires administering real injections and placebos to tens of thousands of people and then waiting until natural infections cause enough infections to show that it is effective.
“We were lucky to have a couple of candidate vaccines that were red hot and they really turned out to be good,” Fauci said. “And unfortunately for the country, but fortunately for vaccine trials, we continue to have a high level of infection, which allowed us to get a response quite quickly.”
Vaccines trigger a well-understood natural immune reaction, making their design and safety testing simpler compared to newer antivirals, Michaelis added. But the US vaccine trials were also significantly more funded than treatments.
“There isn’t a lot of money on antiviral drugs for acute illnesses that are only used for a week or so,” Michaelis said. The lack of a clear path means that new antivirals explicitly designed against the coronavirus will likely require large public investment, Fauci said. The NIH recently began an initiative to research new antivirals, which would be “unlikely to provide treatments in 2021,” NIH chief Francis Collins told the New York Times.
Somehow, the lack of COVID-19 antivirals underscores how fortunate humanity is to have effective vaccines, Michaelis said.
“People tested many, many compounds against SARS-CoV-2, COVID-19, but so far they haven’t had the big, big, successful candidate,” he said. Moving on to create new drugs, he added, “gets harder and harder work.”