Nearly a year into the coronavirus pandemic, with thousands of patients dying every day in the US and months away from widespread vaccination, doctors have few drugs to fight the virus.
A handful of therapies – remdesivir, monoclonal antibodies, and the steroid dexamethasone – have improved care for Covid patients and put doctors in a better position than they did when the virus spiked last spring. But these drugs are not a panacea and are not for everyone. Efforts to reuse other drugs or discover new ones have not been very successful.
The government invested $ 18.5 billion in vaccines, a strategy that resulted in at least five effective products at record speeds. However, investment in drugs was far less, around $ 8.2 billion, most of which went to few candidates, such as monoclonal antibodies. Studies on other drugs were poorly organized.
The result was that many promising drugs that could stop the disease early, known as antivirals, have been neglected. Their studies have stalled either because researchers couldn’t find enough funding or enough patients to participate.
At the same time, some drugs have received sustained investments despite disappointing results. There is now abundant evidence that the anti-malarial drugs hydroxychloroquine and chloroquine did not work against Covid. According to the University of Pennsylvania’s Covid Registry of Off-Label & New Agents, there are still 179 clinical trials involving 169,370 patients in which at least some are receiving the medication. And the federal government poured tens of millions of dollars into an expanded convalescent plasma access program that infused nearly 100,000 Covid patients before there was solid evidence that it worked. In January, these studies showed that this is not the case, at least for hospital patients.
The lack of centralized coordination meant that many studies of Covid antivirals were doomed to failure from the start – too small and poorly designed to provide useful data, said Dr. Janet Woodcock, Acting Commissioner for the Food and Drug Administration. If instead the government had set up an organized network of hospitals to conduct large studies and share data quickly, researchers would now have a lot more answers.
“I blame myself to a certain extent,” said Dr. Woodcock, who oversaw federal government efforts to develop Covid drugs.
She hopes to tame the chaos with new efforts by the Biden administration. In the next few months, she said, the government plans to launch large and well-organized studies on existing drugs that could be repurposed to fight Covid-19. “We are actively working on it,” said Dr. Woodcock.
Brand new antiviral drugs could help too, but it is only now that the National Institutes of Health are putting together a major initiative to develop them, meaning they are not ready in time to tackle the current pandemic.
“These efforts are unlikely to deliver therapeutics in 2021,” said Dr. Francis Collins, the head of the N.I.H., in a statement. “If a Covid-24 or Covid-30 comes, we want to be prepared.”
Although the number of cases and deaths has increased across the country, the survival rate of those infected has improved significantly. A recent study found that the death rate of hospital residents had dropped from 17 percent at the start of the pandemic to 9 percent by June, a trend that has been confirmed in other studies. Researchers say the improvement is in part due to the steroid dexamethasone, which increases survival rates for critically ill patients by suppressing the immune system instead of blocking the virus. Patients may also seek care earlier in the disease. And masks and social distancing can reduce virus exposure.
When the new coronavirus emerged as a global threat in early 2020, doctors desperately tried to find a selection of existing drugs. The only way to tell if they were actually working was to conduct large clinical trials in which some people were given placebos and others were taking the drug in question.
Getting hundreds or thousands of people into such processes was an enormous logistical challenge. At the beginning of 2020, the N.I.H. limited its focus to just a few promising drugs. This support led to the rapid approval of remdesivir and monoclonal antibodies. Remdesivir, which prevents viruses from replicating in cells, may slightly reduce the time it takes patients to recover, but it has no effect on mortality. Monoclonal antibodies, which prevent the virus from entering cells, can be very effective, but only if given before people are sick enough to be hospitalized.
Hundreds of hospitals and universities have started their own trials with existing drugs that are already considered safe, widely used and may also work against the coronavirus. Most of these studies, however, were small and disorganized.
In many cases, the researchers were alone to conduct studies without the support of the federal government or drug companies. In April, when a wave of Covid hit New York City, Charles Mobbs, a neuroscientist at the Icahn School of Medicine on Mount Sinai, heard of interesting work in France pointing to the effectiveness of an antipsychotic.
Doctors in French psychiatric hospitals had found that compared to the staff who cared for them, relatively few patients developed Covid-19. The researchers speculated that the drugs the patients were taking might protect them. One of these drugs, the antipsychotic chlorpromazine, has been shown in laboratory experiments to prevent the coronavirus from multiplying.
Doctors tried starting a try with chlorpromazine, but the pandemic in France – it turned out – temporarily subsided when they finished. Dr. Mobbs then spent weeks preparing to try their own with patients hospitalized on Mount Sinai only to bump into the same wall. “We have no more patients,” he said.
When doctors like Dr. Mobbs could use nationwide networks of hospitals, they could find enough patients to conduct their studies quickly. These networks exist but have not been opened to drug reuse.
Many scientists suggest that the best time to fight the coronavirus is early in an infection, when the virus is multiplying rapidly. However, it is especially difficult to recruit volunteers who are not in a hospital. Researchers need to track down people right after they test positive and find a way to deliver the test drugs to them.
At the University of Kentucky, researchers began one such trial in May to test a drug called camostat, which is usually used to treat inflammation of the pancreas. Scientists thought it could also act as an antiviral Covid-19, as it destroys a protein that the virus depends on to infect human cells. Because Camostat is available in pill form rather than infusion, it would be especially useful for people like the volunteer subjects, many of whom lived in remote rural areas.
But the researchers have tried to recruit enough participants over the past eight months. They have struggled to find patients recently diagnosed with Covid, especially due to the unpredictable rise and fall in cases.
“This was the cause of the delays in essentially all studies around the world,” said Dr. James Porterfield, an infectious disease clinician at the University of Kentucky College of Medicine. Who is running the process?
While doctors like Dr. Porterfield struggled to conduct studies on their own, some drugs have become sensational, hailed as panacea despite the lack of evidence.
The first supposed panacea was hydroxychloroquine, a drug against malaria. TV experts claimed it had healing powers, as did President Trump. Instead of starting one large, well-designed study in many hospitals, doctors started a swarm of small studies.
“There was no coordination and no centralized leadership,” said Ilan Schwartz, an infectious disease expert at the University of Alberta.
Nevertheless, the F.D.A. gave the drug emergency clearance to treat people hospitalized with Covid. When large clinical trials finally showed results, it turned out that the drug was of no benefit – and could even cause harm. The agency withdrew its approval in June.
Many scientists were bitter and viewed all of this work as a waste of valuable time and resources.
“The clear, definite, and compelling lesson from the hydroxychloroquine story to the medical community and the public is that science and politics do not mix,” wrote Dr. Michael Saag of the University of Alabama in Birmingham in November in the New England Journal of Medicine.
Another drug is now gaining popularity before there is strong evidence that it works: the parasite-killing compound ivermectin. Wisconsin Republican Senator Ron Johnson, who extolled hydroxychloroquine in April, held a hearing in December at which Dr. Pierre Kory testified about ivermectin. Dr. Kory, a pulmonary and critical care specialist at Aurora St. Luke Medical Center in Milwaukee, called it “effectively a” miracle cure “for Covid-19.” However, there are no published results from large-scale clinical studies to support such claims, only small, suggestive ones.
Even if the federal government had set up a central test network, as is being tried now, scientists would still have faced inevitable hurdles. It takes time to conduct careful experimentation to discover promising drugs and then confirm that they are really worth investigating further.
“In drug development, we are used to runways that run for 10 to 15 years,” said Sumit K. Chanda, a virologist at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California.
In February, Dr. Chanda and his colleagues looked at a different way of finding a Covid-19 antiviral agent. They examined a library of 13,000 drugs and mixed each drug with cells and coronavirus to see if they had stopped infections.
A couple of drugs showed promise. The researchers tested one of them – a cheap leprosy pill called clofazimine – for several months and conducted experiments on human lung tissue and hamsters. Clofazimin combated the virus in the animals if they received it shortly after infection.
Now, almost a year after starting his research, Dr. Chanda that he can fund the hardest part of drug testing: large and randomized clinical trials that can cost millions of dollars. To complete this phase efficiently, researchers almost always need the support of a large company or the federal government, or both – as was the case with the large clinical trials for the new coronavirus vaccines.
It is unclear how the Biden government’s new drug testing efforts will determine which drug candidates to support. However, if the trials begin in the next few months, they may be able to provide useful data by the end of the year.
Pharmaceutical companies are also starting to fund some studies on reused drugs. A study published in Science this week found that a 24-year-old cancer drug called plitidepsin was 27 times more effective than remdesivir in laboratory experiments at stopping the coronavirus. In October, a Spanish pharmaceutical company called PharmaMar reported promising results from a small safety study involving plitidepsin. Now the company is preparing to launch a late-stage study in Spain to see if the drug works compared to a placebo.
Pharmaceutical company Merck is conducting a large, late-stage study of a pill called molnupiravir, originally developed by Ridgeback Biotherapeutics for influenza that has been shown to cure ferrets from Covid-19. The first results of the study could already be available in March.
Experts are particularly excited to see this data as molnupiravir may treat more than just Covid-19. In April, scientists found that the drug could also treat mice infected with other coronaviruses that cause SARS and MERS.
Any antivirals that could emerge in 2021 will not save the life that Covid-19 has already lost. However, it is possible that one of these drugs could work against future coronavirus pandemics.
Noah Weiland and Katie Thomas contributed to the coverage.