Why don’t we have more COVID-19 drugs?

Even with the launch of vaccines, the holy grail of the pandemic – a drug to successfully treat COVID-19 – continues to escape medicine.

On Monday, a World Health Organization panel called on scientists to stop researching hydroxychloroquine, the poster boy for drugs that did not work against the coronavirus. Meanwhile, more than 40,000 people are still hospitalized across the country with COVID-19, and only a handful of mediocre therapies can help treat them. And with new variants that threaten to prevent vaccines, finding drugs to fight SARS-CoV-2 is even more urgent.

“The end result of what we need to do in the future, and the clear need for it, is the development of potent antivirals that work directly on SARS-CoV-2,” Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, said in 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 sick or dying.

But efforts to develop such drugs have stalled because of a lack of funding and coordination: although Operation Warp Speed ​​has devoted nearly $ 18.75 billion to developing vaccines, it has only set aside $ 6.34 billion for medicines. Instead, scientists tried to redirect older drugs, including antivirals to 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 authorized only one drug to treat COVID-19, remdesivir, initially developed against Ebola. But it is far from being a perfect drug: the results on how it affects length of hospital stay are mixed and it has not been shown to reduce deaths.

“There is nothing wrong with looking for quick solutions, but you also have to make a long-term investment,” said Fauci, noting that the search for new effective 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” ones made against HIV and hepatitis C, which make deadly diseases treatable, he said.

But that is not yet happening. 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 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 those that former President Donald Trump took – that are difficult to administer to patients because they require one-hour transfusions near the onset of an illness.

Scientists tried to redirect older drugs to help treat COVID-19 – without much success.

The most successful reused drug in the pandemic was 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 on 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 biochemist Wenshe Ray Liu of Texas A&M, who is researching new and reused drugs to fight the coronavirus. And testing them is relatively easy: companies need only dose the infected cells in test tubes with their library of existing drugs and remove those that appear to block SARS-CoV-2. As they have already been evaluated, the winners can go straight to clinical trials, without extensive studies to show that they are safe.

Clinical trials are expensive, added Liu, and pharmaceutical companies prefer to test drugs for which they have already spent money. For both reasons, pharmaceutical companies have largely conducted small clinical trials with few patients to show that their own drugs work, in the hope of getting them right at home. These patients have little incentive to sign up to test experimental drugs in the early stages of the disease, when they are not seriously ill.

Molnupiravir, an antiviral developed to fight the flu, is an example of the challenges that clinical trials face in testing promising drugs. Safety tests this summer looked promising for the drug, and pharmaceutical company Merck started a larger clinical trial of 1,300 patients in October to see if it would reduce levels of the virus. It is expected to end in December 2021, taking three to four times as long as vaccine trials involving tens of thousands of people. In addition to other challenges, the study measures reduced viral loads instead of improving patients’ symptoms, which may not convince the FDA of its benefits.

These types of obstacles are one of the reasons why reused drugs have not 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 apart from remitting in tests clinicians Japanese medicine for pancreatitis developed in the 1980s. The results of this trial, which began last August, are projected for later this year.

The results of smaller tests with molnupiravir may arrive as early as May, said University of North Carolina virologist Victor Garcia-Martinez, who led a study in February showing that the drug was very effective in mice equipped with human lung tissue. If it eventually proves to be effective, Garcia-Martinez said: “It will be easy to manufacture and distribute. Particularly if there is an outbreak, say, in a nursing home, you can immediately take it to people. “

Coronavirus has characteristics that make it difficult to find an effective drug to fight it – but there is reason to hope.

Many drugs regularly affect viruses in test tubes, even other coronaviruses, said researcher Martin Michaelis of the University of Kent in the United Kingdom. Scientists were initially optimistic that these drugs would work the same way against SARS-CoV-2, but this virus is different enough that most of these drugs are not effective.

In a recent study, Michaelis and colleagues established the differences between SARS-CoV-2 and its closest infectious relative, the SARS virus, which killed 774 people after the 2002 outbreak. viruses differ in the biological machinery they use to replicate within cells, Michaelis and colleagues found. This is important because interfering with this viral replication is the main task of antiviral drugs. If viruses cannot replicate, they cannot spread.

Although the spikes on the outside of the coronavirus are now mutating uncontrollably to produce more contagious variants, the virus has less freedom to alter its reproductive process, said Michaelis. That’s because the same mechanism is also vital in other basic viral functions, making it a more reliable target for drugs that target the virus.

“You cannot say that these conserved regions will never mutate,” he said, “but it is less likely.”

Examples of new antivirals developed specifically against SARS-CoV-2 are now appearing in animal studies. A February 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 can find COVID-19 drugs useful. A year after the pandemic started, scientists know much more about how SARS-CoV-2 works and may be better equipped to find existing drugs that can attack it, said Texas A&M’s Liu. His team recently discovered a hypertension drug that, in a computer simulation, fits like a key in the coronavirus lock. 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,” said Liu.

More money is needed to boost both treatments as we did with vaccines.

On March 11, 2020, the day the pandemic was first declared by the WHO, Fauci testified in Congress that there were two ways for medicine to deal with the coronavirus: vaccines or drugs.

From a scientific perspective, there were many reasons to expect an effective antiviral drug to appear before the vaccine, Fauci told BuzzFeed News. “You generally know relatively quickly whether a [drug] the treatment works or not because you are giving a treatment to someone who is already sick, ”he said.

The vaccine, however, requires giving 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 some vaccine candidates that were on the rise and really turned out to be good,” said Fauci. “And, unfortunately for the country, but fortunately for vaccine testing, we continue to have a high level of infection, which allowed us to get a response very quickly.”

The vaccines trigger a well-known natural immune reaction, making their design and safety testing simpler compared to the new antivirals, added Michaelis. But US vaccine trials also received significantly more funding than treatments.

“There is not much money in antiviral drugs for acute illnesses that are used for just a week or more,” said Michaelis. The lack of a clear path means that new antivirals designed explicitly against the coronavirus are likely to require a large public investment, said Fauci. The NIH only recently started an initiative to research new antivirals, which would be “unlikely to supply drugs in 2021,” NIH chief Francis Collins told the New York Times.

In a way, the lack of COVID-19 antivirals underscores humanity’s fortune in having effective vaccines, said Michaelis.

“People have tried many, many compounds against SARS-CoV-2, COVID-19, but they just haven’t had the big, big and successful candidate so far,” he said. Moving forward to create new drugs, he added, “becomes an increasingly difficult job.”