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

Ben Kothe / BuzzFeed News; Getty Images (3)

Even as vaccines spread, the holy grail of the pandemic – a drug for the successful treatment of COVID-19 – continues to shun medicine.

On Monday, a panel of the World Health Organization called on scientists to abandon the study of hydroxychloroquine, a child, a poster for drugs that failed to act against the coronavirus. Meanwhile, more than 40,000 people are still hospitalized nationwide with COVID-1

9, and only a handful of mediocre therapies can help treat them. And with new options threatening to thwart vaccines, finding drugs to fight SARS-CoV-2 is even more urgent.

“The bottom line of what we need to look forward to and the clear need for is the development of powerful antiviral drugs that work directly on SARS-CoV-2,” Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, told White House briefing last week. Antivirals would revolutionize the fight against SARS-CoV-2, as they block the replication of viruses and can stop people from getting sick or dying.

But efforts to develop such drugs have failed due to a lack of funding and coordination: Although Operation Warp Speed ​​spent nearly $ 18.75 billion on vaccine development, it spent only $ 6.34 billion on drugs. Instead, the researchers tried to reassign older drugs, including antivirals, to other diseases to see if they worked against COVID-19.

“Everyone was looking for a quick solution,” Fautsi told BuzzFeed News. The FDA has so far approved only one drug to treat COVID-19, remdezivir, originally developed against Ebola. But this is far from a perfect cure: the results of how it affects the length of hospital stay are mixed and have not been shown to reduce mortality.

“There is nothing wrong with looking for quick solutions, but you will also have to make a long-term investment,” Fauci said, noting that the search for effective new drugs will take months to years. The goal will 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 that make deadly diseases curable, he said.

But this is not happening yet. After evaluating hundreds of older drugs, the National Institutes of Health does not have new antivirals for COVID-19 in its public-private partnership of clinical trials called Acceleration of COVID-19 Therapeutic Interventions and Vaccines (ACTIV). There are no newly designed antivirals listed among the 160 clinical trials maintained by the NIH registered with the National Library of Medicine. Warp Speed’s efforts in Operation Warp Speed ​​also do not include new antivirus tools.

The only new treatments on the ACTIV list are monoclonal antibodies – such as those taken by former President Donald Trump – that are difficult to give to patients because they need an hour’s blood transfusion at the onset of the disease.

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

The most successful reassignment 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 mortality among patients with COVID-19 ventilators by about a third, a compelling argument for looking for another needle in the haystack of older drugs that could act directly against the virus.

“There are many reasons to use these FDA-approved drugs because they already know the properties in human patients,” said Texas A&M biochemist Wenshe Ray Liu, who is investigating both new and redesigned coronavirus drugs. And testing them is relatively easy: Companies simply need to dose infected cells in tubes with their library of existing drugs and remove those that appear to block SARS-CoV-2. Since they have already been tested, winners can go straight to clinical trials without extensive research to show that they are safe.

Clinical trials are expensive, Liu added, and pharmaceutical companies prefer to test drugs they have already spent money on. For both reasons, pharmaceutical companies have conducted largely small clinical trials with too few patients to show that their own drugs have worked, hoping to succeed. These patients have little incentive to enroll in experimental drug testing in the early stages of the disease when they are not terribly ill.

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

This type of obstruction is one of the reasons why re-prescribed drugs have not shown much benefit in patients. And while NIH-funded scientists 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 drug other than remdezivir in clinical trials is a Japanese drug for pancreatitis, developed in the 80s. The results of this process, which began last August, are projected for the end of this year.

The results of smaller trials of molnupiravir could come as early as May, said University of North Carolina virologist Victor Garcia-Martinez, who conducted a study in February showing the drug was very effective in mice equipped with human lung tissue. If it turns out to be effective in the end, Garcia-Martinez said: “It will be easy to produce and distribute. Especially if there is a hearth, say, in a nursing home, you can immediately pass it on to people. “

Scott Olson / Getty Images

Jasmine Mitchell treated Curtis Jones with remdezivir to help him recover from COVID-19 at Roseland Community Hospital in Chicago, Illinois on December 15, 2020.

The coronavirus has characteristics that make it difficult to find an effective drug to fight it, but there is reason to hope.

Many drugs regularly dig up viruses in test tubes, even other coronaviruses, said drug researcher Martin Michaelis of the University of Kent in Britain. Initially, scientists were optimistic that these drugs would work in a similar way against SARS-CoV-2, but this virus is different enough that most of these drugs may not be effective.

In a recent study, Michaelis and colleagues outlined the differences between SARS-CoV-2 and its closest human-infecting relative, the SARS virus, which killed 774 people after the outbreak in 2002. Although genetically similar to about 80%, the two viruses are differ in the biological mechanisms they use for replication in cells, Michaelis and colleagues found. This is important because interfering with this viral replication is a major task of antiviral drugs. If viruses cannot replicate, they cannot spread.

Although the peaks on the outside of the coronavirus now mutate wildly to produce more contagious variants, the virus has less freedom to change its reproductive process, Michael said. This is because the same machine is vital for other major viral functions, making it a more reliable target for drugs that target the virus.

“You can’t say that these preserved regions will never mutate,” he said, “but that’s less likely.”

Examples of new antivirals specifically designed against SARS-CoV-2 have emerged in animal studies. A report by Chinese researchers in the February 18 issue of the journal Science found that two drugs successfully reduced the viral load in the lungs of mice.

There are other signs that we can find for useful COVID-19 drugs. 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 could attack it, said Liu of Texas A&M. His team recently discovered a drug for high blood pressure, which in a computer simulation fits like a key in the coronavirus lock. The drug may have been neglected because it is generic and there is no corporate sponsor willing to invest in a clinical trial.

“We will try to start our own clinical trial if we can’t find a corporate sponsor,” Liu said.

Andrew Caballero-Reynolds / Getty images

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, spoke at a hearing of the Chamber’s Oversight and Reform Committee on March 11, 2020.

More money is needed to insist on treatment as strongly as vaccines.

On March 11, 2020, the day the pandemic was first declared by the WHO, Fautsi testified before Congress that there were two medical options for dealing with the coronavirus: vaccines or drugs.

From a scientific point of view, there were many reasons to expect an effective antiviral drug to emerge earlier than a vaccine, Fauci told BuzzFeed News. “In general, you know relatively quickly whether a [drug] the treatment works or not, because you are treating someone who is already ill, ”he said.

Meanwhile, the vaccine requires real photos and a placebo to be taken of tens of thousands of people and then to wait until natural infections cause enough infections to show that it is effective.

“We were lucky to have a few vaccine candidates who were hot and really turned out to be good,” Fauci said. “Unfortunately for the country, but fortunately for the vaccines, we continued to have a high level of infection, which allowed us to get a response quite quickly.”

Vaccines elicit a well-understood natural immune response, making their design and safety tests clearer than new antivirals, Michaelis added. But American vaccine trials also had significantly more funding than treatment.

“There’s not that much money in antiviral drugs for acute illnesses that are only used for a week or more,” Michaelis said. The lack of a clear path means that new antivirus tools developed specifically against the coronavirus are likely to require large public investments, Fauci said. The NIH has only recently launched an initiative to study new antiviral drugs that are “unlikely to provide therapeutic agents in 2021,” NIH chief Francis Collins told the New York Times.

Somehow, the lack of COVID-19 antivirals underscores how happy humanity is to have effective vaccines, Michaelis said.

“People have tried many, many compounds against SARS-CoV-2, COVID-19, but so far they just haven’t had the big, big and successful candidate,” he said. Moving on to creating new drugs, he added, “it’s getting harder and harder.”

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