Why older, cheap drugs that could fight COVID never come out of the lab | Health News from the Healthiest Communities


In March 2020, Dr. Joseph Vinetz left the contemplative world of his infectious disease lab at Yale University and dove into the COVID ward at Yale New Haven Hospital, joining an army of healthcare workers who were struggling to treat the deadly viral disease.

There was no medicine for COVID-19, and no way to predict which infected patients would develop pneumonia or fall into an inflammatory fall leading to severe illness or death. In desperation, Vinetz and countless other medical researchers scoured the literature for existing drugs that might help.

“We were in the hospital. We had nothing,” Vinetz said. “I was one of tens of thousands of doctors around the world who said, ‘We have to figure out what to do.'”

On April 16, 2020, Vinetz saw an article in the journal Cell on a drug called camostat, approved in Japan in 1985 to treat inflammation of the pancreas. Research during the first SARS outbreak, in 2004, had shown the drug had a plausible biochemical mechanism for slowing coronavirus infections, so Vinetz and his colleagues quickly set up a small clinical trial in outpatients with symptoms. mild to moderate.

At that time, before COVID vaccines and COVID-specific treatments appeared on the market, Vinetz’s experiment was one of thousands conducted by doctors who hoped that older vaccines and drugs, usually good market and not patented, could provide them with options.

Most of the time, the drugs were too toxic or had no clear effect. Of more than 1,500 potential COVID drug trials listed on the National Institutes of Health website – including antivirals, anti-inflammatories and drugs used for cancer, asthma, heart disease and dozens of other conditions – few have produced useful drugs.

In fact, only one older drug is commonly used to fight COVID. It’s the steroid dexamethasone, proven by UK scientists to help prevent hospital patients from needing supplemental oxygen or intubation.

Drugs like hydroxychloroquine and ivermectin showed signs of value initially but failed in clinical trials — to stay in circulation, at least in part because their use symbolized affinity in the culture war for some supporters of President Donald Trump.

A few old drugs still show promise, but they’re struggling to catch on. The ivermectin and hydroxychloroquine fiascos have embittered doctors over repurposed drugs, and the pharmaceutical industry has shown little interest in testing them, especially when it can make billions from new, even mediocre ones, say the scientists who follow the field.

American and European scientists have confirmed the theoretical basis of the camostat’s impact on COVID. But the evidence for its effects is weak; last year the drug was removed from a large NIH trial comparing various treatments.

A more promising story emerged with fluvoxamine, licensed under the brand name Luvox in 1994 to treat obsessive-compulsive disorder. The drug belongs to the same class as common antidepressants such as Prozac, Lexapro, and Zoloft.

A child psychiatrist noticed that fluvoxamine may be good for COVID. In March 2020, while recovering from a bout of COVID, Dr. Angela Reiersen of Washington University in St. Louis saw a 2019 study in mice that showed how fluvoxamine could activate a protein similar to that missing in patients with Wolfram syndrome, a genetic condition that causes diabetes, neurological problems and, eventually, death.

Reiersen and his colleague, Dr. Eric Lenze, a geriatric psychiatrist, began a clinical trial of the drug in people with symptoms of COVID. Of the 80 patients in the fluvoxamine group, none suffered a serious decline, while six of the 72 patients given the sugar pills developed pneumonia and four were hospitalized.

In a follow-up trial of 1,500 patients in Brazil, people who took at least 80% of their fluvoxamine pills were 66% less likely to need emergency care or hospitalization than those who took sugar pills. Only one died, compared to 11 in the placebo group.

Since October, when the Brazilian study was published, the future of fluvoxamine has darkened. Neither the NIH nor the Infectious Diseases Society of America recommend fluvoxamine for preventing respiratory distress. NIH panelists noted that the best results in the Brazilian trial were only statistically significant in those who remained in the trial. (Due to nausea and other side effects, only 74% of trial participants in the fluvoxamine wing took all of their pills, compared to 82% in the placebo wing.)

The NIH panel was also put off by the fact that the Brazilian trial counted hospitalizations as well as people placed under a doctor’s care for six hours or more – not a standard measure. Trial organizers said this was necessary because Brazilian hospitals were so full of COVID patients that many people received their care in makeshift outdoor shelters.

Regulators and experts are awaiting the results of two other large trials, one organized by a consortium of universities and hospitals, the other by the NIH. But both studies use doses of 100 milligrams of fluvoxamine per day, compared with 200 or 300 milligrams in the successful trials.

“I’m concerned they’re not using a high enough dose,” Reiersen said, given that fluvoxamine works on a different biochemical pathway to fight COVID than is involved in psychiatric treatment.

The concern is shared by Craig Rayner, a former pharmaceutical company scientist who worked on the Brazilian trial and other large repurposed drug tests. “You can do the largest, best-funded study in the world,” he said, “but if you pick the wrong dose, it sucks.”

The team overseeing the NIH trial opted for a lower dose because higher doses had been used in previous trials — and often caused side effects, said Sarah Dunsmore, program director at the National Center for Advancing. NIH Translational Sciences.

On December 21, David Boulware, an infectious disease expert at the University of Minnesota, asked the Food and Drug Administration to approve a label change for fluvoxamine indicating that it can be used to prevent distress. respiratory tract in at-risk patients with mild to moderate COVID. He has not yet received a response.

It’s a different story for big pharma. Two days after Boulware’s submission, the FDA cleared Merck to market its drug molnupiravir, which in its clinical trial showed about as much efficacy as fluvoxamine, and also had side effects like nausea and dizziness. Fluvoxamine can also cause insomnia and anxiety; Molnupiravir is not recommended for pregnant women or anyone, male or female, who has unprotected sex because it has caused genetic and fetal damage in laboratory animals.

“You hate to say Big Pharma has a lot of clout, but it clearly does,” Boulware said. “The data on molnupiravir wasn’t that good, but we’re spending billions on the drug and it got expedited emergency use authorization,” while fluvoxamine remains in a gray area.

With the advent of effective vaccines and the trickle down of antiviral treatments, the urgency to rehabilitate old drugs for American patients has diminished. But the need remains high in low- and middle-income countries where vaccines and new COVID treatments are still not available.

It’s not uncommon for a pharmaceutical company to synthesize or study a drug for one purpose, only to find that it works better for something else. The classic example is sildenafil, or Viagra, which was being developed as a blood pressure drug when scientists noticed a remarkable side effect. Remdesivir, now a front-line COVID drug, was intended to treat Ebola.

It’s less common for a drug marketed for single use to acquire an entirely different purpose, but the pandemic has prompted scientists to try. They’ve tested thousands of compounds in Petri dishes for their virus-killing potency, but the journey from test tube to human cure is a long one, said Rayner, professor of pharmaceutical sciences at Monash University in Melbourne, Australia. .

If fluvoxamine was a new drug, the company sponsoring it would have spent the money to get the drug approved and show the FDA that it has the means to monitor the drug’s safety and effectiveness. Because this is an older drug, it will be up to independent scientists, or perhaps a reluctant generic manufacturer, to sponsor safety monitoring if the FDA provides emergency use authorization, a said Rayner.

An EUA or approval “comes with strings. You have to keep monitoring the security, to make sure that no signals show up when you move it from thousands to millions of patients,” he said. “It is very expensive.”

US doctors can prescribe off-label drugs, but most are reluctant to do so until a drug has gained approval for the new use. This is especially true now.

Definitive answers on some repurposed drugs have been slow in coming because there were too many small, poorly designed studies by “every man and his dog,” Rayner said. He calculates that up to $5.6 billion has been wasted on clinical trials of hydroxychloroquine alone.

A recent World Health Organization resolution called for better coordination and information sharing between trial organizers so that definitive answers can be obtained quickly with large volumes of data.

As for the camostat, Vinetz says those who took the drug felt better than those who received a placebo. “It basically prevented the loss of smell and taste, which people really care about bitterly,” he said. “That means there is a real biological effect. This deserves further exploration.

“When there’s no profit, it’s tough,” Vinetz said. In the meantime, he resumed his research on the control of a neglected tropical disease: leptospirosis.

This story was produced by KHN Kaiser Health News) a national newsroom that produces in-depth journalism on health issues and a major operating program at KFF (Kaiser Family Foundation). It was published with permission.


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