The global hunt for a coronavirus drug

It was Friday, March 13, when the doctors at New York’s largest health care provider decided to take over the search for a coronavirus drug. Many of their Covid-19 patients did not improve – and some worsened.

Two of the hospital scientists each called their contacts in the US biotechnology companies Gilead Sciences and Regeneron to offer to test their potential treatments: an antiviral called remdesivir and an anti-inflammatory called Kevzara, developed for Ebola and rheumatoid arthritis respectively. Clinicians, researchers and regulators rushed to set up clinical trials, which usually take months, and just four days later, two patients took their first doses of the investigational drugs.

“The patients were very, very sick,” said Kevin Tracey, president of the Feinstein Institute, the research arm of Northwell Health. “Everyone just rolled up their sleeves and said that we are facing a crisis and that patients need it. After 30 years of research, it was one of the proudest days of my life to know that patients were being treated with these drugs that could help them. ”

The hospital hopes the drugs will stop replication of the virus and reduce inflammation in the patients’ lungs.

A technician works at Northwell Health Labs. “After 30 years of research, it was one of the proudest days of my life to know that patients were being treated with these drugs that could help them,” said Kevin Tracey, president of the Feinstein Institute © John Minchillo / AP

As the pandemic spreads – recorded cases more than doubled in the past week to more than 460,000 on Wednesday, with more than 20,000 deaths – no one can afford to wait the 18 months it would take to find a vaccine. Northwell is one of many hospitals around the world to conduct clinical trials on drugs developed for other illnesses, from Ebola to malaria to arthritis, but early research suggests that hope to Covid-19 patients.

Doctors are desperately looking for evidence of what works. Over the next month, they will learn more as some important trials in China are expected to release preliminary results.

Yet the desire of politicians and investors for a miracle cure has led to a whirlwind of misinformation about drugs to treat the virus. Just as Northwell administered its first patients, President Donald Trump said that the U.S. Food and Drug Administration had approved the use of the antimalarials chloroquine and hydroxychloroquine against Covid-19. This turned out to be wrong, with fatal consequences for some people. The FDA was only collecting evidence of its effectiveness.

Christos Kyratsous, vice president of infectious disease research at Regeneron, says anecdotal evidence from China provides reason to be “optimistic” that Kevzara, developed with Sanofi, will help Covid-19 patients with acute respiratory distress syndrome.

“The challenge now is to find the quickest and most effective way to see if it works in the clinic,” he adds. “This is very, very important, because if you can get meaningful data and the data is positive, we can extend access to something like that, which will save lives.”

REFILE - CORRECTING STYLE A Congolese health worker gives an ebola vaccine to a man at the Himbi health center in Goma, Democratic Republic of the Congo, on July 17, 2019. REUTERS / Olivia Acland

Gilead’s remdesivir, an antiviral drug that California-based biotechnology developed for Ebola, but which has also been shown to work against other coronaviruses in animal studies © Olivia Acland / Reuters

Scientists investigate three main types of drugs. The former are antivirals to prevent replication of the virus. Treatment guidelines compiled by the Chinese government during the epidemic include the combination of HIV drugs Kaletra, on which US biotech AbbVie recently renounced its patents in order to make it available in generic form; antimalarials such as chloroquine, which manufacturers of generic drugs are preparing to manufacture on a large scale; and favipiravir, an influenza medication from Fujifilm in Japan.

The second category is that of anti-inflammatory drugs which treat the lungs once the immune system is overwhelmed. Regeneron and Sanofi have teamed up on Kevzara, while Roche has started a trial on Actemra, approved for use on rheumatoid arthritis in 100 countries.

The third group consists of treatments based on antibodies, derived from Covid-19 patients recovered or developed in the laboratory, to be administered to seriously ill people or as temporary prophylaxis for healthcare professionals. Eli Lilly has teamed up with Canadian start-up AbCellera to work on antibodies developed from one of the first American patients of Covid-19, while Japanese Takeda is developing a new drug derived from other people’s blood plasma who survived the virus.

Analysts are eagerly awaiting data from the first trials of remdesivir, an antiviral drug that the California-based biotechnology group developed for Ebola. It has also been shown to work against other coronaviruses in animal studies. Umer Raffat, biotechnology analyst at the American banking consultancy Evercore, says the evidence may be released in the coming weeks.

“He has by far the best prospects,” said Mr. Raffat. His optimism stems from the drug’s ability to deactivate the mechanisms that help the virus to replicate, which is similar to that found in Ebola. But he thinks the first data might not be “spectacular” if too many patients take them too late in the progression of their disease.

Andre Kalil, an investigator in a large trial of remdesivir, who plans to recruit 400 patients and is sponsored by the National Institutes of Health in the United States, says they are forcing patients to take the drug within 72 hours of diagnosis . Dr. Kalil conducted a clinical trial during the 2014 Ebola outbreak. He believes they then progressed too slowly to set up a trial.

“It’s a fight against time. We have to go as fast as possible, ”he says. “We have no idea what is working or not at this stage. There is no specific therapy for coronavirus. ”

(FILES) In this photo taken on February 26, 2020, medical personnel showed at the Institute of Mediterranean Infections of the IHU in Marseille, packages of Nivaquine, tablets containing chloroquine and Plaqueril, tablets containing hydroxychloroquine, medicines which have shown signs of efficacy against the coronavirus. (Photo by GERARD JULIEN / AFP) (Photo by GERARD JULIEN / AFP via Getty Images)

President Donald Trump has stated that the Food and Drug Administration has approved the use of the antimalarial chloroquine against Covid-19. It is not true © Gerard Julien / AFP

Timing will be crucial. A study published last week of the HIV drug combination was dismissed as disappointing, but survival rates were better when patients took the antiviral drug earlier in the disease.

Chloroquine antimalarial has two obvious advantages over remdesivir: it is generic, so it is probably much cheaper; and it is a pill, when remdesivir is given by intravenous infusion, it should probably be given in the hospital. But the studies in France and China, praised by Mr. Trump, are small and have not followed the recommended protocols of a randomized control trial, designed to avoid bias. A study in China published Tuesday found that the drug had no impact.

The first results of clinical trials in China have fueled enthusiasm for a second antiviral – favipiravir – after reports of faster recovery times for patients who have taken the drug. Junji Okada, president of Fujifilm Toyama Chemical, the unit that produces the Avigan branded version, says the company is responding to a flood of inquiries from around the world.

“Our sense of mission grew stronger when it became clear that Avigan could be effective,” said Okada. “We have made preparations to be able to increase production if necessary.”

Kimiyasu Shiraki, professor emeritus at Toyama University who was involved in the early development of Avigan, says studies show that the drug does not generate an Avigan-resistant virus that could make it less effective in the long term: ” This suggests that Avigan could treat the first to the last patient with the same effectiveness during the epidemic. “

South Korean medical workers wear protective equipment in a separate medical center for MERS at Konkuk University Hospital in Seoul on June 24, 2015. Two large hospitals in the capital of South Korea suspended their services to patients June 24 to stop the spread of MERS after four new cases of the deadly virus were reported. AFP PHOTO / JUNG YEON-JE (Photo credit should read JUNG YEON-JE / AFP via Getty Images)

South Korea: plasma-derived therapies proved effective in reducing mortality during the outbreak of the Middle East respiratory syndrome (Mers) in 2009 © Jung Yeon-Je / AFP

Antibody-based treatments could be important in helping those most affected and the key workers who need to stay healthy. New York – now at the center of the crisis in the United States, with nearly 200 deaths – is expected to begin testing the plasma of patients recovered in a trial of the critically ill. But most drug makers are looking to refine the process to create a concentrated, purified product, or to create artificial antibodies, which are often developed in mice. Their products will have to undergo clinical trials, which will likely take several months.

AbCellera was working on a flu test project with the US Defense Advanced Research Projects Agency when Covid-19 emerged – so he quickly moved on to preparing his platform for antibodies to the new virus. They took blood samples from a patient and generated almost 6 million immune cells for antibodies, using an AI-based platform that can filter down to the individual cell and allow them to find more cells. secreting antibodies. The researchers reduced it to the 500 most potent against Covid-19 and teamed up with Eli Lilly for the first human trials of the drug by July.

“Every day between today and the first human test is mapped and precious,” explains Daniel Skovronsky, chief physician of Eli Lilly.

Takeda began to study plasma-derived therapies after they proved effective in reducing mortality during the outbreaks of severe acute respiratory syndrome (Sars) in 2002-03 and Middle East respiratory syndrome (Mers) in 2009 But treatment will not be widely available – plasma will have to be donated by recovered patients. It is not yet known how many patients could be treated with the plasma of a single recovered patient.

Another obstacle is that all of the drugs tested have potentially serious side effects: remdesivir can cause liver damage, Avigan can cause birth defects, and Kevzara from Regeneron and Sanofi works by suppressing the immune system – but it could potentially go too far. far.

Rajeev Venkayya, president of Takeda’s vaccines division, says the industry is facing a new challenge. “It’s unprecedented,” he says. “[But] what is very different is the opportunity we have with the tools and technologies that can help us solve this problem in a way that we did not have in the past. ”

Drug manufacturers face similar challenges to vaccine developers: when they have the evidence they need, the new virus may be gone. But at least it’s now clear that Covid-19 is likely to be a longer-term problem.

This photo taken on March 17, 2020 shows laboratory technicians working on samples of people to be tested for the COVID-19 coronavirus in a laboratory in Changzhou in China's eastern Jiangsu province. - China marked an important step in its fight against the coronavirus pandemic on March 19, as it recorded no domestic infection for the first time since the start of the epidemic, but a peak of imported cases threatened its progression. (Photo by STR / AFP) / China OUT (Photo by STR / AFP via Getty Images)

Laboratory technicians test samples of Covid-19 in a laboratory in Changzhou © AFP

“When it becomes a global health crisis, it is easy for companies like us to make investment decisions. . . There is a concern for well-being, patients, society, ”says Dr. Skovronsky. “But when it first emerges and there are five or 10 patients, is it worth it to generate incredible financial resources and costs when you will never be reimbursed if the virus is successfully brought under control?”

Even if a drug succeeds, there will be political pressure to make it affordable. Rising Pharmaceuticals, a generic manufacturer of chloroquine, almost doubled the price to $ 7.66 per 250 mg pill in the United States in January, as the coronavirus epidemic raged in China. This month, as the crisis hit the United States, it brought the price down to its previous level.

AbbVie, the maker of the HIV drug combination, will allow generic manufacturers to make the drug, giving up its intellectual property claims, in a move that should make it cheaper.

But Gilead first took a different approach: it obtained the right to extend its intellectual property rights over remdesivir using an “orphan drug designation” in the United States. The rule was designed to encourage drug manufacturers to perform treatments for rare diseases, further fueling criticism of industry pricing policies. Ellen ’t Hoen, director of the non-governmental organization Medicines Law & Policy, called it” the most egregious violation “of the law. But Wednesday Gilead asked the FDA to cancel the request citing “urgent public health needs posed by the Covid-19 pandemic”.

Drug manufacturers will need to make large investments to quickly increase production. Kenneth Kaixin, director of the Tufts Center for the study of drug development, says, “You don’t want to invest a lot in manufacturing until you know you’re going to have a drug on the market. [Yet] you want to make sure you can make as much as you need, maybe hundreds of thousands of doses at the end of the day. “

Once a drug is ready to be sold, governments are likely to compete to put their citizens first. There are already reports that the White House has tried to buy the German vaccine manufacturer CureVac, Berlin trying to find ways to keep it at home. The UK has banned the “parallel export” of three drugs: Kaletra, chloroquine and hydroxychloroquine.

The main options

Antivirals

Medicines designed to treat Ebola, HIV, flu and malaria. They try to stop replication of the coronavirus by interfering with enzymes that help it copy and spread. They are thought to be most useful in the early stages of the disease. The virus uses similar mechanisms to copy itself like Ebola, giving some experts hope that Gilead’s remdesivir for Ebola could help patients.

Anti-inflammatory

Designed for conditions such as arthritis. Several groups are studying the potential of IL6 inhibitors, which reduce the production of inflammatory proteins called cytokines. They are most useful in the later stages of the disease, when some patients suffer from acute respiratory distress syndrome because their immune systems are overwhelmed.

Antibodies

Medicines derived from the immune response of Covid-19 patients. They reproduce antibodies from the patient’s immune system to support people with less robust responses. The plasma of recovered patients is injected into seriously ill people. But drug manufacturers aim to refine the process, boost the potency of antibodies, or create artificial ones that will be more effective.

Some believe that the pharmaceutical business model simply does not work for pandemics, because diseases will always compete for resources with successful drugs that people have been taking for years. Emergent Biosolutions takes a different approach: it specializes in developing “life-saving therapies” for unlikely events, selling the only antidotes against smallpox, anthrax and botulism to the United States and to allied governments for store in case of bioterrorism. He is currently working on an antibody treatment for Covid-19.

“What sets us apart from almost all the other pharmaceutical companies is that they want an immediate return, very quickly within six to 12 months, and we take a slightly longer view,” explains Robert Kramer, CEO of Maryland. specialized pharmaceutical company.

Despite the hurdles, finding drugs that can be reused to help coronavirus patients recover is one of the only hopes for their health, their families – and ultimately, the economy.

Dennis DeBusschere, who heads the Evercore portfolio strategy team, is closely watching when the drugs might be ready, as he believes they are essential to re-spending these people outside. Even if the virus continues to spread, the availability of drugs would ease the fear of infection.

“You may want to go on vacation, go to a restaurant, go to the movies,” he says.

Wang Xueqiao’s additional report in Shanghai

Trump has been criticized for his “reckless assumption”

From the White House briefing room, President Donald Trump told the observer country last week that the “beauty” of drugs like chloroquine is that they can be taken safely. But while the drug has been approved to treat malaria, it can cause acute poisoning.

Within days, patients in Nigeria, Vietnam and the United States were hospitalized after an overdose of chloroquine. An Arizona couple drank the dangerous fish food version of the compound after watching a Trump press conference – and the man died.

Trump has persisted, tweeting study charts that scientific experts believe are insufficient to justify such a crucial decision. But you are not fighting a pandemic based on anecdotes. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases and a member of the US Coronavirus Task Force, said the studies were not controlled clinical trials. “The anecdotal reports are true, but they are anecdotal,” he said on March 21.

Senator Patty Murray, senior Democrat on the health, education, work and pensions committee, said: “It is irresponsible for President Trump to get ahead of the experts on something like that with guesses. reckless. We need to make sure that we follow the science and provide people with reliable information, not pulling from the hip and creating new problems for patients. “

Bruce Lewenstein, professor of science communication at Cornell, says hailing a drug as a gamble too early has already led to a race for chloroquine, depriving people who need it, such as lupus patients, and could make it more difficult people’s participation in trials for what may prove to be better therapies.

“You have to have honest and trustworthy spokespeople about what they know and what they don’t know,” he says. “President Trump, clearly, deeply believes in his own expertise and his own ability to make judgments on many complicated things.”

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