It was Friday March 13th when doctors at the largest healthcare provider in New York City decided to take the search for a coronavirus drug into their own hands. Many of their Covid-19 patients were not getting better – and some were getting worse.
Two of the hospitals' scientists each called their contacts at US biotech 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 the clinical trials, which usually take months, and just four days later two patients took their first doses of the experimental drugs.
"The patients were very, very sick," says Kevin Tracey, president of the Feinstein Institute, the research arm of Northwell Health. "Everybody just rolled up their sleeves and said we're facing a crisis and the patients need this. After 30 years of doing research, it was one of the proudest days of my life to know patients were getting treated with these drugs that may help them."
The hospital hopes the drugs will stop the replication of the virus and reduce the inflammation in the lungs of the patients.
As the pandemic spreads – recorded cases have more than doubled over the past week to over 460,000 on Wednesday, with more than 20,000 deaths – no one can afford to wait the 18 months it might take to find a vaccine. Northwell is one of many hospitals across the globe running clinical trials on drugs that were developed for other diseases, from Ebola to malaria to arthritis, but that early studies suggest could offer some hope to Covid-19 patients.
Doctors are desperate for evidence of what works. In the next month, they will learn more as some important trials in China are due to publish preliminary results.
Yet the desire from politicians and investors for a miracle cure has led to a maelstrom of misinformation about drugs to treat the virus. Just as Northwell was dosing its first patients, president Donald Trump said the US Food and Drug Administration had approved the antimalarials chloroquine and hydroxychloroquine for use against Covid-19. This turned out to be not true, with fatal consequences for some. The FDA was actually just collecting evidence on whether it worked.
Christos Kyratsous, vice-president of research in infectious diseases at Regeneron, says anecdotal evidence from China provides a reason to be "optimistic" that Kevzara, developed with Sanofi, will help Covid-19 patients suffering from acute respiratory distress syndrome.
“The challenge now is finding the best and quickest way to see if it is effective in the clinic,” he adds. “That’s very, very important, because if you can get meaningful data, and if the data is positive, we can expand access to something like this, which is going to be life saving.”
Three main drug types
Scientists are investigating three main types of drugs. The first are antivirals to stop the virus from replicating. Treatment guidelines compiled by the Chinese government during the outbreak include HIV drug combination Kaletra, which US biotech AbbVie recently waived its patents on so it can be made available as a generic; antimalarials such as chloroquine, which generic drugmakers are gearing up to manufacture at scale; and favipiravir, an anti-flu drug from Japan’s Fujifilm.
The second category is anti-inflammatories that treat the lungs after the immune system is overwhelmed. Regeneron and Sanofi have partnered on Kevzara, while Roche has started a trial on Actemra, approved for use on rheumatoid arthritis in 100 countries.
The third group are antibody-based treatments, derived either from recovered Covid-19 patients or developed in labs, to be given to the seriously ill or as a temporary prophylactic for healthcare workers. Eli Lilly has paired up with Canadian start-up AbCellera to work on antibodies developed from one of the first US Covid-19 patients, while Japan's Takeda is developing a new drug derived from the blood plasma of others who have survived the virus.
Analysts are eagerly awaiting data from early trials into remdesivir, an antiviral drug that the California-based biotech group developed for Ebola. It has also been shown to work against other coronaviruses in animal studies. Umer Raffat, a biotech analyst at US bank advisory firm Evercore, says evidence could be published in the next couple of weeks.
“It has by far the best prospects,” Mr Raffat says. His optimism stems from the drug’s ability to disable the machinery that helps the virus replicate, which is similar to that found in Ebola. But he believes the early data may not be “spectacular”, if too many of the patients took it too late in the progression of their disease.
Andre Kalil, an investigator in a large remdesivir trial, which plans to recruit 400 patients and is sponsored by the US National Institutes of Health, says they are making patients take the drug within 72 hours of diagnosis. Dr Kalil ran a clinical trial during the 2014 Ebola outbreak. He believes they moved too slowly to set up a trial then.
“This is a fight against time. We need to move as fast as possible,” he says. “We have no idea what works or does not at this point. There are zero therapies specifically against coronavirus.”
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 had taken the antiviral drug earlier in the disease.
The antimalarial chloroquine does have two clear advantages over remdesivir: it is a generic, so is likely to be far cheaper; and it is a pill, when remdesivir is delivered by an intravenous infusion, so would probably need to be given in hospital. But studies in France and China, hailed by Mr Trump, are small and did not follow the recommended protocols of a randomised control trial, designed to prevent bias. A study in China released on Tuesday found the drug had no impact.
Early results
Early results from clinical trials in China fuelled enthusiasm for a second antiviral – favipiravir – after reports of faster recovery times for patients that took the drug. Junji Okada, president of Fujifilm Toyama Chemical, the unit that produces the branded version Avigan, says the company is responding to a flood of inquiries from across the world.
“Our sense of mission became bigger and bigger as it became clear that Avigan may be effective,” Mr Okada says. “We have made the preparations so that we can increase production if needed.”
Kimiyasu Shiraki, an emeritus professor at the University of Toyama who was involved in Avigan's early development, 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 Avigan could treat the first to the last patient with the same efficacy during the epidemic."
Antibody-based treatments could be important for helping the hardest hit and those key workers that need to stay healthy. New York - now the centre of the crisis in the US, with almost 200 deaths - is set to start testing plasma from recovered patients in a trial with the seriously ill. But most drugmakers are looking at refining the process to create a concentrated and purified product, or creating artificial antibodies, often developed in mice. Their products will have to go through clinical trials, likely to take many months.
AbCellera was working on a test project on influenza with the US Defense Advanced Research Projects Agency when Covid-19 emerged – so it rapidly switched to preparing their antibody-finding platform for the new virus. They took blood samples from one patient and generated almost six million immune cells for antibodies, using an AI-based platform that can screen down to the individual cell and allows them to find more antibody-secreting cells. Researchers have narrowed it down to the 500 most potent against Covid-19 and partnered with Eli Lilly for the first human trials of the drug by July.
"Every day between now and the first human testing is mapped out and precious," says Daniel Skovronsky, chief medical officer of Eli Lilly.
Takeda began looking at plasma-derived therapies after they proved effective in reducing mortality during the outbreaks of both severe acute respiratory syndrome (Sars) in 2002-03 and Middle East respiratory syndrome (Mers) in 2009. But the treatment will not be widely available – the plasma will need to be donated by recovered patients. It is not yet known how many patients could be treated with the plasma from a single recovered patient.
Another obstacle is that all the drugs being tested have potentially serious side effects: remdesivir may cause liver damage, Avigan can cause birth defects, and Regeneron and Sanofi’s Kevzara works by suppressing the immune system – but it could potentially go too far.
Unprecedented challenge
Rajeev Venkayya, president of Takeda's vaccine business, says the industry is facing a new challenge. "It is unprecedented," he says. "[But] what is very different is the opportunity we have with the tools and technologies that can help us to address this in ways that we didn't have in the past."
Drugmakers face similar challenges to vaccine developers: by the time they have the evidence they need, the new virus may have disappeared. But at least it is now clear that Covid-19 is likely to be a longer-term problem.
“When it becomes a global health crisis, it is easy for companies like us to make decisions to invest . . . There is a concern for wellbeing, patients, society,” says Dr Skovronsky. “But when it first emerges and there are five or 10 patients, is it worth spinning out incredible resources and financial costs when you’ll never get repaid if the virus is successfully contained?”
Even if a drug succeeds, there will be political pressure to price it affordably. Rising Pharmaceuticals, a generic maker of chloroquine, almost doubled the price to $7.66 (€6.99) per 250mg pill in the US in January, as the coronavirus outbreak raged in China. This month, as the crisis hit the US, it cut the price to its previous level.
AbbVie, maker of the HIV drug combination, will allow generics makers to manufacture the drug, relinquishing its intellectual property claims, in a move that should make it cheaper.
But Gilead initially took a different approach: it won the right to extend its intellectual property rights for remdesivir by using an "orphan drug designation" in the US. The rule was designed to encourage drugmakers to make treatments for rare diseases, further fuelling criticism of the industry's pricing policies. Ellen 't Hoen, director at non-governmental organisation Medicines Law & Policy, called it "the most blatant abuse" of the act. But on Wednesday Gilead asked the FDA to rescind the application citing the "urgent public health needs posed by the Covid-19 pandemic."
Drugmakers will need to make large investments to increase production fast. Kenneth Kaixin, director of the Tufts Center for the study of drug development, says: "You don't want to invest a lot in manufacturing before you know you are going to have a drug on the market. [YET]you want to make sure you can manufacture as much as needed, perhaps hundreds of thousands of doses at the end of the day."
Once a drug is ready to sell, governments are likely to compete to put their citizens first. Already, there are reports that the White House tried to buy German vaccine maker CureVac, with 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
Drugs designed for treatment of Ebola, HIV, flu and malaria. They try to stop the replication of coronavirus by interfering with enzymes that help it copy itself and spread. They are believed to be most useful in the earlier stages of the disease. The virus uses similar machinery to copy itself as Ebola, giving some experts hope that Gilead’s Ebola drug remdesivir may help patients.
Anti-inflammatories
Designed for conditions such as arthritis. Several groups are investigating the potential of IL6 inhibitors, which lower the production of inflammatory proteins called cytokines. They are most useful in the latter stages of the disease, when some patients suffer from acute respiratory distress syndrome because their immune systems are overwhelmed.
Antibodies
Drugs derived from Covid-19 patients’ immune response. They reproduce the antibodies of patients’ immune systems to support people with less robust responses. Plasma from recovered patients is being infused into the seriously ill. But drugmakers aim to refine the process, strengthening the potency of the antibodies or creating artificial ones that will be more effective.
Some believe the pharmaceutical business model simply does not work for pandemics, because the diseases will always compete for resources with blockbuster drugs that people take for years. Emergent Biosolutions takes a different approach: it specialises in making “rescue therapies” for unlikely events, selling the only antidotes to smallpox, anthrax and botulism to US and allied governments to stockpile in case of bioterrorism. It is now working on an antibody treatment for Covid-19.
"What differentiates us from just about any other pharma company is that they want an immediate return, very quickly within six to 12 months, and we take a little bit of a longer view," says Robert Kramer, chief executive of the Maryland-based speciality pharmaceuticals company.
Despite the obstacles, finding drugs that can be repurposed to help coronavirus patients’ recovery is one of the only hopes for their health, their families - and ultimately, the economy.
Dennis DeBusschere, who leads Evercore’s portfolio strategy team, is closely watching when medications might be ready because he believes they are crucial to getting those people in lockdowns outside to spend again. Even if the virus continues to spread, having medications available would take some of the fear out of infection.
“You may want to go on vacation again, actually go to a restaurant, to the movies,” he says. – Copyright The Financial Times Limited 2020
