When his doctors asked him if he was interested in taking part in a drug trial, Peter Becker (whose name has been changed) agreed immediately. It was early April and Becker, 62, had been admitted to the University Hospital of Düsseldorf with a severe case of pneumonia caused by COVID-19. He was being administered 6 liters of oxygen per minute. "I felt like everything in my body was all mixed up," he says.
For 10 days, Becker was treated with remdesivir, an experimental antiviral drug that is one of dozens of substances being tested around the world as a possible treatment for COVID-19. On the first day, he was given 200 milligrams of the drug, and half of that dose thereafter. "Already that first night, I could tell that something was happening in my body," he says. "The next day, I felt significantly better."
He was sent home from the hospital in mid-April. "It will likely take me several weeks to fully recover," Becker says. "But who cares? I'm back home."
Reports such as this one, from patients and doctors in countries around the world, have led many to believe that remdesivir could be the drug that finally alleviates people's fears of the pandemic. They have also led share prices of the drug's U.S. producer, Gilead Sciences, to spike on several occasions, only to sink again when data cast doubt on the drug's effectiveness.
Since Wednesday, however, it has been clear that the individual reports do, in fact, have a scientific basis. A U.S. study performed by the National Institute of Allergy and Infectious Diseases (NIAID) involving 1,063 hospitalized COVID-19 patients found that those treated with remdesivir recovered faster than those who received a placebo. On average, the patients who received remdesivir recovered in 11 days, around four days faster than the control group - an approximately 30 percent reduction in the duration of the illness. That makes remdesivir the first drug to exhibit a proven effect against COVID-19.
In comments at the White House, NIAID head Anthony Fauci spoke of a "clear-cut, significant positive effect," adding: "What it has proven is that a drug can block this virus."
"A Relevant Disparity"
Biochemist Matthias Götte of the University of Alberta in Canada, who has conducted research on the effectiveness of remdesivir, finds it "unbelievable" that "a clinical study has been completed just four months after the discovery of the disease." And the infectious disease specialist Torsten Feldt of the University Hospital of Dusseldorf, who is leading a remdesivir study in Germany (the one in which Peter Becker participated), says: "Whether a patient needs 15 or 11 days to recover is a relevant disparity."
The NIAID study is important because, in contrast to most other remdesivir studies, it adheres to the strictest of scientific standards. The decision regarding which patients received the drugs and which were merely given a placebo was made completely at random, and neither the doctors nor the patients knew to which group the patients belonged. This form of study is the only way for doctors to be certain that it was the drug and not the patients' own immune systems that successfully fought off the virus.
Still, experts warn against drawing premature conclusions. "The study that is now being celebrated can't yet be subjected to serious scientific evaluation because it hasn't yet been published," says Wolfgang Becker-Brüser, publisher of arznei-telegramm, a journal that takes a critical look at the pharmaceutical industry. Jeremy Faust, a specialist for emergency medicine at Brigham and Women's Hospital in Boston, also doesn't believe the study's results are particularly earthshaking. "It doesn't change the curve of this pandemic," he says.
The study leaves two important questions unanswered: Can remdesivir prevent patients from having to go onto ventilators? And can it really save lives?
Mortality in the NIAID study did fall from 11.8 percent to 8 percent. But that drop is not considered significant - which is to say, it could have been luck. And there is no data yet on the drug's effect on patients’ need for ventilation.
And not everything that seems to work from a statistical point of view actually has an effect on day-to-day realities in the clinic, says Marcio da Fonseca, an infectious disease medical advisor for Doctors Without Borders currently in Brazil. Remdesivir is "not a game changer," he says. "A game changer would be a drug that has been proven to prevent the need for mechanical ventilation or prevent death."
Refocusing the Study
In the study's original design, these two factors carried significantly more weight. But in mid-April, almost a month and a half after the study was launched, its primary outcome measure was changed. Initially, the focus was to be on the comparison between patients' condition prior to entering the study and their condition 15 days into it. The need for mechanical ventilation and fatalities would have been decisive factors. But the primary focus was shifted to the day of recovery. Why was such an important change made in the middle of the study? According to a NIAID statement provided to DER SPIEGEL, statistical models revealed that "meaningful treatment effects" could have been missed if the wrong day was chosen for assessment. By refocusing on "time to recovery," that risk was sidestepped.
Now, to know for sure whether remdesivir really can help save lives, the scientists will have to evaluate even more patient data. But the question as to whether to continue such a study was fraught with a moral dilemma: Can you continue to give patients a placebo in the name of science when there is clear evidence that the drug being tested has positive effects? The scientists behind the NIAID study decided that the answer was no – which means that they won't be able to answer the question as to whether remdesivir really can save lives that might otherwise have been lost. Indeed, a conclusive answer may never be found.
"It is regrettable that the study is not being continued with the placebo control group," says Karl Lauterbach, a health expert with Germany's Social Democratic Party (SPD). Faust, the emergency medicine specialist, also believes it is dangerous to dilute scientific standards in the middle of a pandemic. Doing so might save human lives on the short term, he says, but on the long term, it could endanger lives if the drug turns out to be ineffective. "In this moment of urgency, we have to lean on our best principles," he says, "the same way a race car driver has to use his best technique in the tightest turn."
Despite the skepticism, it is astounding just how effective remdesivir has proven to be. Developing antiviral drugs is extremely challenging, because viruses don't offer many weaknesses. They are little more than a shell containing a strand of genetic material (RNA or DNA). To multiply, they essentially hijack the machinery inside the cells they invade. Remdesivir works in that it is erroneously identified by the virus as a building block for an RNA strand and then included in the reproduced copies of the virus RNA. That interrupts further reproduction - like a factory production line coming to a halt when a part is installed incorrectly.
Scientists at Gilead initially produced remdesivir 10 years ago, intending it as a kind of multi-purpose weapon. They tested it against numerous viral pathogens, including those that cause the flu, hepatitis C and dengue fever, with limited success. In a large study performed last year, remdesivir was also found to be less effective against Ebola than other drugs. Nevertheless, once COVID-19 began ricocheting around the globe in January, Gilead pulled it out of the storeroom.
A mad rush for a treatment had broken up. Medical studies likely haven't been the focus of this much attention since the outbreak of AIDS. "I have never experienced anything this crazy," says Lauterbach.
On April 10, the New England Journal of Medicine published clinical data from 53 patients who had been independently treated with remdesivir. A study of that type could not answer the question of whether the drug was effective or not, but it raised hopes.
Six days later, a newswire focused on life sciences called STAT obtained a copy of a video conference in which doctors in a Chicago hospital discussed their experiences with remdesivir as a treatment for COVID-19. According to the doctors in the video, almost all of the 125 COVID-19 patients treated with the drug had rapidly recovered. The scientific value of the video was essentially zero, but within hours, share prices in Gilead Sciences shot up by 20 percent.
A week later, though, those hopes looked to be premature. Allegedly unintentionally, the results of a Chinese study appeared on the website of the World Health Organization (WHO). That study found that the drug was ineffective – and the share price dropped again, only to spike once again on Wednesday of this week.
These studies provide vital information on the safeness of remdesivir, but they are insufficient in determining its effectiveness. That is also true of the Chinese study, which was published on Wednesday in The Lancet, a highly respected medical journal. The study was brought to a premature end due to a lack of patients and is thus apparently unable to deliver statistically reliable results. Still, the data from the studies performed thus far was sufficient for an emergency use authorization by the U.S. Food & Drug Administration (FDA). The European Medicines Agency (EMA) announced on Thursday evening that it is starting a "rolling review" of the drug "to speed up the assessment" of its effectiveness.
"We Aren't There Yet"
Which means that another vital question is now on the horizon: the drug's price. Gilead Sciences has been accused of greed on many occasions and the company is currently the focus of a class-action lawsuit in the U.S. for allegedly seeking to block the production of cheaper, generic alternatives to its HIV treatments. In March, Gilead applied for a special status for remdesivir that would have granted it a seven-year monopoly.
In the face of widespread ire, the company withdrew the application a short time later. The company claims that it is not focused on profit in these exceptional times. The company's director of medical affairs in Germany, Karsten Kissel, points out that Gilead made the drug freely available for the studies that have been performed. "We boosted production back in the beginning of the year at our own risk," he says. Charity, though, doesn't satisfy investors.
Aaron Kesselheim, a specialist in pharma-economics at Harvard Medical School, is hoping the drug will be sold at a fair price that is close to the cost of production. "Especially given the fact that a lot of the development of this drug was funded by public sources," he says. A calculation by a team led by Andrew Hill at the University of Liverpool found that the amount of remdesivir needed to treat a single patient could be produced for as little as $9, including taxes and a profit margin. Gilead believes this calculation to be too low and has pointed out that production is extremely complex from a chemical point of view and takes months. Observers such as Ben Locwin, a U.S. adviser in the pharmaceutical field, believe that Gilead could demand several thousand dollars from insurers, at least in the U.S.
The search for a miracle cure, though, will continue. Scientists now intend to combine several compounds, and research on remdesivir will proceed apace. There are indications that it is most effective when used in the illness' early stages. But it must be administered intravenously, a significant hurdle when it comes to the early treatment of patients or the prophylactic administration of the drug to high-risk groups, such as medical workers. Gilead medical-affairs director Kissel says the company is working on ways to simplify administration, including a type that can be inhaled like an asthma drug. "But," Kissel says, "we aren't there yet."