When Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Disease touted the anti-viral drug remdesivir for the treatment of COVID-19 on April 29 in the Oval Office, it was music to the ears of executives at Gilead Sciences, the drug’s manufacturer, headquartered in Foster City, California. Fauci declared that the preliminary results of the NIAID trial were proof that “a drug can block the virus”.
Since then, hospitals across the U.S. have been clamoring for what was considered to be the next best hope for patients succumbing to the virus in record numbers across the nation’s hospitals. At the time Fauci sang the praises of the virus-fighting medication, the study done by his own agency, NIAID, had not yet been submitted for peer review. But on May 22, the prestigious New England Journal of Medicine published a peer-reviewed article on the remdesivir study, which showed mild improvement in hospitalized patients who took the drug, but didn’t appear to help the sickest patients who were on ventilators. Nor did the drug significantly improve a patient’s chance of surviving COVID-19, according to the study.
“It showed there’s a statistically significant decrease in number of hospitalized days from 15 to 11,” said Dr. David Mushatt, M.D., section chief of infectious disease at Tulane University School of Medicine. “What’s really important are the mortality findings which decreased from 11 percent to 7 percent, but that didn’t quite meet statistical significance in this area. It was close, but it didn’t meet it.”
Statistical significance in the scientific world is important because it means that the results didn’t happen by chance. Without statistical significance, replicating the results is uncertain.
This isn’t the first rodeo for remdesivir, as it’s been on the scene since 2009 when it was being touted as a treatment for hepatitis C, but didn’t work as hoped. When Ebola erupted in the Democratic Republic of Congo in 2013, remdesivir was given a second opportunity to stop a deadly pathogen, but it showed limited effects.
But when lab tests showed it might be effective against coronaviruses like SARS and MERS and it became clear that the outbreak in China was another coronavirus, this revived hope that remdesivir might be able to fight COVID-19. Gilead already knew the game well and prepared the drug for clinical trials, and word spread quickly that there might be new hope on the horizon. By January 25, Gilead was distributing the antiviral drug on a compassionate-use basis. On May 1, the FDA authorized its emergency use, and plans were in the works to donate the experimental drug to hospitals in need across the U.S. Deliveries to Louisiana would arrive this month to around 50 hospitals around the state, those with at least five COVID-19 patients, Gov. John Bel Edwards said at a press conference last week.
“Doses were allocated simply based on the number of COVID patients in the various hospitals,” explained Dr. Joseph Kanter, assistant state health officer at the Louisiana Department of Health. “These health facilities are free to use the drug however and to whomever they choose. As a resource for guidance, we sent along the protocol from the NIH study showing the drug’s efficacy, and recommended to hospitals that they follow the inclusion/exclusion criteria used in that study.”
According to Dr. Sandra Kemmerly, Ochsner Health infectious disease specialist, and system medical director of hospital quality, the guidelines for treatment were right in line with what the specialists at the hospital had discussed long before there was any expectation of exactly when this drug would arrive.
“There was a small core group of critical care and infectious disease doctors as well as pharmacists who discussed this drug long before we saw the first case,” Kemmerly said. “We knew the drug had a prior history with Ebola and had been tried on COVID in China. But the drug at this point hasn’t been studied with COVID-19 over enough time to know which patients precisely are best for this drug, based on limited studies.”
‘We were hoping this drug would be used on the sickest people’
One of the problems with the randomized clinical trial guided by NIH has been that while doctors in ICUs treating the sickest of patients were hoping for a reversal of progression with this drug, it seems when patients have already reached a stage at which ventilators are part of the equation, or if patients are already in organ failure, it could be too late for remdesivir intervention.
“Although we were hoping this drug would be used on the sickest people, because those are the ones we want to impact, when the study was finally released, the biggest bang for your buck came when treating those in the intermediate phase of the disease — not at the earliest symptoms, but not on a ventilator — those that were having trouble breathing with low oxygen saturation, but not in critical distress,” explained Dr. Julio Figueroa, chief of infectious disease, LSU Health New Orleans School of Medicine. “It’s difficult to know upon admission exactly what stage a patient might be in, but when one sees a patient 10-12 days after they’ve been infected, the horse has more than likely left the barn.”
Just what the drug’s ultimate capability might be is difficult to determine in part because Gilead Sciences has yet to release their own data from their internal trials.
“It’s frustrating that Gilead doesn’t release their data when we’re trying to treat patients,” Figueroa said. “A lot of information being put out is via press release, or non-peer reviewed material, and it’s difficult to sift through all of it. People, as you can imagine, are desperate and they’ll try anything, but we need more than studies with large numbers, we need blind studies with placebos, so we really have good reliable data.”
To add insult to injury, a long-awaited study out of China that found that remdesivir failed to show patient improvement or keep them from dying was briefly posted to the World Health Organization’s website, and then abruptly taken down when the WHO realized it had been posted prior to peer review.
Among others less than enamored with the hype surrounding remdesivir is Dr. William Haseltine, who founded the divisions of biochemical pharmacology and human retrovirology at Harvard University’s School of Public Health. Writing in an article in Forbes, he noted that the data about remdesivir is too scant thus far to support it as any wonder drug, and emphasizes that NIH controversially ended their large trial of the drug and Gilead itself has suspended smaller trials.
“The patients who benefit from the drug are those ‘who are hospitalized with Covid-19 and require supplemental oxygen therapy,’ ” Haseltine wrote. “Why must patients be hospitalized to receive the drug? Because the drug has to be administered intravenously, through an in-dwelling catheter. This means that patients cannot take the drug from their homes. The data, preliminary though it is, shows that the drug only helps those with moderate Covid-19. If you view the severity of Covid-19 on an eight point scale, with 1 being those not hospitalized and 8 being dead, the drug only helps those in groups 4 (hospitalized, but no need for extra oxygen) and 5 (hospitalized and needing oxygen). In other words, the drug is only useful for those who are likely to recover anyway, with or without remdesivir.”
‘We need to proceed with caution and follow the science’
In late April, British journal The Lancet published the Chinese study finding that drug did not lower a patient’s viral load.
Another study published on May 8 in The Lancet discusses combination therapies with a 3-drug regimen (which doesn’t include remdesivir) that offered a greater reduction in the time it took COVID patients to recover than remdesivir did — with patients getting better in only seven days. The therapy included immune suppressants in combination with antivirals in a regimen that made sense to the experts in New Orleans.
“There’s a study now at the New Orleans VA in conjunction with Tulane’s infectious disease folks as part of an adaptive study,” Mushatt said. “The remdesivir is used in conjunction with Biricitinab, an immune modulator, which makes sense because it dampens the immune system which often has an overblown response in those who become the sickest.”
“It could very well be that a combination of antivirals and immune suppressants makes sense,” Kemmerly said. “Some of our severe patients here at Ochsner have been treated with other drugs, and even convalescent plasma [extracted from former COVID-19 patients who have made antibodies]. However, without a control group it’s tough to know exactly which combinations are working. For that, you would need randomized clinical trials. Certainly at this point no one can say that remdesivir as a single agent will treat COVID-19 successfully.”
Many physicians agree that we may already have the right combination of drugs sitting on shelves, possibly including drugs whose patents have expired. By contrast, Gilead stands to make a small fortune if this drug is approved by the FDA, and the overriding question becomes how much they will charge per dose, since they own the intellectual property for this drug, in spite of the government’s massive underwriting, totaling $79 million in taxpayer money. As The Intercept noted in a March report on remdesivir, Gilead Sciences has previously been under fire for its exorbitant pricing of the HIV medicine Truvada and its hepatitis C drug Sovaldi, which has a hefty price tag of $1,000 a pill.
“Look, the bottom line here is that we need to have a better understanding of what this virus does in the human body,” Figueroa said. “Once we know what’s happening in the lungs, the kidneys, and the vasculature, we may certainly be able to intervene with drugs which are already part of our repertoire. Right now we’re looking at the results of trials and lab studies, but some things work in vitro and just don’t work in humans. To take a little bit of information and say ‘everyone gets it’ is frustrating. We really just need more data — period. Remdesivir may have potential, but it’s something we just can’t prove at this point.”
It’s no secret that there is intense pressure to find not only a treatment but a vaccine or a virus that many scientists believe may be with us for some time to come. But when marketing coming from biotech entities and hype from the White House overrule good science, it’s dangerous for everyone. Recently biotech company Moderna announced their preliminary results of a vaccine trial that they characterized as “triumphant.” The results were based on only eight people.
President Trump announced his “Operation Warp Speed” on May 14, in an attempt to produce and distribute a vaccine for COVID-19 by the end of the year. But scientists worry that mistakes are made in haste and making a vaccine that will probably be given to a billion people means that producing something with minor side effects could quickly turn into a tragedy.
“We need to proceed with caution and follow the science,” said Figueroa. “It’s hard to know where we’ll be in six months, but my hope is that we’re not in the middle of the ‘winter phase” of this virus when it may come roaring back, which would be compounded by seasonal influenza. Hopefully, by then we’ll have better diagnostics with more accurate antibody tests that will let us know more about immunity. We certainly have the brightest minds in the world working to find answers.”