WSJ | Nearly a year and a half into the pandemic, researchers are still struggling to find effective, easy-to-use drugs to treat Covid-19.
Ten drugs have been cleared or recommended in the U.S. for use. Two of those later had their authorizations rescinded after they failed to work. The government recently paused shipments of a third because it wasn’t effective against new variants. The best medicines for early treatment are cumbersome to administer, and drugs for those in the hospital can only do so much for patients who are already severely ill.
“We’re really limited, to be honest,” says Daniel Griffin, chief of infectious disease at healthcare provider network ProHealth New York. “We do not have any dramatic treatments.”
A long list of factors played into the checkered development of drugs to treat Covid-19 cases—exposing flaws in the infrastructure of medical research and healthcare, particularly in fighting a fast-moving pandemic.
Federal officials concentrated their resources on quickly developing vaccines, with success. However, a relative dearth of drug research focused on coronaviruses, despite previous outbreaks, held back a fast response on treatments. Scattered U.S. clinical trials competed against each other for patients. When effective yet hard-to-administer drugs were developed, a fragmented American healthcare system struggled to deliver them to patients.
Covid-19 cases, and the need for treatments, are continuing. U.S. hospitals are bracing for new surges of cases with the Delta variant spreading among the unvaccinated. Vaccination drives are slowing in many countries, and poorer countries face a shortage of doses. No vaccine is 100% effective against Covid-19.
The Biden administration recently said it would spend $3.2 billion to support the development of Covid-19 antiviral pills.
Current clinical trials are evaluating more than 225 drug treatments, including new medicines as well as already-approved ones for conditions such as obsessive-compulsive disorder and gout, to see if they might also be effective against Covid-19, according to data from the Milken Institute, a nonprofit think tank.
A few potential Covid-19 therapies in development have shown promise. Merck & Co. and Pfizer Inc. are each testing antiviral pills that could be taken at home soon after someone is infected. Merck’s widely anticipated pill, which it is developing with partner Ridgeback Biotherapeutics, hit a setback in April when it failed to help hospitalized patients. Researchers are still studying its effectiveness among the newly infected.
Government-funded researchers in the U.S. and U.K. recently began large studies of ivermectin—an antiparasitic pill used for decades to treat river blindness in sub-Saharan Africa.
A lack of knowledge among healthcare providers has made it difficult to get even the available treatments. When Bob Bellin of Austin, Texas, tested positive for Covid-19 last December, he remembered that then-President Donald Trump had taken a monoclonal antibody treatment from Regeneron Pharmaceuticals Inc.
Suffering from a mild cough and a headache, the retiree was worried about his chances of developing a bad case of the virus because he has a compromised immune system condition. He says he called a telemedicine provider to inquire about antibody treatment, but the physician assistant on the call initially didn’t know about it. After some pleading, the healthcare worker agreed to research the drug’s availability, he says.
Several minutes later, she got back to him with the names of sites where he could get the antibody treatment. The next week, Mr. Bellin received the infusion over a three-hour visit. A week later, he started his regular running routine again.
Paltry research
When the pandemic hit, drug researchers and pharmaceutical companies rushed to explore potential remedies.
The problem was that research into coronavirus vaccines and antivirals “was only being done by a handful of people around the world,” says Barney Graham, deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. His previous work on coronaviruses allowed him and other researchers to quickly develop a key piece of technology used in mRNA vaccines for Covid-19.
Outbreaks of severe acute respiratory syndrome in 2003 and Middle East respiratory syndrome in 2012 raised alarms about the need for more research into viruses. Yet interest mostly waned after the outbreaks were contained. Most drug researchers focused on finding potentially more lucrative treatments for diseases like cancer, rheumatoid arthritis and hepatitis.
From 2000 to 2017, global funding for coronavirus-related research was $500 million, or 0.5% of the total spent on infectious diseases over the period, according to an analysis published in the Lancet.
In February last year, before the virus was declared a pandemic, researchers in China and the U.S. turned to the antiviral remdesivir as a potential Covid-19 treatment. University of North Carolina and Vanderbilt University researchers, supported by U.S. government grants, had been working with Gilead Sciences Inc. since 2014 to investigate its effectiveness against coronaviruses.
Experiments had showed that it helped clear SARS from the lungs of infected mice, but suggested one issue with the therapy’s real-world use: The drug was most effective when given as soon as possible after infection.
Remdesivir wasn’t easy to administer in humans, however, requiring several days of intravenous infusions inside a hospital. In pill form, the liver would break it down before it reached the bloodstream, says a Gilead spokesman.
The need to give remdesivir intravenously prompted researchers to study the drug against Covid-19 in patients who were already sick enough to go to the hospital—but by that point, the virus levels of many had already started to come down, though their bodies were still struggling with the damage. In clinical trials, the drug sped recovery times, but didn’t have a statistically significant effect in reducing deaths.
Remdesivir, first authorized by the Food and Drug Administration in May 2020 and later granted full approval, is now given to roughly half of all hospitalized patients. Yet patients often recover slowly regardless of whether they receive the treatment or not, doctors say.
“The effect of remdesivir is something a statistician can show you in a trial of 1,000 people, but it’s not something where you really can see a day-to-day impact on your patients,” says Dr. Griffin of ProHealth.
Gilead says its drug provides an important benefit in helping patients to recover faster and leave the hospital days sooner than they otherwise would.
Slow-moving system
From January 2020 through June 2021, drug researchers launched thousands of studies world-wide, including more than 650 in the U.S., according to data from market-research firm Informa Pharma Intelligence.
Their uncoordinated efforts weren’t suited for responding urgently or efficiently to a pandemic, according to health officials.
The trials competed with each other for study subjects, slowing down the research, says Janet Woodcock, now the FDA’s acting commissioner, who oversaw drug development for Operation Warp Speed during the Trump administration.
In addition, of 2,895 clinical trial arms launched globally through November, only 5% were rigorous enough to yield data that would alter treatment practices, according to an analysis co-written by Dr. Woodcock in February.
“People would publish theories or very small trials, and they would be misleading,” says Dr. Woodcock. “We failed to generate evidence we could have generated if we had a more organized approach.”
American trials are often labor intensive and time consuming, requiring doctors to collect reams of data from patients. Scientists at the University of Oxford pursued a simpler, more pragmatic trial. The study, called Recovery, dispensed with some hallmarks of modern clinical trials, such as comparing drugs to placebos and conducting copious blood tests to measure secondary effects.
Researchers rapidly enrolled thousands of subjects. Each was given one of the drug candidates to test. Researchers measured whether an agent worked by focusing on a single metric: whether a drug reduced the risk of death compared with standard treatment.
The Recovery study, which has examined at least 12 drugs so far, found the most effective of all Covid-19 treatments for hospitalized patients to date, dexamethasone, which cut the risk of death in patients on ventilators by a third. The Oxford scientists reported the results in June 2020, less than three months after they first began evaluating it.
The Recovery researchers “were able to reel off a series of important answers much faster than the U.S., which has six times the capacity and way more money,” says Robert Califf, a former FDA commissioner and now head of clinical policy and strategy at Alphabet Inc.’s Verily Life Sciences and Google Health. The U.K.’s centralized national healthcare system also made it easier to coordinate research priorities across hospitals, he says.
When the National Institutes of Health launched multiple trials to test drugs against Covid-19, the agency’s usual reliance on elite academic medical centers proved to be another bottleneck. Infection rates were often highest in local private or publicly owned community hospitals that frequently weren’t trained to conduct clinical trials, leading to delays, says Dr. Woodcock, who helped organize the NIH studies.
“We had tens of thousands of people hospitalized around the country who were not getting enrolled in studies,” she says.
The NIH did eventually start working to set up community hospitals to do trials, but “doing that earlier probably could have gotten us faster enrollments,” says Cliff Lane, deputy director for clinical research and special projects at the NIAID.
Poorly equipped
Last November, the FDA authorized the first drugs designed specifically to target Covid-19 in people who weren’t hospitalized based on preliminary trial results. These monoclonal antibodies were modeled after the natural antibodies people produce to fight the new coronavirus.
Researchers at companies including Regeneron and Eli Lilly & Co. developed these monoclonal antibody therapies in less than a year, compared with the decade or longer it usually takes to bring a drug to market. The work was sped by earlier research by Regeneron and others to develop antibodies for the MERS virus. The new drugs worked well in early Covid-19 patients, reducing the risk of hospitalization or death by 70% in trials.
Yet of the nearly one million doses shipped to hospitals and clinics from November through early May, just 49% were used by patients over the period.
One factor in their limited use was the fact that influential panels that issue Covid-19 treatment guidelines balked at endorsing them before full clinical trial data was available. The NIH and the Infectious Diseases Society of America didn’t recommend using the drugs until February and March, respectively, after Lilly provided results from a Phase 3 study.
Adarsh Bhimraj, an infectious-disease specialist at the Cleveland Clinic and lead author of the IDSA guidelines, said that the initial FDA authorizations were based on Phase 2 data with small numbers of patients, making it hard to determine how effective the drugs were against placebos.
Hospitals were slow to embrace the drugs because they required intravenous infusions that took up to an hour to complete, followed by an hour of monitoring for side effects. Many infusion clinics faced the risk that Covid-19 patients would spread the virus to others with weakened immune systems who were being treated for cancer or other diseases.
When severely ill Covid-19 patients began flooding its wards, the Ohio State University Wexner Medical Center set up a makeshift infusion center in a small auditorium to deliver monoclonal antibodies to people with confirmed cases, before they turned worse.
The hospital treated 1,469 patients with the drugs through early July, and as many as 30 people a day at the peak, says Jonathan Parsons, a pulmonologist and executive vice chair of clinical operations for Wexner’s internal medicine department.
Of the patients treated so far, 4.8% have gone on to be hospitalized, compared with an estimated 8% to 9% for similar patients not infused with the drug, he says.
Looking ahead, the best solution would be an antiviral that can be taken early in the disease as a pill, doctors say.
Finding highly effective treatments with tolerable side effects is likely to take years and require more coordination between government, universities and industry, similar to the campaign to find HIV drugs in the 1980s and 1990s, says Carl Dieffenbach, director of the NIAID’s AIDS division.
“We need to transition out of the emergency phase and into a period where we can have sustained support for drug development,” he says. “Because this or something else is going to come back, and if we don’t learn the lesson this time, God help us.”
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