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Addressing a 'massive unmet need' in COVID-19 treatment

COVID-19 Clinical Research Center tests drugs to reduce severe infections
A photo of the COVID-19 Clinical Research Center located on the Fred Hutch campus
The Minor Building (foreground) is home to the COVID-19 Clinical Research Center. Located on the campus of Fred Hutchinson Cancer Research Center, it provides a safe, outpatient setting for clinical trials of drugs meant to blunt the effects of SARS-CoV-2 in newly infected patients. Photo by Robert Hood / Fred Hutch News Service

Just two days after her COVID-19 test came back positive in January, retired grocery store checker Erin Brennan found herself in a reclining chair at Fred Hutchinson Cancer Research Center in Seattle, with an IV drip in her left arm. She was participating in a clinical trial.

Trickling through the tubes for the next half hour was a either a dose of the antiviral drug remdesivir or a solution of salt water — a placebo. She returned on consecutive days for two more infusions. Today, the 58-year-old resident of Shoreline, Washington, is fully recovered from a mild case of COVID-19, but she does not know whether she received remdesivir or the placebo. In her view, it did not matter. She had volunteered for science.

“I felt it was my duty as a citizen, and as a self-described ‘empath,’” she said. “I received nothing but the best care, and I can’t thank the nurses enough.”

Even as vaccine distribution expands, it is still important as ever to find medications that can take the lethal edge off SARS-CoV-2, the virus that causes COVID-19. Doctors want new drugs that are highly effective, easily delivered to large numbers of patients, and can stop the disease before symptoms become severe.

Dr. Rachel Bender Ignacio
Dr. Rachel Bender Ignacio is medical director for the COVID-19 Clinical Research Center, or CCRC, located on the Fred Hutch campus. Photo by Robert Hood / Fred Hutch News Service

“It remains a massive unmet medical need,” said Dr. Joshua Schiffer, a Fred Hutch infectious disease physician who uses computer modeling to assess how medical interventions might change the course of the pandemic.

“A widely available and widely implemented treatment, given early during infection, is the most effective way to lower hospitalizations, death and long-term debilitating symptoms associated with COVID-19,” he said.

Brennan is one of more than 200 volunteers who have signed up for a variety of trials at the COVID-19 Clinical Research Center, or CCRC, since it opened its doors on the Hutch campus in October to help test experimental drugs that might blunt the impact of the coronavirus.

It is a field that is rapidly changing.

On April 12, remdesivir maker Gilead Sciences stopped the Phase 3 trial in which Brennan had taken part. The company said it has shifted its focus from developing a three-day intravenous regimen of remdesivir in patients with COVID-19 that do not need to be hospitalized, toward development of potential oral or inhaled antiviral treatments that can be taken at home. The decision to stop the trial was not due to the safety or effectiveness of the remdesivir in this patient population, but the impracticality of requiring three visits to an infusion clinic to receive remdesivir as IV infusions.

“I am still very thankful that I partook in it, and if I’m asked to participate in other studies, I will do it,” said Brennan.

Ongoing trials test several potential drugs

As the pandemic continues, researchers at the CCRC are focused on four other trials of potential COVID-19 treatments, with more in the offing.

“Some people are thinking that because there are fewer cases than last winter, and that we are getting out the vaccines, that you don’t need treatments anymore, and that’s absolutely not true. We’re not done yet. Not at all,” said Hutch physician-scientist Dr. Rachel Bender Ignacio, who is medical director of the CCRC.

As the nature of the virus and the disease benefits from more data and further study, researchers and drug companies will look at both novel therapies as well as repurposing existing medicines.

The Hutch-based group is actively recruiting for a clinical trial of fluvoxamine, an antidepressant in the selective serotonin reuptake inhibitor class that has been used for decades to treat obsessive compulsive disorder. Unlike some other SSRIs commonly used to treat depression or anxiety, fluvoxamine also appears to block a specific inflammatory process that raises havoc in patients infected by SARS-CoV-2.

“I think that for me, this is the most interesting and most promising of those drugs that might provide accessible treatment before patients become ill,” Bender Ignacio said.

In November, a small initial study led by researchers at Washington University, in St. Louis, found the drug might be effective in keeping infected COVID-19 patients out of the hospital. That work led to a kind of natural experiment, which took place at a Berkeley, California, racetrack late last year. When 113 workers living in close quarters became infected, they were quickly offered a two-week supply of fluvoxamine. Of the 65 employees who took up the offer, none were hospitalized. Of the 48 who declined, six were hospitalized, and one died.

Now the CCRC is participating in a Phase 3 clinical trial that is overnighting up to 1,100 boxes containing a 15-day supply of fluvoxamine or a placebo to hundreds of volunteers around the country and Canada. The Stop COVID 2 participants also receive a thermometer, a blood pressure monitor and a pulse oximeter, which slips onto a finger to read oxygen saturation levels.

The COVID-19 Early Treatment Fund, supported by philanthropic donations, is a funder of the study. The goal is to see if the results of the original Washington University study can be replicated on a large scale.

Dr. Elizabeth Duke (left) is principal investigator at the Hutch site for a clinical trial of the drug molnupiravir. Dr. Joshua Schiffer (right) said there is a "massive unmet need" for COVID-19 treatments.
Dr. Elizabeth Duke (top) is principal investigator at the Hutch site for a clinical trial of the drug molnupiravir. Dr. Joshua Schiffer (below) said there is a "massive unmet need" for COVID-19 treatments.

Fred Hutch file photos

“Part of the beauty of doing this all-remote study is that we are enrolling people from Wenatchee (in Eastern Washington) and Idaho to Alabama and rural South Carolina,” Bender Ignacio said.

Clinical trial access is commonly limited to people who live near cities with big academic centers; the all-remote study provides opportunities to people anywhere mail can be delivered and may be more convenient for those hesitant to try out research participation.

The second ongoing trial at the CCRC is enrolling pregnant women for part of a study of Regeneron’s Phase 3 trial of a monoclonal antibody combination drug. The trial tested the efficacy of these lab-made proteins on more than 6,000 men and women, 50 of whom were treated at CCRC. Now that the drug has received an Emergency Use Authorization from the Food and Drug Administration, Hutch researchers are enrolling participants for an expanded segment of the study that is verifying the safety of the IV-infused treatment during pregnancy.

The Hutch CCRC researchers have also completed enrollment in a third trial, this one for a twice-a-day pill called molnupiravir. The small study of this potential treatment for COVID-19 has drawn significant attention because the drug, originally developed by Emory University and sold to biotech startup Ridgeback Biotherapeutics, was acquired by U.S. pharmaceutical powerhouse Merck & Co.

Preliminary results, presented in March at the Conference on Retroviruses and Opportunistic Infections, showed a rapid reduction in infectiousness among those who took the drug compared those who were randomly selected to receive a placebo.

Physician-researcher Dr. Elizabeth Duke, who was principal investigator of the molnupiravir trial’s Hutch site, said the drug is promising because it has shown signs of activity against a variety of RNA viruses, including influenza, and can be formulated into a pill.

“The fact that it is oral means that it can be made available quickly and inexpensively to a large population both in the U.S. and abroad,” she said. “Proving its safety in a COVID-19 trial might make another drug available against common respiratory pathogens, in addition to having a medication ready in the event of a future pandemic.”

Now that molnupiravir has been shown to be safe and active in this first study, a larger Phase 3 trial of the drug is ongoing throughout the U.S., and the CCRC expects to open this study to enrollment this month.

Finally, the CCRC has completed enrollment in a clinical trial of a monoclonal antibody infusion for early treatment of COVID-19. The study is sponsored by Vir Biotechnology, a San Francisco startup, in collaboration with GlaxoSmithKline. Enrollment in the study was halted after interim data showed the treatment lowered hospitalization and death by 85% compared with placebo. On that basis, the companies are seeking emergency use authorization from the FDA, and new studies are in the pipeline, including more accessible formulations, like injections rather than IV infusions.

Bender Ignacio said that progress in studies of potential treatments has lagged the lightning speed of the very large vaccine trials in part because it is inherently more difficult to enroll patients who are newly infected with COVID-19 than it is to sign up healthy people to test a vaccine. Participants typically need to enroll within 72 hours of a positive test.

“Even though the numbers of participants needed is small (compared to giant vaccine trials), it is much harder because you are looking for people who already have infections, and you need to get in touch with them in a short period of time,” she said.

Cases of new infections have dropped significantly from the winter, and while public health experts are warning of a possible fourth wave of infections, vaccination rates are highest among the elderly who are most at risk for severe disease.

“We’ve seen a decrease in older folks coming into clinical trials,” Bender Ignacio said, “and we are hopeful that’s because people are being protected by the vaccine.”

Help for long-haulers

In addition to preventing the worst possible outcomes of SARS-CoV-2 infection, new treatments are needed to address the burgeoning problem of people who have extended periods of exhaustion, brain fog, loss of sense of taste and smell, or malaise after recovering from acute infection — the so-called “long-haulers.”

Bender Ignacio said that CCRC researchers are keen to find treatments that can alleviate the condition, which now has an official name, post-acute sequelae of SARS-CoV-2 infection, or PASC. In February, the National Institutes of Health announced a $1.5 billion initiative to study the cause of PASC (then called Long COVID) and find ways to prevent and treat it.

In March, NIH Director Dr. Francis Collins warned in his blog that a large British study suggests about one in 50 COVID-19 survivors have persistent symptoms lasting three months or more. This implies that PASC could affect “many hundreds of thousands of people in the U.K. alone and millions more worldwide,” Collins wrote.

That could be an underestimate of the scope of the problem. A survey of COVID-19 patients, conducted recently by University of Washington researchers and published in JAMA, found that about 30% of those patients reported at a least one persistent symptom when asked, on average, six months after the onset of their illness.

The CCRC is positioned to carry on research on the growing population of Seattle residents who have survived COVID-19 but are now struggling with PASC. The number of people infected with the COVID-19 virus is likely far greater the number of recorded cases, leading epidemiologists to conclude the impact of the disease is likely larger than the 31 million infections reported to date. As the pandemic continues in its second year, the CDC estimates that last year 83.1 million Americans have been infected with the virus, and 70.4 million have experienced symptomatic illness.

“Hutch immunologists like Dr. Julie McElrath can help us find drug targets, and then we can start enrolling people that already have PASC into studies of treatment,” Bender Ignacio said. McElrath, who holds the Joel D. Myers Endowed Chair and is senior vice president and director of the Vaccine and Infectious Disease Division at the Hutch, leads the Seattle COVID Cohort Study, which focuses on individuals at high risk of exposure and tracks their immune responses to infection over time.

“Even after we have good treatments for acute COVID-19, we will still need treatments for PASC,” Bender Ignacio said.

Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at srussell@fredhutch.org.

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Last Modified, May 06, 2021