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    Academic researchers investigate treatments amid urgent need

    Scientists at university labs and hospitals are running scores of trials to find drugs and other treatments to save patients stricken by COVID-19. Here are five different approaches, explained.

    Hussin Rothan, PhD, of Georgia State University investigates the impact of an arthritis drug on stopping the coronavirus from replicating itself in infected cells
    Hussin Rothan, PhD, of Georgia State University investigates the impact of an arthritis drug on stopping the coronavirus from replicating itself in infected cells.
    Courtesy: Georgia State University

    Can a drug that prevents heartburn save the life of someone stricken by COVID-19? How about a medication that has previously been used to ease the pain of arthritis? Should doctors try a drug that faltered against a similar virus? Will the blood of survivors save others suffering from this devastating pathogen?

    Researchers at academic medical institutions around the country are trying those treatments and more as they pursue scores of experiments to combat COVID-19. In labs, clinics, and intensive care units (ICUs), they’re working through multiple trials with partners in academia, government, and business to slow a disease that each day grows by over 20,000 confirmed cases in the United States and kills more than 2,000.

    “Many avenues are being pursued,” said Richard Novak, MD, head of the Division of Infectious Diseases at UI Health, during a break from one of the trials he guides at the University of Illinois at Chicago (UCI). “There’s an urgent need to find something.” 

    That “something” will be more than one thing. The National Institutes of Health (NIH) has cataloged more than 280 clinical trials, observational studies, and expanded access projects in the United States that target COVID-19. Those efforts are pursuing not so much a blanket cure as treatments that target certain types of damage, in certain types of patients, at specific stages of the disease. Some treatments might be used in combination.

    For any experimental treatment, Novak said, the question is, “If it works, is it going to work for everybody?”

    Many of the experiments involve repurposing existing drugs designed to treat other afflictions. That approach brings the advantages of knowing a drug is safe for many people in certain doses and having an existing manufacturing process to bring a drug to market quickly. Other trials involve adjunctive therapies, which might work in combination with drug treatments.

    Below is a sample of treatments being explored at academic medical institutions.

    Antiviral: Halting replication

    Deployed to combat Ebola with disappointing results, the antiviral drug remdesivir has become a leader in showing promise against COVID-19. Preliminary results from a recent NIH trial showed that patients with severe cases of COVID-19 recovered 31% faster than those who received a placebo, prompting the Food and Drug Administration (FDA) to approve remdesivir on May 1 for emergency use in severe cases of the disease.

    “It's a really big deal," said Novak, who oversaw the trial at UIC, which enrolled 15 patients. “We now have something that has some proven efficacy. It is not a cure, but it clearly benefits those who get it [the virus].”

    A few miles north along Lake Michigan, Babafemi Taiwo, MBBS, oversaw a portion of the same trial with 19 patients at Northwestern Medicine. The drug provides “hope,” said Taiwo, the chief of infectious diseases at Northwestern University Feinberg School of Medicine. “Hope is something we need in the current climate.”

    Novak said remdesivir prevents RNA viruses from replicating by mimicking adenosine, one of the building blocks of RNA. After the virus infects a cell and tries to make copies of itself, remdesivir gets inserted into the sequence, causing the duplication to stop or produce nonviral mutations.

    The results from the human trials are noteworthy for remdesivir because its previous effectiveness in animal trials didn’t carry over into people. About five years ago, remdesivir was used to combat the outbreak of Ebola in West Africa, but it was discontinued after other drugs proved more effective.

    Testing remdesivir against COVID-19 makes sense because the virus that causes COVID-19 is an RNA virus, like Ebola. Also, remdesivir has shown promising results in animal trials against other coronaviruses — severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) — and recently showed strong effects against COVID-19 in an NIH animal trial this year.

    The double-blind randomized human trial funded by the NIH included more than 1,000 patients getting the drug or a placebo. It produced slight but not statistically significant reductions in patient deaths, the NIH said. 

    Antiviral: In a pill

    Similar to remdesivir, EIDD-2801 is an antiviral that seeks to block a coronavirus from replicating after it infects a cell. But while remdesivir is administered intravenously, EIDD-2801 can be taken orally — which some believe would allow it to reach more patients than remdesivir.

    “People diagnosed with COVID-19 could take it at home,” said Ralph Baric, PhD, a professor in the Departments of Epidemiology and of Microbiology and Immunology at the University of North Carolina’s (UNC) Gillings School of Global Public Health.

    Researchers at UNC, Vanderbilt University Medical Center (VUMC), and Emory University have been working together to develop and test the drug.

    EIDD-2801 was developed by the nonprofit Drug Innovation Ventures at Emory (DRIVE) and recently showed promising results in animal trials to treat influenza and two forms of coronavirus, SARS and MERS. After the COVID-19 outbreak, researchers from the universities tested the drug in mice and cultured human cells and found that it reduced lung damage and virus replication.

    “When the virus starts replicating in the presence of the drug, it makes so many mistakes that the progeny genomes are effectively dead,” Baric said.

    Last month, the FDA approved EIDD-2801 for human clinical trials, which are being established now.

    Baric noted that the pill form of the drug makes it easier to treat patients with early and mild symptoms because they do not have to be hooked up to an IV. That aligns with what appears to be the best timing for the use of antivirals, because as COVID-19 progresses, it damages different organs and systems in ways beyond the reach of virus replication inhibitors.

    “With any antiviral, the timing of delivery is key,” Baric said.

    Plasma: Can survivors save lives?

    When actor and COVID-19 survivor Tom Hanks gave blood last month at a donation center run by UCLA Health, he contributed to an effort spearheaded by academic medical institutions to fight the disease with plasma from people who have recovered from it.

    Researchers hope that antibodies in the plasma of COVID-19 survivors will attack the virus in current patients and help them recover.

    “We get some remarkable stories back,” said Michael Joyner, MD, of Mayo Clinic, which is the lead coordinator on the effort — the National COVID-19 Convalescent Plasma Project — to expand access to convalescent plasma, collect information about the results of plasma treatment, and develop a trial to analyze the effectiveness of the approach.

    The project grew from inquiries by doctors around the country about whether plasma from recovered victims could help COVID-19 patients. “The head of our blood bank said we occasionally do this for really weird infections, like once every couple of years,” Joyner recalled. “I said, ‘Why don’t we try a treatment protocol to see if we can keep them [COVID-19 patients] out of the ICU?’”

    Eight doctors from six academic medical institutions lead the project, which includes a database for plasma donations, needs, and supplies. Joyner said that more than 2,000 health care facilities have signed on. (The University of Southern California, part of UCLA Health, is among them.) The project began in early April, and at the end of last week it reported that 7,200 patients had been infused with plasma through the project.

    Despite positive results in some patients — including higher oxygen levels and avoidance of ICU admission — Joyner cautioned that “we have to look at the data” to determine true effectiveness. Project leaders are planning a study to compare the outcomes of patients enrolled through the project with comparable patients treated at the same institutions who did not receive the plasma.

    Anti-arthritis: Quelling the storm

    One of the devastating impacts of COVID-19 is that it sometimes turns the body against itself through an excessive immune response that causes severe inflammation, damaging such organs as the heart and lungs. When Antonio Abbate, MD, PhD, read about that phenomenon in the early days of the pandemic, he wondered: Could drugs that tamp down the inflammation of rheumatoid arthritis do the same for people stricken by COVID-19?

    “I’ve been working on inflammation all my career,” said Abbate, medical director of the Clinical Research Unit at VCU Health, part of Virginia Commonwealth University. “I was on the lookout for therapies” to apply to COVID-19.

    He found clues in reports from China that some patients “had a remarkable response” after being given tocilizumab, a drug that treats rheumatoid arthritis by suppressing immune responses. Abbate had worked with similar drugs and joined a trial for one such treatment, sarilumab, that involves hundreds of patients at more than 60 sites in several countries. (The trial is overseen by one of the drug's manufacturers, Regeneron.)

    Abbate said sarilumab works by blocking interleukin-6, a cytokine that signals the body’s immune system to release other cytokines — sometimes excessively, in what researchers call a cytokine storm. The storm can kill cells, including in the lungs.

    “That contributes to the inability of the lung to exchange oxygen, prolongs the illness, and increases the need for ventilators,” Abbate said.

    Early results indicate that the drug might be useful for certain patients in late stages of the disease. Based on mixed results in phase 2 of the trial, Regeneron limited phase 3 to include only the most critical patients struggling with oxygen depletion: those who need ventilation or ICU care. Nine patients are enrolled so far in the double-blind randomized trial at VCU. Sarilumab, usually administered by injection under the skin, is being administered intravenously in the trial.

     “It’s not for everybody with the infection,” Abbate said — a statement that applies to just about all therapies under investigation.

    Anti-heartburn: Surprising interference

    “At first, it doesn’t make sense,” Joseph Conigliaro, MD, MPH, said about experiments to treat COVID-19 with a heartburn drug.

    “Why would an H2 [histamine] blocker for reflux have any therapeutic benefit for a virus such as COVID-19?”

    But early in the novel coronavirus outbreak, he said, researchers who pored over observational data about hospitalized patients in China noticed something odd: “Patients who have been on famotidine [a heartburn drug] and also are admitted with COVID-19 actually do better.”

    That compelled researchers from Alchem Laboratories Corp. to run computer models of how the drug, which reduces stomach acid, might work against the novel coronavirus, then to conduct in vitro studies on the virus itself. With promising results in hand, they asked Conigliaro and researchers at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and the Feinstein Institutes for Medical Research to study it in patients.

    They started quietly.

    “We didn’t announce it anywhere,” said Conigliaro, the principal investigator.

    The reason: Concern that if word got out that famotidine might allay COVID-19 symptoms, people would buy up supplies to fight the disease. (The drug is sold under several trade names, including Pepcid and Fluxid.) Researchers wanted to make sure they could get enough of the drug for the trial and didn’t want people to use the drug as a treatment for COVID-19 before trials showed if it was effective.

    The in vitro experiments showed that although famotidine isn’t an antiviral, it behaves like one in the presence of the novel coronavirus. It binds to an enzyme involved in reproduction of the virus, inhibiting the virus from duplicating itself.

    Hofstra/Northwell started a randomized, double-blind control trial in April. It has enrolled about 230 patients and hopes to reach 1,200, Conigliaro said. The drug can be administered orally.