In pursuit of coronavirus treatments and why we need to be cautious

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It’s impossible to keep up with entries at ClinicalTrials.gov that include the search term “COVID-19.”

Last week when I posted Can Existing Drugs Treat COVID-19? From Viagra to Thalidomide to Cough Syrup here at DNA Science, the number of studies was a tad over 100. Right now, it’s at 158, a 50% increase. These are just registered studies – being listed doesn’t imply approval, but rather intent to carry out an investigation.

On March 18, Dr. Anthony Fauci, who no longer needs introduction, mentioned chloroquine as an example of a drug that might possibly be repurposed against the novel coronavirus, and that several clinical trials are already evaluating its safety and efficacy against the new disease. Dr. Fauci said this at a webinar series that the Journal of the American Medical Association holds regularly for media. The drug has been used for years to treat malaria, rheumatoid arthritis, lupus, and other conditions.

On March 19, after I’d included Dr. Fauci’s statement in my post and presumably other journalists did too, President Trump inexplicably hurled out the drug name as a fait accompli, an instantaneous magic bullet, because he “had a feeling,” conjuring up “very encouraging early results” from the ether and insisting FDA had greenlighted it to treat COVID-19.

Of course no such thing had happened. And the president’s bizarre comments inspired a man in Arizona to drink a fish-parasite treatment because the chemical name sounded similar. The president was right, the drug indeed had a “tremendous impact.” The man died. I don’t know what happened to the fish.

It was a misunderstanding of the drug approval process so profound that all I could do was smack my head. I wasn’t the only one.

Progress

At ClinicalTrials.gov since last week, new registered studies have gone beyond China, with many from Italy and Spain, but also Egypt, Jordan, the UK, Canada, France, Germany, Denmark, Romania, Israel, and the US. In addition to more repurposing candidates are a sprinkling of studies on the social manifestations and consequences of the pandemic, such as “social media effect on knowledge dissemination.”

Some new entries:

  • Leronlimab, a monoclonal antibody that has been in phase 2/3 clinical trials for HIV/AIDS.
  • Sarilumab (Kevzara), another MAb, blocks interleukin-6 receptors and is used to treat rheumatoid arthritis. It’s one of several repurposing candidates being borrowed from the autoimmune pharmacopeia, which may stress supplies to patients already taking them.
  • PUL-042 is an inhalation solution with a mixture of drugs that bind Toll-like receptors on lung epithelia, dampening the binding of viruses that can trigger the runaway immune response, called a cytokine storm, that causes many COVID-19 deaths.
(NIAID)

We need clinical trials

Dr. Fauci struggled when asked about off-label prescribing for desperate patients at a follow-up JAMA webinar, held March 23. That’s when a health care provider prescribes a drug that is FDA-approved to treat one condition for a different one. It’s legit, a judgment call.

“This is painful for me. Having been through so many of these outbreaks, you can understand the desire that when there’s either in vitro evidence or an animal model that shows some degree of optimism, despite the public health situation, you want to just give it to people,” he said.

But a one-by-one approach makes it impossible to learn whether a drug works or not.

Related article:  Genetic analysis tracks spread of 3 primary coronavirus variants

“If you’ve given a lot of stuff to people and don’t know what works, you may have satisfied your humanitarian instincts, but you’ve done a disservice. That’s why we lean heavily toward intervening in an ethical, sound, randomized controlled clinical trial, to define whether something works or not,” Dr. Fauci said.

The only instance in which a control is unnecessary is based on logic: if a condition is 100% fatal. There’s nothing to lose. “But when dealing with a disease, typically a certain percentage of people will have a spontaneous recovery. If they’re given something, you can’t say they got better because of the treatment. A study is meaningless if it is not controlled,” Dr. Fauci said.

During the Ebola outbreak in Africa in 2014, a rush to try anything sacrificed an opportunity to collect information that might have helped confront future epidemics. “This tragedy of not discovering new therapies during an outbreak cannot be repeated,” Andre C. Kalil, MD, MPH, Professor, Department of Internal Medicine and Director, Transplant Infectious Diseases at the University of Nebraska Medical Center, wrote in a Viewpoint in JAMA March 24.

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Pharmaceuticals aren’t like noodles, flung against a wall to see what sticks.

But even though the “RCT” – a randomized controlled clinical trial – is widely recognized as the gold standard, many researchers, Dr. Fauci said, are uneasy at the prospect of giving a placebo in a study, even if it is an existing treatment. Is doing so a betrayal of their oath to “do no harm?”

Fortunately, a novel clinical trial strategy, called an adaptive design, may help speed the drug approval process. Dr. Kalil describes it in his Viewpoint. It allows a clinical trial to test more than one treatment. That’s what the National Institutes of Health is doing in a trial of Remdesivir, which has been much talked about and is already through phase 2 to treat HIV/AIDS. It is an intravenous infusion.

The phase 3 trial of Remdesivir is enrolling 440 patients with COVID-19 at 75 sites, and will use the inactive ingredients as the control. But if and when the drug shows efficacy, it can be moved to the control arm and a new candidate drug added to the evaluation protocol. The trial began February 21 and is slated to run until April 1, 2023.

Wrote Dr. Kalil, “This unprecedented speed from concept to implementation in just a few weeks is noteworthy and provides proof that clinical trials can be promptly initiated even in the middle of a pandemic.”

Hope.

Stay well all. And many thanks to the readers who have posted their ideas for possible treatments.

A version of this article originally ran at PLOS and has been republished here with permission.

Ricki Lewis is the GLP’s senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis

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