Could These Old Drugs Help Fight COVID and Save Lives?

Laura Stokowski, RN, MS

September 08, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Early in the COVID-19 pandemic, entrepreneur and philanthropist Steve Kirsch realized that until we have a vaccine against SARS-CoV-2, we would be at the mercy of this virus. He realized that the fastest and most effective way to reduce COVID-19 fatalities would be to leverage existing drugs to treat patients at the onset of infection — before they become sick. A lack of funded research in this area prompted him to establish the COVID-19 Early Treatment Fund (CETF) with the purpose of funding outpatient clinical trials of promising repurposed drugs.

Dr Lisa Danzig

Medscape spoke with CETF's chief medical advisor, Lisa Danzig, MD, about the organization's aim to fund promising research on repurposed drugs to treat COVID-19.

What is CETF trying to do?

Two things: save lives, and get control of this pandemic.

We are facing perhaps the greatest crisis of our lifetime. Doctors who have taken care of patients with COVID are really frustrated about not having anything to offer; they just watch patients die. We want to change that. CETF was founded to find treatments that, when given early, could improve outcomes and avoid catastrophic complications in patients suffering from COVID-19. That means reducing hospitalizations, which can reduce mortality, but it also can mean reducing viral load, and that can have a profound impact on transmission within communities. We are a funding organization — a Band-Aid. We shouldn't exist, but we do, aiming to close gaps until a coordinated response can get set up.

Tell us about drug repurposing and why you think existing drugs might have a role in mitigating COVID-19 or slowing its transmission.

This disease has two components — the viral infection, and the immunopathology. So the two promising categories of drugs are classical antivirals (or repurposed drugs with antiviral activity), and the immunomodulators. We are mechanism-agnostic. It doesn't matter what kind of drug it is if it keeps people out of the hospital and prevents chronic morbidity and mortality.

Repurposed drugs are sort of the low-hanging fruit of clinical drugs. The QBI Coronavirus Research Group identified 69 compounds that have theoretical activity against SARS-CoV-2, 29 of which are already FDA-approved drugs. We thought, why don't we start testing them?

Some people might call this a long shot. Does drug repurposing really work?

Drugmakers don't test their drugs on every disease they might be effective for. Drug repurposing can work, but if we don't look, we definitely won't find anything. The classic repurposed drug is Viagra, a failed hypertension drug. When the studies ended because it didn't work, the drug company asked patients to send back the unused drugs. The women all returned the drugs, but the men didn't. And the rest is history.

There's a long list of potential drugs that can be repurposed, but few are being tested. The famous poster child of a repurposed drug — hydroxychloroquine — has been the subject of more than 250 clinical trials, but the others weren't getting much attention.

The beauty of a repurposed drug is that if you can get funding and start enrolling patients, you could potentially find out fairly quickly, as early as a few months, if that drug has an antiviral effect or not. These data would help prioritize drugs to be tested in larger confirmatory studies.

Your focus is on early treatment. What's the rationale for that?

We are focusing on early treatment because it has been overlooked. The attention has been on vaccines and therapeutics for hospitalized patients. But if you are spending $20 billion on potential vaccines and billions more on diagnostics, we need to give proportional resources towards drugs that might actually work, when given early, in preventing severe disease and death.

Early treatment, if successful, would allow us to avoid the severe complications that we are seeing now. If we can find an early treatment with an existing drug, it would be the fastest, most clinically- and cost-effective way to mitigate the impact of COVID-19 and get us on the road to recovery.

How do you get from a potential repurposed drug for COVID-19 to having a therapeutic agent that will save lives?

Most of the studies we are funding are smaller outpatient studies with virologic endpoints. We are looking for a signal that the drug has antiviral activity. We want to know whether a drug works before we spend the money on questions that take a much larger sample size to answer, for example, a big postexposure prophylaxis study. We'd like to see a meaningful signal in proof-of-concept studies, so we can look at a small group of patients with positive tests and see whether their viral load dropped by more than half if they got the drug compared with those who took the placebo. If the drug had an impact on the viral load and shortened the period of infectivity and was safe, these findings would provide justification to spend a lot of money on a large clinical trial. That would probably encourage the NIH and ACTIV collaboration to prioritize the drug for one of their big platform trials. That's what we are aiming for.

CETF isn't a drug developer — we are a funder for a good proposal to study a repurposed drug. We want to help move the dial — can we get an early yes or an early no? In drug development, we say, "fail fast and fail early." It's a numbers game. Only 10% of early candidates will become approved drugs. The value is in the data, whether they are positive or negative — it doesn't matter. If the study is a definitive "no," that is just as helpful as a definitive "yes." Of course, we all want the definitive "yes," but there are so many things to look at, the "no's" will help us redirect resources toward what may really help.

You first announced these funding opportunities in April. How is it going so far?

As soon as the website went up, we got 40 applications. Our scientific advisory board , which has expertise from medicinal chemistry and coronavirology to translational and clinical trial expertise, reviewed the applications and prioritized 11 fundable proposals. We are using milestone-based funding; in other words, funding those who are ready to go.

Which drugs are being tested in the funded studies?

One of the earliest grants we supported was Dr David Boulaware's randomized controlled trial of hydroxychloroquine (NCT 04308668) in 821 asymptomatic patients within 4 days after a high-risk or moderate-risk exposure. That trial did not show any benefit of hydroxychloroquine as postexposure prophylaxis against COVID-19. This trial was important for another reason. It proved the feasibility of a no-contact trial design in the setting of COVID-19, and participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.

Camostat, a transmembrane serine protease (TMPRSS2) inhibitor licensed for use in Japan to treat pancreatitis and esophagitis, combined with the antiandrogen bicalutamide, is being explored for early COVID-19 treatment. TMPRSS2 primes the SARS-CoV-2 spike protein to bind to the ACE2 receptor and gain entry to the cell, and has been shown to have antiviral activity. CETF has provided funding support to ongoing trials of Camostat at Yale University and Aarhus University in Denmark.

Another outpatient trial for fluvoxamine, a drug approved in the United States and routinely prescribed for depression, was also partially funded by a CETF grant to Washington University in St. Louis. Fluvoxamine is a serotonin regulator but also activates the sigma-1 receptor, which reduces the body’s immune response to prevent an overactive immune response or cytokine storm, a major cause of clinical deterioration, serious organ damage, and even death from COVID. This trial was recently completed, and the results have been submitted for publication.

Other promising drugs include niclosamide, doxazosin, favipiravir, leronlimab, interferon beta, interferon lambda, and other monoclonal antibodies. New compounds considered to have potential against COVID include MK-4482/EIDD-2801 and GS-441524, a metabolite of the antiviral drug, remdesivir.

Why not just put all of our resources into vaccine development?

We absolutely need a vaccine to control the outbreak and stop the pandemic. However, it's a long road to finding an effective vaccine, and in the meantime, we need tools to keep people alive. If we can find an antiviral drug that acts early, we can reduce transmission and contribute to outbreak control. All these tools help us get back to normal while we are waiting for a vaccine. The vaccine is only good if we can give it to everyone who susceptible person in the world ― which will take longer than 3 years. And there are no guarantees. Remember, we are still waiting for an HIV vaccine.

You are calling on Americans to help. What do you want them to do?

Everyone must participate in the behavioral changes designed to control the outbreak ― physical distancing, face-covering, and paying attention to case counts in local areas to enable them to take appropriate precautions. I know people are bored of that message, but we are going to repeat it until we have a vaccine or herd immunity.

This organism is ripping like wildfire through our unimmunized population. Personal behaviors might slow it down, but finding a drug that can be given to people after they've been exposed and test positive will have a meaningful impact on helping us get back to normal.

There's a great spirit of volunteerism — people are constantly asking how they can help. Through us at CETF, we offer three ways that people can help. They can participate as subjects in clinical trials, many of which are ongoing, including clinical trials, surveillance studies, and follow-up studies. They can donate to our fund and help support the research needed to find an effective early treatment. We have a link on our website, And finally, researchers can apply for funding. We think everybody can help in one of these ways by participating in trials, donating, or applying for funding. It's an all-hands-on-deck moment for our country.

Danzig is the chief medical advisor of the COVID-19 Early Treatment Fund. She has spent more than 20 years in the pharmaceutical industry developing vaccines, diagnostics, and drugs and is currently advising companies and investors.

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