Would a Broad-Spectrum Antiviral Drug Stop the Pandemic?

An illustration of the novel coronavirus infecting human tissue.

(© Negro Elkha/Adobe)

The refocusing of medical research to COVID-19 is unprecedented in human history. Seven months ago, we barely were aware that the virus existed, and now a torrent of new information greets us each day online.

There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself.

Clinicaltrials.gov, the most commonly used registry for worldwide medical research, listed 1358 clinical trials on the disease, including using scores of different potential drugs and multiple combinations, when I first wrote this sentence. The following day that number of trials had increased to 1409. Laboratory work to prepare for trials presents an even broader and untabulated scope of activity.

Most trials will fail or not be as good as what has been discovered in the interim, but the hope is that a handful of them will yield vaccines for prevention and treatments to attenuate and ultimately cure the deadly infection.

The first impulse is to grab whatever drugs are on the shelf and see if any work against the new foe. We know their safety profiles and they have passed some regulatory hurdles. Remdesivir is the first to register some success against SARS-CoV-2, the virus behind the disease. The FDA has granted it expedited-use status, pending presentation of data that may lead to full approval of the drug.

Most observers see it as a treatment that might help, but not one that by itself is likely to break the back of the pandemic. Part of that is because it is delivered though IV infusion, which requires hospitalization, and as with most antiviral drugs, appears to be most beneficial when started early in disease. "The most effective products are going to be that ones that are developed by actually understanding more about this coronavirus," says Margaret "Peggy" Hamburg, who once led the New York City public health department and later the U.S. Food and Drug Administration.

Combination therapy that uses different drugs to hit a virus at different places in its life cycle have proven to work best in treating HIV and hepatitis C, and likely will be needed with this virus as well. Most viruses are simply too facile at evolving resistance to a single drug, and so require multiple hits to keep them down.

Laboratory work suggests that other drugs, both off-the-shelf and in development, particularly those to treat HIV and hepatitis, might also be of some benefit against SARS-CoV-2. But the number of possible drug combinations is mind-bogglingly large and the capacity to test them all right now is limited.

Broad-Spectrum Antivirals

Viruses are simple quasi-life forms. Effective treatments are more likely to be specific to a given virus, or at best its close relatives. That is unlike bacteria, where broad-spectrum antibiotics often can be used against common elements like the bacterial cell wall, or can disrupt quorum sensing signals that bacteria use to function as biofilms.

More than a decade ago, virologist Benhur Lee's lab at UCLA (now at Mt. Sinai in New York City) stumbled upon a broad-spectrum antiviral approach that seemed to work against all enveloped viruses they tested. The list ranged from the common flu to HIV to Ebola.

Other researchers grabbed this lead to develop a compound that worked quite well in cell cultures, but when they tried it in animals, a frustrating snag emerged; the compound needed to be activated by light. As the greatest medical need is to counter viruses deep inside the body, the research was put on the shelf. So Lee was surprised to learn recently that a company has inquired about rights to develop the compound not as a treatment but as a possible disinfectant. The tale illustrates both the unanticipated difficulties of drug development and that one never knows how knowledge ultimately might be put to use.

Remdesivir is a failed drug for Ebola that has found new life with SARS-CoV-2. It targets polymerase, an enzyme that the virus produces to use host cell machinery to replicate itself, and since the genetic sequence of polymerase is very similar among all of the different coronaviruses, scientists hope that the drug might be useful against known members of the family and others that might emerge in the future.

But nature isn't always that simple. Viral RNA is not a two-dimensional assemblage of genes in a flat line on a table; rather it is a three-dimensional matrix of twists and turns where a single atom change within the polymerase gene or another gene close by might change the orientation of the RNA or a molecular arm within it and block a drug from accessing the targeted binding site on the virus. One drug might need to bind to a large flat surface, while another might be able to slip a dagger-like molecular arm through a space in the matrix to reach its binding target.

That is why a broad-spectrum antiviral is so hard to develop, and why researchers continue to work on a wide variety of compounds that target polymerase as a binding site.

Additionally, it has taken us decades to begin to recognize the unintended consequences of broad-spectrum rather than narrowly targeted antibiotics on the gut microbiome and our overall health. Will a similar issue potentially arise in using a broad-spectrum antiviral?

"Off-target side effects are always of concern with drugs, and antivirals are no exception," says Yale University microbiologist Ben Chen. He believes that "most" bacteriophages, the viruses that infect bacteria and likely help to maintain stability in the gut microbial ecosystem, will shrug off such a drug. However, a few families of phages share polymerases that are similar to those found in coronaviruses. While the immediate need for treatment is great, we will have to keep a sharp eye out for unanticipated activity in the body's ecosystem from new drugs.

Is an Antiviral Needed?

There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself. Mounting evidence indicates that up to half the people who contract the infection don't seem to experience significant symptoms and their immune system seems to clear the virus.

The most severe cases of COVID-19 appear to result from an overactive immune response that damages surrounding tissue. Perhaps downregulating that response will be sufficient to reduce the disease burden. Several studies are underway using approved antibodies that modulate an overly active immune response.

One of the most surprising findings to date involves the monoclonal antibody leronlimab. It was originally developed to treat HIV infection and works modestly well there, but other drugs are better and its future likely will be mainly to treat patients who have developed resistance to those other drugs.

The response has been amazingly different in patients in the U.S. with COVID-19 who were given emergency access to leronlimab – two injections a week apart, though the company believes that four might be better. The immune response and inflammatory cytokines declined significantly, T cell counts were maintained, and surprisingly the amount of virus in the blood declined too. Data from the first ten patients is available in a preprint while the paper undergoes peer review for publication. Data from an additional fifty patients will be added.

"We got lucky and hit the bulls' eye from a mile away," says Jay Lalezari, the chief science officer of Cytodyn, the company behind leronlimab. Dr. Jay, as he is widely known in San Francisco, built an adoring fan base running many of the early-phase drug studies for treating HIV. While touting leronlimab, Lalezari suspects it might best be used as part of a combination therapy.

The small, under-capitalized firm is struggling for attention in the vast pool of therapies proposed to treat COVID-19. It faces the added challenge of gaining acceptance because it is based on a different approach and mechanism of action, which involves a signaling molecule important to immune cell migration, than what most researchers and the FDA anticipate as being relevant to counter SARS-CoV-2.

Common Issues

All of the therapeutics under development will face some common sets of issues. One is the pressure to have results yesterday, because people are dying. The rush to disseminate information "make me worry that certain things will become entrenched as truth, even in the scientific community, without the actual scientific documentation that ordinarily scientists would demand," says Hamburg.

"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue."

Lack of standardization in assays and laboratory operations makes it difficult to compare results between labs studying SARS-CoV-2. In the long run, this will slow down the iterative process of research that builds upon what has gone before. And the shut down of supply chains, from chemicals to cell lines to animals to air shipment, has the potential to further hobble research.

Almost all researchers consult with the FDA in putting together their clinical trials. But the agency is overwhelmed with the surge of activity in the field, and is even less capable of handling novel approaches that fall outside of its standard guidance.

"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue. It is that conventional clinical development paths are far too lengthy and cumbersome to address the current public health threat," John Hodgson wrote in Nature Biotechnology.

Another complicating factor with this virus is the broad range of organ and tissue types it can infect. That has implications for potential therapies, which often vary in their ability to enter different tissues. At a minimum, it complicates the drug development process.

Remdesivir has become the de facto standard of care. Ideally, clinical trials are conducted using the existing standard of care rather than a placebo as the control group. But shortages of the drug make that difficult and further inhibit learning what is the best treatment regimen for regular clinical care.

"Understandably, we all really want to respond to COVID-19 in a much, much more accelerated fashion," says Hamburg. But ultimately that depends upon "the reality of understanding the nature of the disease. And that is going to take a bit more time than we might like or wish."

[This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]

Bob Roehr
Bob Roehr is a biomedical journalist based in Washington, DC. Over the last twenty-five years he has written extensively for The BMJ, Scientific American, PNAS, Proto, and myriad other publications. He is primarily interested in HIV, infectious disease, immunology, and how growing knowledge of the microbiome is changing our understanding of health and disease. He is working on a book about the ways the body can at least partially control HIV and how that has influenced (or not) the search for a treatment and cure.
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The event on November 12th will explore what lies ahead for science and policy in the near-future.

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EVENT INFORMATION

________

Date

Thu Nov 12, 2020 12:00pm - 1:10pm EDT

                            


Contact

kira@goodinc.com

Location

Virtual

Hosts

LeapsMag, the Aspen Institute's Science and Society Program, and GOOD

"The Future of Science in America Summit" will dive into the high stakes ahead as we emerge from a hotly contested election, with the pandemic on the upswing.

Through rotating paired conversations with five experts from academia, industry, advocacy, and government, followed by a public Q&A, this event will explore (re)building public trust in science, the latest science and policy developments on the COVID vaccine front, and moonshots in science that deserve prioritization over the next four years.


________

Nancy Messonnier, M.D.
Director of the National Center for Immunization and Respiratory Diseases (NCIRD)

Saad Amer
Founder, Plus1Vote, a nonprofit organization dedicated to getting out the vote on issues such as climate change and equality

France Córdova, Ph.D.
Astrophysicist, past Director of the National Science Foundation, past President of Purdue University

Joseph DeRisi, Ph.D.
Professor of Biochemistry and Biophysics, University of California San Francisco and Co-President, Chan Zuckerberg Biohub

Seema Kumar
Global Head of the Office of Innovation, Global Health, and Policy Communication, Johnson & Johnson

Michelle McMurry-Heath, M.D., Ph.D.
President and CEO of the Biotechnology Innovation Organization (BIO)

This summit is co-hosted by LeapsMag, the Aspen Institute Science & Society Program, and the social impact company GOOD, with support from the Gordon and Betty Moore Foundation and the Rita Allen Foundation.

The event accompanies our recently published digital magazine, The Future of Science in America: The Election Issue.

Kira Peikoff
Kira Peikoff is a journalist whose work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and son.

Understanding the vulnerabilities of our own brains can help us guard against fake news.

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This article is part of the magazine, "The Future of Science In America: The Election Issue," co-published by LeapsMag, the Aspen Institute Science & Society Program, and GOOD.

Whenever you hear something repeated, it feels more true. In other words, repetition makes any statement seem more accurate. So anything you hear again will resonate more each time it's said.

Do you see what I did there? Each of the three sentences above conveyed the same message. Yet each time you read the next sentence, it felt more and more true. Cognitive neuroscientists and behavioral economists like myself call this the "illusory truth effect."

Go back and recall your experience reading the first sentence. It probably felt strange and disconcerting, perhaps with a note of resistance, as in "I don't believe things more if they're repeated!"

Reading the second sentence did not inspire such a strong reaction. Your reaction to the third sentence was tame by comparison.

Why? Because of a phenomenon called "cognitive fluency," meaning how easily we process information. Much of our vulnerability to deception in all areas of life—including to fake news and misinformation—revolves around cognitive fluency in one way or another. And unfortunately, such misinformation can swing major elections.

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Gleb Tsipursky
Dr. Gleb Tsipursky is an internationally recognized thought leader on a mission to protect leaders from dangerous judgment errors known as cognitive biases by developing the most effective decision-making strategies. A best-selling author, he wrote Resilience: Adapt and Plan for the New Abnormal of the COVID-19 Coronavirus Pandemic and Pro Truth: A Practical Plan for Putting Truth Back Into Politics. His expertise comes from over 20 years of consulting, coaching, and speaking and training as the CEO of Disaster Avoidance Experts, and over 15 years in academia as a behavioral economist and cognitive neuroscientist. He co-founded the Pro-Truth Pledge project.