Would a Broad-Spectrum Antiviral Drug Stop the Pandemic?
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.]
Opioid prescription policies may hurt those in chronic pain
Tinu Abayomi-Paul works as a writer and activist, plus one unwanted job: Trying to fill her opioid prescription. She says that some pharmacists laugh and tell her that no one needs the amount of pain medication that she is seeking. Another pharmacist near her home in Venus, Tex., refused to fill more than seven days of a 30-day prescription.
To get a new prescription—partially filled opioid prescriptions can’t be dispensed later—Abayomi-Paul needed to return to her doctor’s office. But without her medication, she was having too much pain to travel there, much less return to the pharmacy. She rationed out the pills over several weeks, an agonizing compromise that left her unable to work, interact with her children, sleep restfully, or leave the house. “Don’t I deserve to do more than survive?” she says.
Abayomi-Paul’s pain results from a degenerative spine disorder, chronic lymphocytic leukemia, and more than a dozen other diagnoses and disabilities. She is part of a growing group of people with chronic pain who have been negatively impacted by the fallout from efforts to prevent opioid overdose deaths.
Guidelines for dispensing these pills are complicated because many opioids, like codeine, oxycodone, and morphine, are prescribed legally for pain. Yet, deaths from opioids have increased rapidly since 1999 and become a national emergency. Many of them, such as heroin, are used illegally. The CDC identified three surges in opioid use: an increase in opioid prescriptions in the ‘90s, a surge of heroin around 2010, and an influx of fentanyl and other powerful synthetic opioids in 2013.
As overdose deaths grew, so did public calls to address them, prompting the CDC to change its prescription guidelines in 2016. The new guidelines suggested limiting medication for acute pain to a seven-day supply, capping daily doses of morphine, and other restrictions. Some statistics suggest that these policies have worked; from 2016 to 2019, prescriptions for opiates fell 44 percent. Physicians also started progressively lowering opioid doses for patients, a practice called tapering. A study tracking nearly 100,000 Medicare subscribers on opioids found that about 13 percent of patients were tapering in 2012, and that number increased to about 23 percent by 2017.
But some physicians may be too aggressive with this tapering strategy. About one in four people had doses reduced by more than 10 percent per week, a rate faster than the CDC recommends. The approach left people like Abayomi-Paul without the medication they needed. Every year, Abayomi-Paul says, her prescriptions are harder to fill. David Brushwood, a pharmacy professor who specializes in policy and outcomes at the University of Florida in Gainesville, says opioid dosing isn’t one-size-fits-all. “Patients need to be taken care of individually, not based on what some government agency says they need,” he says.
‘This is not survivable’
Health policy and disability rights attorney Erin Gilmer advocated for people with pain, using her own experience with chronic pain and a host of medical conditions as a guidepost. She launched an advocacy website, Healthcare as a Human Right, and shared her struggles on Twitter: “This pain is more than anything I've endured before and I've already been through too much. Yet because it's not simply identified no one believes it's as bad as it is. This is not survivable.”
When her pain dramatically worsened midway through 2021, Gilmer’s posts grew ominous: “I keep thinking it can't possibly get worse but somehow every day is worse than the last.”
The CDC revised its guidelines in 2022 after criticisms that people with chronic pain were being undertreated, enduring dangerous withdrawal symptoms, and suffering psychological distress. (Long-term opioid use can cause physical dependency, an adaptive reaction that is different than the compulsive misuse associated with a substance use disorder.) It was too late for Gilmer. On July 7, 2021, the 38-year-old died by suicide.
Last August, an Ohio district court ruling set forth a new requirement for Walgreens, Walmart, and CVS pharmacists in two counties. These pharmacists must now document opioid prescriptions that are turned down, even for customers who have no previous purchases at that pharmacy, and they’re required to share this information with other locations in the same chain. None of the three pharmacies responded to an interview request from Leaps.org.
In a practice called red flagging, pharmacists may label a prescription suspicious for a variety of reasons, such as if a pharmacist observes an unusually high dose, a long distance from the patient’s home to the pharmacy, or cash payment. Pharmacists may question patients or prescribers to resolve red flags but, regardless of the explanation, they’re free to refuse to fill a prescription.
As the risk of litigation has grown, so has finger-pointing, says Seth Whitelaw, a compliance consultant at Whitelaw Compliance Group in West Chester, PA, who advises drug, medical device, and biotech companies. Drugmakers accused in National Prescription Opioid Litigation (NPOL), a complex set of thousands of cases on opioid epidemic deaths, which includes the Ohio district case, have argued that they shouldn’t be responsible for the large supply of opiates and overdose deaths. Yet, prosecutors alleged that these pharmaceutical companies hid addiction and overdose risks when labeling opioids, while distributors and pharmacists failed to identify suspicious orders or scripts.
Patients and pharmacists fear red flags
The requirements that pharmacists document prescriptions they refuse to fill so far only apply to two counties in Ohio. But Brushwood fears they will spread because of this precedent, and because there’s no way for pharmacists to predict what new legislation is on the way. “There is no definition of a red flag, there are no lists of red flags. There is no instruction on what to do when a red flag is detected. There’s no guidance on how to document red flags. It is a standardless responsibility,” Brushwood says. This adds trepidation for pharmacists—and more hoops to jump through for patients.
“I went into the doctor one day here and she said, ‘I'm going to stop prescribing opioids to all my patients effective immediately,” Nicolson says.
“We now have about a dozen studies that show that actually ripping somebody off their medication increases their risk of overdose and suicide by three to five times, destabilizes their health and mental health, often requires some hospitalization or emergency care, and can cause heart attacks,” says Kate Nicolson, founder of the National Pain Advocacy Center based in Boulder, Colorado. “It can kill people.” Nicolson was in pain for decades due to a surgical injury to the nerves leading to her spinal cord before surgeries fixed the problem.
Another issue is that primary care offices may view opioid use as a reason to turn down new patients. In a 2021 study, secret shoppers called primary care clinics in nine states, identifying themselves as long-term opioid users. When callers said their opioids were discontinued because their former physician retired, as opposed to an unspecified reason, they were more likely to be offered an appointment. Even so, more than 40 percent were refused an appointment. The study authors say their findings suggest that some physicians may try to avoid treating people who use opioids.
Abayomi-Paul says red flagging has changed how she fills prescriptions. “Once I go to one place, I try to [continue] going to that same place because of the amount of records that I have and making sure my medications don’t conflict,” Abayomi-Paul says.
Nicolson moved to Colorado from Washington D.C. in 2015, before the CDC issued its 2016 guidelines. When the guidelines came out, she found the change to be shockingly abrupt. “I went into the doctor one day here and she said, ‘I'm going to stop prescribing opioids to all my patients effective immediately.’” Since then, she’s spoken with dozens of patients who have been red-flagged or simply haven’t been able to access pain medication.
Despite her expertise, Nicolson isn’t positive she could successfully fill an opioid prescription today even if she needed one. At this point, she’s not sure exactly what various pharmacies would view as a red flag. And she’s not confident that these red flags even work. “You can have very legitimate reasons for being 50 miles away or having to go to multiple pharmacies, given that there are drug shortages now, as well as someone refusing to fill [a prescription.] It doesn't mean that you’re necessarily ‘drug seeking.’”
While there’s no easy solution. Whitelaw says clarifying the role of pharmacists and physicians in patient access to opioids could help people get the medication they need. He is seeking policy changes that focus on the needs of people in pain more than the number of prescriptions filled. He also advocates standardizing the definition of red flags and procedures for resolving them. Still, there will never be a single policy that can be applied to all people, explains Brushwood, the University of Florida professor. “You have to make a decision about each individual prescription.”
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.
When COVID-19 cases were surging in New York City in early spring, Chitra Mohan, a postdoctoral fellow at Weill Cornell, was overwhelmed with worry. But the pandemic was only part of her anxieties. Having come to the United States from India on a student visa that allowed her to work for a year after completing her degree, she had applied for a two-year extension, typically granted for those in STEM fields. But due to a clerical error—Mohan used an electronic signatureinstead of a handwritten one— her application was denied and she could no longerwork in the United States.
"I was put on unpaid leave and I lost my apartment and my health insurance—and that was in the middle of COVID!" she says.
Meanwhile her skills were very much needed in those unprecedented times. A molecular biologist studying how DNA can repair itself, Mohan was trained in reverse transcription polymerase chain reaction or RT-PCR—a lab technique that detects pathogens and is used to diagnose COVID-19. Mohan wanted to volunteer at testing centers, but because she couldn't legally work in the U.S., she wasn't allowed to help either. She moved to her cousin's house, hired a lawyer, and tried to restore her work status.
"I spent about $4,000 on lawyer fees and another $1,200 to pay for the motions I filed," she recalls. "I had to borrow money from my parents and my cousin because without my salary I just didn't have the $7,000 at hand." But the already narrow window of opportunity slammed completely shut when the Trump administration suspended issuing new visas for foreign researchers in June. All Mohan's attempts were denied. In August, she had to leave the country. "Given the recent work visa ban by the administration, all my options in the U.S. are closed," she wrote a bitter note on Twitter. "I have to uproot my entire life in NY for the past 6 years and leave." She eventually found a temporary position in Calcutta, where she can continue research.
Mohan is hardly alone in her visa saga. Many foreign scholars on H- and J-type visas and other permits that let them remain employed in America had been struggling to keep their rights to continue research, which in certain cases is crucial to battling the pandemic. Some had to leave the country, some filed every possible extension to buy time, and others are stuck in their home countries, unable to return. The already cumbersome process of applying for visas and extensions became crippled during the lockdowns. But in June, when President Trump extended and expanded immigration restrictions to cut the number of immigrant workers entering the U.S., the new limits left researchers' projects and careers in limbo—and some in jeopardy.
"We have been a beneficiary of this flow of human capacity and resource investment for many generations—and this is now threatened."
Rakesh Ramachandran, whose computational biology work contributed to one of the first coronavirus studies to map out its protein structures—is stranded in India. In early March, he had travelled there to attend a conference and visit the American consulate to stamp his H1 visa for a renewal, already granted. The pandemic shut down both the conference and the consulates, and Ramachandran hasn't been able to come back since. The consulates finally opened in September, but so far the online portal has no available appointment slots. "I'm told to keep trying," Ramachandran says.
The visa restrictions affected researchers worldwide, regardless of disciplines or countries. A Ph.D. student in neuroscience, Morgane Leroux had to do her experiments with mice at Gladstone Institutes in America and analyze the data back home at Sorbonne University in France. She had finished her first round of experiments when the lockdowns forced her to return to Paris, and she hasn't been able to come back to resume her work since. "I can't continue the experiments, which is really frustrating," she says, especially because she doesn't know what it means for her Ph.D. "I may have to entirely change my subject," she says, which she doesn't want to do—it would be a waste of time and money.
But besides wreaking havoc in scholars' personal lives and careers, the visa restrictions had—and will continue to have—tremendous deleterious effects on America's research and its global scientific competitiveness. "It's incredibly short-sighted and self-destructing to restrict the immigration of scientists into the U.S.," says Benjamin G. Neel, who directs the Laura and Isaac Perlmutter Cancer Center at New York University. "If they can't come here, they will go elsewhere," he says, causing a brain drain.
Neel in his lab with postdocs
(Courtesy of Neel)
Neel felt the outcomes of the shortsighted policies firsthand. In the past few months, his lab lost two postdoctoral researchers who had made major strides in understanding the biology of several particularly stubborn, treatment-resistant malignancies. One postdoc studied the underlying mechanisms responsible for 90 percent of pancreatic cancers and half of the colon ones. The other one devised a new system of modeling ovarian cancer in mice to test new therapeutic drug combinations for the deadliest tumor types—but had to return home to China.
"By working around the clock, she was able to get her paper accepted, but she hasn't been able to train us to use this new system, which can set us back six months," Neel says.
Her discoveries also helped the lab secure about $900,000 in grants for new research. Losing people like this is "literally killing the goose that lays the golden eggs," Neel adds. "If you want to make America poor again, this is the way to do it."
Cassidy R. Sugimoto at Indiana University Bloomington, who studies how scientific knowledge is produced and disseminated, says that scientists are the most productive when they are free to move, exchange ideas, and work at labs with the best equipment. Restricting that freedom reduces their achievement.
"Several empirical studied demonstrated the benefits to the U.S. by attracting and retaining foreign scientists. The disproportional number of our Nobel Prize winners were not only foreign-born but also foreign-educated," she says. Scientific advancement bolsters the country's economic prowess, too, so turning scholars away is bad for the economy long-term. "We have been a beneficiary of this flow of human capacity and resource investment for many generations—and this is now threatened," Sugimoto adds—because scientists will look elsewhere. "We are seeing them shifting to other countries that are more hospitable, both ideologically and in terms of health security. Many visiting scholars, postdocs, and graduate students who would otherwise come to the United States are now moving to Canada."
It's not only the Ph.D. students and postdocs who are affected. In some cases, even well-established professors who have already made their marks in the field and direct their own labs at prestigious research institutions may have to pack up and leave the country in the next few months. One scientist who directs a prominent neuroscience lab is betting on his visa renewal and a green card application, but if that's denied, the entire lab may be in jeopardy, as many grants hinge on his ability to stay employed in America.
"It's devastating to even think that it can happen," he says—after years of efforts invested. "I can't even comprehend how it would feel. It would be terrifying and really sad." (He asked to withhold his name for fear that it may adversely affect his applications.) Another scientist who originally shared her story for this article, later changed her mind and withdrew, worrying that speaking out may hurt the entire project, a high-profile COVID-19 effort. It's not how things should work in a democratic country, scientists admit, but that's the reality.
Still, some foreign scholars are speaking up. Mehmet Doğan, a physicist at University of California Berkeley who has been fighting a visa extension battle all year, says it's important to push back in an organized fashion with petitions and engage legislators. "This administration was very creative in finding subtle and not so subtle ways to make our lives more difficult," Doğan says. He adds that the newest rules, proposed by the Department of Homeland Security on September 24, could further limit the time scholars can stay, forcing them into continuous extension battles. That's why the upcoming election might be a turning point for foreign academics. "This election will decide if many of us will see the U.S. as the place to stay and work or whether we look at other countries," Doğan says, echoing the worries of Neel, Sugimoto, and others in academia.
Dogan on Zoom talking to his fellow union members of the Academic Researchers United, a union of almost 5,000 Academic Researchers.
(Credit: Ceyda Durmaz Dogan)
If this year has shown us anything, it is that viruses and pandemics know no borders as they sweep across the globe. Likewise, science can't be restrained by borders either. "Science is an international endeavor," says Neel—and right now humankind now needs unified scientific research more than ever, unhindered by immigration hurdles and visa wars. Humanity's wellbeing in America and beyond depends on it.
[Editor's Note: To read other articles in this special magazine issue, visit the beautifully designed e-reader version.]
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.