For an antiviral researcher, Covid brings a flood of attention — and opportunity

In February 2020, Jeffrey Glenn was prepping for a meeting at the Food and Drug Administration when his phone suddenly rang.

“What do you think about this virus?” asked the caller, a philanthropist who was worried about the pathogen that would later be named SARS-CoV-2.

Like everyone else, Glenn, a gastroenterologist and molecular virologist at Stanford Medicine, knew precious little about the virus at the time. He was in the process of designing new medicines for influenza and other viruses. But having spent years in drug development, he knew how hard it was to convince others to care about the threat of pandemics. In most cases, after all, the money was in developing drugs for diseases such as cancer, not infectious diseases.

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That, however, was about to change.

“We want to write you a check, so you can start working on it immediately,” Glenn recalls the philanthropist saying.

The offer was a testament to how dramatically the world has changed for virologists over the past two years. Researchers seeking to develop antivirals have long warned that a new virus could wreak disaster around the globe and sought funding for their work, only to be largely ignored. Now, the Covid-19 pandemic has unleashed a flood of new money for studies on antivirals, with interest surging from both the government and industry.

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Over the summer, President Biden unveiled a $3.2 billion blueprint for spending on the development of new antiviral medicines for Covid-19 and other viruses that have pandemic potential. Meanwhile, according to a tracker maintained by the Biotechnology Innovation Organization, biopharmaceutical companies are currently testing a staggering 268 potential antivirals against Covid.

Already, one such drug, remdesivir, has been approved. An FDA advisory committee narrowly recommended another, molnupiravir, for emergency authorization late last month. And other more promising drugs may come soon, including an antiviral from Pfizer, Paxlovid, that the company says showed 89% efficacy in a clinical trial.

At the heart of the effort to develop these therapies are scientists like Glenn. For them, Covid is a chance to prove that they can make a difference by developing new treatments not just for the current pandemic but also future threats.

“We’ve always believed that what we work on is meaningful and can be very impactful, but now the world gets it,” Glenn said.

There remain questions about how long the boom times will last. Antiviral researchers have seen interest in their work flare — with the 2003 SARS outbreak, for instance, or the anthrax attacks after Sept. 11, 2001 — only to quickly dissipate. The same could happen with Covid, though many experts are hoping this time is different.

“I seriously hope there is a realization that this needs to be a sustained effort,” said Kara Carter, entrepreneur-in-residence at the biotechnology company Evotec and president of the International Society for Antiviral Research. “We’ve already had multiple viral epidemics and pandemics in our lifetimes, and this is not going to stop.”

The interest in antivirals is understandable. With Covid expected to be endemic, the world needs drugs, particularly oral drugs, to help treat patients with the disease and prevent more severe outcomes.

And even though molnupiravir and Paxlovid are likely to be authorized soon, researchers say we’ll need a war chest of treatments to prevent drug- and vaccine-resistant Covid strains from emerging. Beyond Covid, Glenn and other scientists think we need drugs that work against many viruses, because it’s impossible to predict what will hit us next.

“As bad as this is, things could be so much worse,” Glenn said.

Despite the grim observation, Glenn is an eternal optimist who has spent his nearly 30-year career searching for treatments for diseases including cancer, hepatitis, and other viral threats. He’s unusually entrepreneurial for a physician-scientist, having founded three companies that are testing six drugs in clinical trials, including potential Covid treatments.

“It’s rare for a physician to have been as successful as he’s been in terms of drug discovery and drug development,” said Gail Cassell, former vice president of public and scientific affairs at Eli Lilly and an adviser to Glenn’s academic research.

A Covid-19 virus model with an antibody represented in yellow sits on a table at Glenn’s lab. Constanza Hevia for STAT
Novel drug candidates and intermediates, and a glass with written formulas for antiviral drugs, at Glenn’s lab. Constanza Hevia for STAT

On a recent afternoon, Glenn’s lab buzzed with activity. A research assistant was preparing plates of diluted viruses, while another scientist disappeared behind a door plastered with orange and red biohazard labels. A third scientist was working under a fume hood decorated with Sharpie diagrams of chemical structures.

Glenn, clad in a blue shirt, jeans, and pink-and-white socks, toured the benches. “It’s a mini Manhattan Project in here,” he said.

Glenn has already received $30 million from the National Institutes of Allergy and Infectious Disease and philanthropies for his Covid antiviral research. He’s applying for a slice of a new $1 billion NIH program on antiviral drug discovery, part of the antiviral investment unveiled by Biden. And he’s organizing a new Stanford Biosecurity and Pandemic Preparedness Initiative, funded in part by private donors.

Glenn said he aims to “bring industry-level rigor” to his academic research. He’s founded companies and consults with pharmaceutical firms. Multiple lab members previously worked in industry. He also has a network of advisers and collaborators in areas such as drug chemistry, manufacturing, toxicology testing, and regulatory filings. Glenn says this gives him a better understanding than many academic scientists of what it takes to develop a drug.

“In academia, people get excited and think they have a drug if they get a hit in an assay, but that’s like putting your toe in the swimming pool,” Glenn says. “Getting a drug is like winning the Olympics.”

Glenn’s positivity and sociability have helped him recruit collaborators and drive drugs to the clinic.

Aijaz Ahmed, a gastroenterologist, recalls being nervous while speaking at a journal club when he first arrived at Stanford. After the presentation, Glenn approached Ahmed and struck up a conversation. He later guided Ahmed through his fellowship, helping him navigate everything from how to use Stanford’s scheduling system to how to treat patients. The pair are now friends and collaborators.

“He’s a superstar, but he’s also a wonderful, kind, person — colorblind and easily approachable,” Ahmed said.

Glenn gives each departing lab member a pocket knife in a white box decorated with a smiley face and the inscription, “Be happy and go for the jugular” — the killer experiment that proves an idea can work.

That approach has worked for him before.

In 2008, Glenn founded a company called Eiger BioPharmaceuticals to develop drugs against hepatitis. Like many other viruses, hepatitis viruses use human enzymes to copy themselves. While most hepatitis drugs are “direct-acting” antivirals that target viral machinery, Glenn wanted to test whether a drug called lonafarnib could block the hepatitis virus from hijacking enzymes. The idea was that such a strategy might cure hepatitis by removing essential tools from its toolbox.

In 2011, Eiger ran out of money while Glenn was testing lonafarnib in hepatitis D, a rare, incurable form of the disease. Eiger let its three employees go. But Glenn believed in the trial and hired the company’s sole scientist, Ingrid Choong, to work on his own academic research in his lab at Stanford.

Finally, in 2014, Glenn was vindicated. He found that lonafarnib reduced levels of hepatitis D virus in patients. Eiger raised multiple rounds of funding, hired Choong back, and kept going. In 2020, the FDA approved lonafarnib to treat the rare premature aging condition progeria. Eiger is now studying lonafarnib in Phase 3 trials for hepatitis D.

Compared to that long slog, the push for Covid drugs has moved at lightning speed.

Glenn is developing multiple candidate drugs against Covid, including direct-acting antivirals, new “broad spectrum” compounds that could work against multiple viruses, and “host-targeting” treatments that aim to block viruses from exploiting human components on which they depend.

Among the drugs he’s testing are what he calls “programmable antivirals” designed to distort the shape of virus components. They contain pieces of genetic material that prevent viruses from assembling properly, like a bent key that can’t open a lock.

Glenn is also developing host-targeted drugs to target human, rather than viral, components. These drugs might avoid some problems of direct-acting antivirals, such as drug resistance and viral variants viruses that evade targeted drugs.

Glenn (left) and colleague Edward Pham work at Glenn’s lab in November. Constanza Hevia for STAT

Scientists are testing one of these, an immune molecule called interferon lambda, in clinical trials against Covid. Glenn, who sits on Eiger’s board of directors, convinced the company to license the drug in 2016 and test it in hepatitis D. Glenn thinks it will also work against Covid, and has organized clinical trials of the drug with academic colleagues.

So far, the drug has appeared safe, but has delivered mixed results in Phase 2 clinical trials. In September, the drug passed an interim checkpoint in a Phase 3 trial in 453 patients in Brazil. That trial continues.

Some scientists are skeptical, based on poor results from other interferons. “With these host-directed molecules like interferons and interleukins and antibodies, it really isn’t clear how much activity they have,” said Carl Dieffenbach, director of the AIDS division at the NIAID.

But Glenn believes in the drug. He says that interferon lambda has proven safer in clinical trials than other types of interferons, and that the trial data show that the drug works best in Covid patients most likely to get severe symptoms.

Lambda is also given as a single injection, unlike molnupiravir and Paxlovid, which are oral pills. Companies are prioritizing pills, which patients can take themselves outside of a hospital. But Glenn points out that both molnupiravir and Paxlovid require patients to take 40 and 30 pills over five days, respectively, and that many patients might not comply with the whole regimen, increasing the chances of drug-resistant Covid strains. “Once lambda is out there, it will be a game-changer, where we can have a new paradigm, ‘test, treat, done,’” he said.

On a recent Friday afternoon, Glenn and his colleagues gathered for happy hour. Glenn sipped bourbon while his lab members snacked on pretzels in a suite outside his office. The shelves were stocked with boxes of Costco snacks and a formidable selection of beverages — he celebrates each positive result in the lab by popping the cork on a bottle of champagne.

Glenn stopped to check a WhatsApp message on his phone. It was from a collaborator in Asia; despite being vaccinated and boosted, the collaborator had just tested positive for Covid.

The somber news quieted the room, a reminder of why the scientists are so focused on finding new Covid drugs in the first place.

“This should have been done a long time ago,” Glenn said. “But we still can save millions of peoples’ lives.”

Source: STAT