How the rise of antivirals may change the course of the pandemic

Years before the rise of the COVID-19 pandemic, virologists started a quest to find drugs called antivirals that can protect people against emerging coronaviruses. The journey has been slow and failures have been frequent. But with Britain’s authorization this week of Merck’s new drug molnupiravir, and a cash infusion into antiviral R&D, the outlook for these treatments is getting much brighter.

Unlike vaccines that can prevent infection, antivirals act as a second line of defense, slowing down and eventually arresting progression of a disease when infections occur. They’re also important when effective vaccines aren’t available against viral diseases, as is the case for HIV, hepatitis C, and herpes.

But developing antivirals is an expensive and difficult endeavor. That’s especially true for acute respiratory diseases, for which the window for treatment is short. In the case of SARS-CoV-2, the coronavirus that has unleashed the devastating COVID-19 pandemic, researchers have resorted to repurposing old drugs or compounds that were being tested against other diseases.

“That’s typical,” says Katherine Seley-Radtke, a medicinal chemist at the University of Maryland, Baltimore County. “Every time a new virus emerges or an old one re-emerges, you pull out what’s there in the cupboard to see what works.”

So far remdesivir, originally developed by biopharmaceutical company Gilead Sciences for hepatitis C and Ebola infections, is the only antiviral drug approved by the U.S. Food and Drug Administration to treat COVID-19. It must be administered via injection while a patient is in the hospital, although there isn’t consensus regarding its ability to treat COVID-19.

Experts think oral antivirals like Merck’s are set to be the most promising tools to work alongside vaccines at combating the pandemic. Provided they are affordable, antivirals could be especially important among people who remain unvaccinated either out of choice or due to limited access and economic constraints.

“People don’t mind taking pills,” Seley-Radtke says. “You can stockpile them. You don’t need specifical conditions to store them. You can ship them all across the world.”

In June 2021 President Joe Biden announced an investment of more than a billion dollars to advance the development of antivirals for COVID-19. As part of the same plan, he also promised an additional $1.2 billion in funding toward discovering new compounds that can treat SARS-CoV-2 as well as other emerging viruses with pandemic potential.

“Finally, the government and funding agencies are taking it seriously,” Seley-Radtke says of antiviral development. “We cannot continue to sit back and wait for the next pandemic to occur. We have to be proactive. We have to be prepared.”

How antivirals work

Unlike bacteria, viruses can’t reproduce on their own. They rely on their host cell’s machinery to replicate. That means a virus must insert itself into a living cell and hijack its machinery to make thousands of copies of itself. These “offspring” then escape and go on to infect nearby host cells, spreading the disease inside the body and ultimately to new carriers.

Antiviral drugs often work by preventing the virus from attaching to or entering the host cell, or by obstructing its replication once it’s in there.

The drug remdesivir, for instance, mimics one of the genetic building blocks essential for SARS-CoV-2 to replicate; it then gets incorporated into the viral genome, stalling its replication. The experimental antiviral molnupiravir, developed by Ridgeback Biotherapeutics LP and Merck & Co., engages in similar mimicry and induces errors during viral replication.

“Then you reach a point where you have so many errors that the virus is unable to replicate,” says critical care virologist William Fischer at the University of North Carolina at Chapel Hill.

Pfizer’s experimental antiviral PF-07321332 also targets viral replication but does so by thwarting enzymes called proteases. SARS-CoV-2 and other viruses, such as HIV, use these enzymes to split large proteins into smaller fragments that then combine with viral genetic material to form new copies of the virus.

Many experts think targeting the human cell’s hijacked machinery can be highly effective, but the concern is that such antivirals could damage otherwise healthy cells, causing a range of side effects. Only targeting viral proteins isn’t a permanent fix either. “If you try to develop an antiviral against a particular viral protein, there is very quick evolutionary pressure on the virus to mutate and develop resistance,” says Tia Tummino, a pharmacologist at the University of California, San Francisco.

A more effective strategy is to use several of these antiviral drugs in combinations of two to four to target different viral proteins and life stages simultaneously, which is standard practice for fighting HIV or treating hepatitis C infections. “That makes it hard for a virus to escape,” Tummino says.

The complicated path to developing antivirals

However, developing safe and effective antivirals isn’t easy. Just over a hundred have been approved by the FDA since 1963, when the first antiviral, idoxuridine, was given the green light to treat herpes of the eye. More than a third of the FDA-approved antivirals are for HIV.

Historically antiviral drug development has focused on a “one bug, one drug” approach, which meant targeting proteins common to specific groups of viruses. While such antivirals can be extremely effective, viruses produce very few proteins of their own, giving drug makers limited options to target.

There’s also the risk of the drugs damaging cells. Some viral proteins can be unique, in that they don’t overlap with the ones produced by the host, making them ideal targets for antiviral drugs. But if the target proteins do overlap or perform the same functions as the human host cells, there’s potential for collateral damage, resulting in side effects.

One other challenge is the increasing diversity of viruses causing severe disease in humans, and thus the need for antivirals that work against a variety of these pathogens. Remdesivir targets a viral enzyme called polymerase, which has a genetic architecture that’s similar across different coronaviruses. But few such broad-spectrum antivirals exist because they often require complex design or they could lead to unanticipated side effects.

Once drugmakers have identified a target, the compound has to go through a lengthy testing phase. The first step involves demonstrating that the compound works on infected cells in Petri dishes, then assessing if it is safe and effective in laboratory animals and finally in clinical trials in humans. Sometimes with a new virus the challenge can be finding the right cells and relevant animal models to use in these trials. In the early days of hepatitis C research, for instance, chimpanzees were the only lab animals that could be experimentally infected with the virus, raising ethical concerns. It took a few years to develop genetically engineered mice that the virus could infect instead.

The entire process thus requires substantial funding. Because hepatitis C and HIV infections are chronic and affect millions of people across the world, they sustain the interest of for-profit pharmaceutical companies. “But when you think of medications available for acute respiratory diseases, you can count them on your hand,” says Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill. “The time in which you have to intervene and give therapy is really short,” which may not be a money-making enterprise unless lots of people are affected.

Coronaviruses were not even known to cause severe human disease until 2002-04, when the virus that causes SARS infected nearly 8,000 people worldwide and killed 774. That was followed a few years later by the Middle East Respiratory Syndrome (MERS) coronavirus, which infected more than 2,000 people and killed nearly 900—including six this year.

In the wake of SARS and MERS, virologists started investigating antivirals for coronaviruses—and then came the COVID-19 pandemic.

The race to develop antivirals against SARS-CoV-2 

Normally making antiviral therapies for new viruses can take at least a decade. Unsurprisingly, the urgency presented by COVID-19 meant finding new ways to use old drugs.

“Repurposing is typical for understudied diseases and epidemics arising from new viruses,” Tummino says. “It cuts down time from discovery to the drug reaching humans.”

Researchers started screening molecular collections, such as the California Institute for Biomedical Research’s ReFRAME, to test if any FDA-approved drugs and investigational compounds were effective against SARS-CoV-2. Laura Riva, a computational biologist formerly at the Sanford Burnham Prebys Medical Discovery Institute in California, conducted one such screen along with her colleagues and identified more than a dozen compounds, including remdesivir, that blocked SARS-CoV-2 replication in animal and human cells.

In a June 2020 study involving monkeys, researchers observed remdesivir’s antiviral potential against SARS-CoV-2. And in one of the earliest clinical trials involving hospitalized COVID-19 patients, they noted its role in shortening recovery time. The experimental drug was granted approval in October 2020, making it the first FDA-approved COVID-19 treatment, despite lacking unequivocal support from other clinical trials.

However, identifying candidate antivirals without knowing what aspect of the virus’s biology they target is tricky. There’s also a risk that many compounds will turn out to have the same ineffective method of attack. For instance, 33 of the repurposed drugs tested, including the infamous hydroxychloroquine, were similar in that they accumulated fat-like substances in cells in Petri dishes that somehow reduced SARS-CoV-2 replication, but they weren’t quite as effective when tested in more than 300 COVID-19 clinical trials.

“That’s why I’m critical of repurposing drugs,” says Miguel Ángel Martínez, a clinical virologist at Spain’s IrsiCaixa AIDS Research Institute. “There is no shortcut to developing antivirals.”

Still, other experts think experimental antivirals like molnupiravir, which was first developed for influenza, hold potential to combat COVID-19.

Clinical trial outcomes spark hope

Unlike remdesivir, which is administered intravenously, molnupirvair can be swallowed as a pill. Meant for patients with mild to moderate COVID-19, the oral antiviral is taken within five days of symptoms surfacing. In an October 1 press release, drugmakers Merck and Ridgeback Biotherapeutics announced their phase 3 results, which indicated that taking the pill twice a day for five days cuts hospitalization and deaths among those infected by half.

Although these are interim findings that aren’t yet peer-reviewed, the companies jointly applied for an emergency use FDA authorization of the pill on October 11; the U.K. authorized molnupirvair’s use on November 4.

Another oral antiviral, favipiravir, also known as Avigan and first developed as an anti-flu pill in Japan, is undergoing clinical trials to assess if it can be used early in a COVID-19 infection. Previous favipiravir trials, albeit small, had suggested that in mild to moderate hospitalized COVID-19 patients, the drug could clear SARS-CoV-2 in their nose and throats. So far, countries including Japan, Russia, and India have approved its use to treat COVID-19.

Pfizer’s PF-07321332 experimental antiviral pill also aims to target SARS-CoV-2 infections early to prevent rapid viral replication. Developed as a potential treatment for SARS-CoV nearly two decades ago, the repurposed experimental drug is now being given in combination with a small dose of HIV antiviral ritonavir to COVID-19 patients in ongoing phase 2/3 clinical trials.

As of now, there are a handful of other experimental antivirals in early stages of clinical trials, and at least a few others might join the list.

“We’re experiencing an opportunity to test antivirals for an acute respiratory disease unlike any we’ve ever had,” says Sheahan. “Getting antivirals approved is worth celebrating. Getting more than one approved for a single disease will be even more amazing.”