The pandemic is not over, despite some proclamations to the contrary. The good news is that we now have some effective therapeutics that are helping drive fatality rates down. Chief among these is Paxlovid, which significantly reduces the risk of hospitalization and death and was first granted an emergency use authorization by the Food and Drug Administration in December 2021. Paxlovid is not an option for everyone, though. And SARS-CoV-2, the virus that causes COVID, has the potential to evolve resistance to it. The world desperately needs more options to ensure we stay ahead of the virus.
Now a new antiviral treatment is showing promise. Clinical trial results show that a single injection of a substance called pegylated interferon lambda (PEG-lambda) is highly effective at preventing severe COVID. In a cohort of mostly vaccinated patients, participants given the drug within seven days of showing symptoms were 51 percent less likely to be hospitalized or to go to an emergency room, compared with those given a placebo. People given PEG-lambda within three days saw that risk reduced by 58 percent. The treatment may also lower the risk of death, but the numbers were too small to be significant. The findings were published on Wednesday in the New England Journal of Medicine.
The drug was even more effective in unvaccinated patients. Side effects were minimal, and PEG-lambda has other advantages. It is a “broad spectrum” antiviral that could be useful against numerous diseases. The researchers hope the new data will lead to FDA authorization that will enable doctors to give PEG-lambda to patients. “The tragedy is, had we been able to use this at the beginning of the pandemic, we could have saved millions of lives,” says Jeffrey S. Glenn of Stanford University, who is senior author of the study. “We still can.”
“This was a well-designed, well-controlled trial. Confounding factors, such as age, race, comorbidities, etcetera have all been taken into account,” says immunologist Evangelos Andreakos of the Academy of Athens, who was not involved in the work. “The findings are convincing.” One caveat is the large number of people who had to be treated for just a few to benefit, but this is not specific to PEG-lambda. “Antivirals need to be administered early, before anyone knows if these individuals will develop severe disease,” Andreakos says. “This will be solved with better identification of high-risk patients and targeted treatment.”
PEG-lambda is a synthetic version of a naturally produced protein called an interferon that is attached to a molecule that slows its clearance from the blood. It is administered with a single subcutaneous injection. Paxlovid, by comparison, involves taking three pills twice a day for five days.
Interferons are signaling molecules that are part of the innate immune response, the body’s first line of defense against invaders. Type I interferons (such as alpha and beta) have been explored as antivirals for decades, but they can have significant side effects, including fever, nausea, vomiting and muscle aches. This happens because the receptor they bind to is found in numerous tissues, as well as on immune cells, so boosting type I interferons can put the immune response into overdrive. But interferon lambda (a type III interferon) only binds to receptors on epithelial cells, such as those located in the lungs, airways and gut—where SARS-CoV-2 primarily acts—and the liver. Researchers think this is why lambda has minimal side effects. This was not a big surprise because it has been safely given to more than 3,000 patients in clinical trials as a treatment for hepatitis.
Type I interferons’ reputation for unpleasant and sometimes deadly side effects, as well as interferons’ lack of efficacy in trials of hospitalized patients, may have slowed progress on researching interferon lambda. Earlier, smaller trials were sufficiently encouraging to warrant the current phase 3 study, however. The company developing PEG-lambda, Eiger BioPharmaceuticals, announced results from the trial in a press release last year, but researchers have had to wait until now to see the data for themselves.
Interferons are produced by cells that sense an intruder as a signal to activate cellular defenses. Yet many viruses have evolved ways to dampen cells’ interferon production or evade detection. “SARS-CoV-2 is very good at hiding from the immune response. It tries to do a lot of damage without turning on the alarms,” says geneticist Ludmila Prokunina-Olsson of the National Cancer Institute, who was not involved in the new trial. It can’t block interferon receptors, though, so injecting interferons into the body can sound the alarm, readying cells to fight the virus. “After this boost, the awakened immune system will take care of the intruder by itself,” Prokunina-Olsson says.
Glenn founded Eiger in 2008, and he owns equity in the company and sits on its board of directors. Eiger began developing interferon-lambda for viral hepatitis. When the pandemic struck, Glenn and his colleagues turned their attention to SARS-CoV-2. He recruited independent researchers from the TOGETHER Trial network to test the drug, which Eiger supplied. The trial was conducted in Canada and Brazil, and it included nearly 2,000 participants. Of them, 931 received the treatment, and 1,018 received a placebo. The participants had to have first shown symptoms within the past week and to have tested positive in a rapid antigen assay. Most had a heightened risk of developing severe disease because of at least one trait, including being older than age 49, a smoker, or obese or having a health condition such as diabetes or heart disease.
More than 80 percent of the participants were vaccinated. Among people who were not, however, those who were treated within three days were 89 percent less likely to be hospitalized. That’s comparable to Paxlovid’s efficacy against hospitalization, Glenn says. “But Lambda can do this with one shot. It has 100 percent compliance by definition.” Through circumstance, the drug was tested against several variants because the study spanned multiple COVID waves. The Omicron variant showed the best response to the drug, but “it worked across all variants,” Glenn says.
“This is not a ‘whack-a-mole’ fix for a specific viral variant,” Prokunina-Olsson says. “This is a way to generally boost the first line of defense to any viral infection.”
One limitation with Paxlovid is that the active ingredient is given alongside another drug that reduces how fast the body metabolizes it, and this can also affect other drugs a patient is on. Older patients, for whom COVID is more dangerous, are more likely to be taking additional medications, which they may not be able to interrupt. Furthermore, viruses can mutate to evade protease inhibitors, the class of drugs Paxlovid belongs to, although researchers have not seen that happen with Paxlovid yet. This is not a problem for PEG-lambda because it does not interact directly with the virus at all, so no mutation can evade it. “This is exciting, not just for COVID but more broadly for any emerging infectious diseases of pandemic potential,” Andreakos says.
Eiger plans to request an emergency use authorization from the FDA. If lamba-interferon is approved on an emergency basis, it could be “a tremendous tool in our fight against COVID,” Glenn says. Ultimately, he envisions the drug being used more widely to fight other viruses. “I hope we’ll be able to do a study to generate data against flu, [respiratory syncytial virus], other coronaviruses, etcetera,” he says.