A single dose of lambda-interferon reduced hospitalization among COVID-19 outpatients in a late-stage study spearheaded by a Stanford Medicine virologist.
February 9, 2023 - By Bruce Goldman
In an international, multicenter, pivotal Phase 3 trial, a single under-the-skin injection of a biological drug given to patients within seven days of the onset of COVID-19 symptoms cut the likelihood they needed to be hospitalized in half. Patients treated within three days of showing symptoms fared even better. Among unvaccinated patients who were treated soon after symptom onset, hospitalization likelihood plummeted markedly.
The drug, pegylated lambda-interferon, or PEG-lambda, proved effective against all COVID-19 viral variants tested, including omicron. Side effects were no greater than those reported by placebo recipients.
A report on the success of the randomized, double-blind, placebo-controlled trial of nearly 2,000 newly infected COVID-19 patients was published online Feb. 9 in the New England Journal of Medicine.
PEG-lambda is a synthetic version of lambda-interferon, a naturally occurring protein that infected cells secrete as a first line of defense against viral infection.
“This drug would have saved millions of lives if we’d had it at the beginning of the pandemic, and it could still save millions of other lives,” said Jeffrey Glenn, MD, PhD, professor of medicine and of microbiology and immunology and director of ViRx@Stanford, a Stanford Medicine program devoted to discovering and developing novel antiviral agents to prepare for pandemics.
“There’s been a lot of talk to the effect that COVID’s over,” Glenn said. “I don’t think the virus got that memo. Meanwhile, lots of people are still unvaccinated, and this drug showed profound benefits for vaccinated and unvaccinated people alike.”
Glenn, the study’s senior author, is a co-principal investigator along with lead author Gilmar Reis, MD, PhD, associate professor of medicine at Pontificia Universidade Catolica de Minas Gerais in Brazil; Edward Mills, PhD, professor of health research methods, evidence and impact at McMaster University in Hamilton, Ontario; and Jordan Feld, MD, associate professor of medicine at the University of Toronto.
PEG-lambda is a long-acting conjugate of lambda-interferon and polyethylene glycol, a long-chain hydrocarbon that slows the protein’s clearance from the bloodstream.
Lambda-interferon belongs to a family of interferons, denoted by different Greek letters. Interferons are secreted by cells that sense they’ve been invaded by a virus. Different interferon types use different receptors, whose distribution in the body varies widely from one interferon to another.
Interferon molecules may bind to receptors on the surface of the same cell that secreted them. They may connect with receptors on neighboring cells. Or they may make their way into the bloodstream and contact more distant cells. Interferons exert virtually identical antiviral effects on the cells they latch onto — but only those cells that have receptors for them.
Viruses, including SARS-CoV-2 (the virus that causes COVID-19), have evolved ways to shut down interferon production in the cells they infect. But they can’t gum up cells’ interferon receptors, so they can’t stop injected interferons from binding to those receptors and triggering potent antiviral activity.
A closely related substance, alfa-interferon, has been injected as a drug to treat hepatitis C and other viral infections, as well as cancer. But alfa-interferon has proved toxic to numerous organ systems, as receptors for alfa-interferon abound on the surfaces of cells in many of the body’s tissues and on immune cells. Patients receiving alfa interferon report often-debilitating side effects such as fever, chills, intense muscle aches, nausea and more.
Receptors for lambda-interferon, though, are largely limited to the linings of the lungs, airways and intestine — serendipitously, the main places SARS-CoV-2 strikes — as well as the liver. As a result, side effects resulting from injecting this interferon tend to be quite mild, Glenn said.
That turned out to be the case in this trial. “You couldn’t tell who got PEG-lambda and who got placebo,” Glenn said. This wasn’t surprising, he added, because the drug has already been given to more than 3,000 people in other trials and been proven to be well tolerated even when given weekly for a year.
Some years ago Glenn, who is the Joseph D. Grant Professor II, founded Eiger BioPharmaceuticals Inc., a biotechnology company that acquired the rights to lambda-interferon to develop it as a drug for hepatitis D. When the COVID-19 pandemic struck, the company turned its attention to the new pathogen.
Glenn has since forged ties with the TOGETHER network, which operates test sites in countries around the world and has methodically conducted clinical trials of numerous prospective therapeutic agents for COVID-19.
The PEG-lambda trial took place between June 2021 and February 2022 at 12 sites in Brazil and five sites in Canada. To participate, patients had to test positive on a COVID-19 rapid-antigen test and receive PEG-lambda or a placebo within seven days of manifesting COVID-19 symptoms. Their average age was 43. Slightly more than half were women, and about 95% were mixed race. Only 3% were white. Some 85% had been vaccinated for COVID-19.
About 930 patients received a single subcutaneous injection of PEG-lambda, and about 1,020 were given a placebo injection. Of patients receiving PEG-lambda, 25 (2.7%) were hospitalized — or, due to a shortage of hospital space, placed under observation for more than six hours in an emergency clinic — within four weeks for COVID-19, versus 57 (5.6%) of patients who received the placebo.
Vaccinated patients treated with PEG-lambda experienced a 51% reduction in hospitalization relative to placebo. In unvaccinated patients treated within the first three days of symptom onset, there was an 89% reduction compared with placebo — the same 89% reduction that was observed with Pfizer’s Paxlovid.
Only 11 (1.9%) of the 567 patients treated with PEG-lambda within the first three days after symptoms appeared wound up in the hospital within four weeks of getting the shot, versus 28 (3.1%) of the 590 who got a placebo injection within three days of symptom onset — a relative reduction of 58%.
PEG-lambda was equally effective against several SARS-CoV-2 variants, including omicron. There were no deaths among patients treated with PEG-lambda within three days of symptoms’ onset. There were four COVID-19-related deaths in the placebo group.
With vaccine-induced immunity wearing off more rapidly than has been hoped, new SARS-CoV-2 variants constantly striving to outwit our immune systems, and people shying away from repeated rounds of vaccination due to fear of side effects both real and imagined (or due to vaccine fatigue), the need for effective COVID-19 therapies is paramount, Glenn said.
But even the best treatments available today have drawbacks.
“Paxlovid is a very good drug,” Glenn said of the drug now most commonly prescribed for newly infected COVID-19 outpatients. “But it’s not perfect. You need to take six pills a day for five days. One of its component medications can interfere with your metabolism of many other drugs. The older you get, the more drugs you’re likely to be taking, and the more susceptible you are to COVID-19.”
Glenn is an inventor on intellectual property associated with the use of lambda-interferon for treating COVID-19. While he no longer actively consults for Eiger BioPharmaceuticals, he owns equity in the company and sits on its board of directors. The company has supplied PEG-lambda free of charge to several investigators for use in independent clinical trials, including this one. Eiger BioPharmaceuticals played no role in the design of this trial, patient recruitment, data acquisition, analysis or any other function in the trial’s operation, and was informed of the trial’s results only after its completion.
Additional researchers from Eiger BioPharmaceuticals Inc., Cardresearch, Platform Life Sciences, RainCity Analytics and the TOGETHER Network contributed to the work.
The study was funded by FastGrants, the Rainwater Charitable Foundation, the Latona Foundation and Eiger BioPharmaceuticals Inc.
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