A Toronto study of interferon-lambda shows promise in COVID-19
In lab experiments with cells and in some people, infection with SARS-CoV-2 is associated with decreased production of proteins called interferons. These proteins help cells resist viral infections or, if cells are already infected, slow the production of copies of the invading virus. Interferons can also marshal help from the immune system.
One family of interferons is called interferon-lambda. There are subtypes of interferon-lambda, such as lambda-1, -2 and so on. Cells lining the lungs and intestines are sensitive to interferon-lambda. In lab experiments with cells and viruses, interferon-lambda has potent antiviral activity and is not generally associated with inflammation.
A long-lasting form of interferon-lambda-1 called peg-interferon-lambda-1 has been developed. It has been previously tested in more than 3,000 people with viral hepatitis. In these studies, it was as effective as interferon-alpha and better tolerated.
Lab experiments have found that interferon-lambda can reduce production of SARS-CoV-2 in mice. All of the findings with interferon-lambda suggest that it is worth studying in people with COVID-19.
A team of researchers in Toronto, led by Jordan Feld, MD, conducted a randomized, placebo-controlled, double-blind pilot study of peg-interferon-lambda-1 (hereinafter called interferon-lambda) in people in the early stages of COVID-19. The researchers found that interferon-lambda “accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7.” They further stated that interferon-lambda has the potential to “prevent clinical deterioration and shorten duration of viral shedding.”
Researchers enrolled volunteers from many clinics in Toronto. All participants had SARS-CoV-2 infection confirmed with nasal swab analysis.
The average profile of participants at the start of the study was as follows:
- age – 46 years
- 42% men, 58% women
- 52% were white and 48% were people of colour
- 19% had no symptoms of COVID-19
- viral loads were more than 1 million copies/mL
- most people had mild-to-moderate symptoms of COVID-19
Twenty-nine participants received a single injection of interferon-lambda (180 micrograms) and 30 others received an injection of placebo with a weak salt solution.
Participants were taught how to perform nasal swabs to collect virus for the study.
Nurses monitored participants for up to two weeks.
Clinical trial procedures such as randomization, use of placebos and double blinds are useful and help to reduce possible bias when interpreting the results. In theory, randomization helps to distribute people with different characteristics more evenly in a trial between the group getting the active drug and the group getting the placebo.
Despite randomization, at the start of this study the amount of virus was higher in people who were given interferon-lambda. Regardless of this difference, the amount of virus decreased significantly in people who subsequently received interferon-lambda. The greatest decline was found in people who entered the study with viral levels of 1 million copies/mL or greater. The distribution of people with an undetectable viral load by day seven of the study was as follows:
- interferon-lambda – 79%
- placebo – 38%
Participants who received interferon-lambda cleared SARS-CoV-2 faster (seven days) vs. those who received placebo (10 days).
Side effects and complications
Researchers assessed symptoms of participants at the start and throughout the study, and they classified the symptoms as follows:
- muscles and bones
The researchers stated: “Overall, most symptoms in both groups were mild to moderate and we found no difference in frequency or severity of any of the seven symptom categories between treatment groups.”
Seven participants who received interferon-lambda graded their symptoms as severe on multiple occasions; these generally involved the temporary loss of sense of smell and taste. These symptoms could have been due to infection with SARS-CoV-2.
Seven participants who received placebo graded their symptoms as severe on multiple occasions, specifically, fever, chills, shivering and fatigue.
Note that symptoms decreased over the course of the study.
Respiratory symptoms—including chest pain, cough, runny nose, shortness of breath and sore throat—decreased faster among people given interferon-lambda.
Levels of liver enzymes in the blood increased very modestly in most people taking interferon-lambda. Only two people who received interferon-lambda had severely elevated levels of liver enzymes—ALT in one person and AST in another. In comparison, three people on placebo had highly elevated levels of ALT and one other person had highly elevated levels of AST.
Inflammation and clotting
D-dimer is a small protein in the blood that increases with inflammation and excess blood clots. At the start of the study, D-dimer levels were elevated in both groups of participants. They declined significantly only in people who took interferon-lambda. This is a promising finding.
Five participants sought care in a hospital emergency room within 14 days of entering the study, distributed as follows:
- interferon-lambda – one person
- placebo – four people
All five went to the ER because of worsening respiratory symptoms, but only one person from each group was hospitalized:
- interferon-lambda – shortness of breath due to a blood clot in the lung
- placebo – shortness of breath due to complications of COVID-19
No one died while in the study.
Bear in mind
A single subcutaneous injection of interferon-lambda resulted in faster time to clearance of SARS-CoV-2 compared to placebo. This effect of interferon-lambda was greatest in people with high levels of SARS-CoV-2.
Interferon-lambda was well tolerated, with similar side effects to placebo. About 20% of participants entered the study without symptoms of COVID-19. In this subgroup of people there were no side effects when they received interferon-lambda. These results may seem surprising to some because interferons have a historical reputation for causing unpleasant side effects. This reputation arose because interferons, specifically interferon-alpha, had to be injected repeatedly over time in people with hepatitis C virus (HCV). In the COVID-19 study, however, only one injection was needed because the cells that are sensitive to interferon-lambda are distributed in a limited way in the body. This should reassure future study participants that, for treating COVID-19, interferon-lambda is well-tolerated.
Altogether, the tolerability and antiviral activity from a single injection of interferon-lambda make this drug a very promising candidate for future research in people with COVID-19. California-based Eiger Biopharmaceuticals is in discussion with the U.S. Food and Drug Administration about conducting a phase II/III trial of interferon-lambda in people with COVID-19.
—Sean R. Hosein
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