Trials of Interferon Lambda for SARS-CoV-2 /COVID-19: A Status Report

Thomas R. O’Brien, MD, MPH

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA [email protected]

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content of this publication and the opinions expressed reflect those of the individual author solely and do not necessarily reflect the views or policies of the Department of Health and Human Services, the National Institutes of Health or the National Cancer Institute nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Early in the COVID-19 pandemic, several groups of scientists proposed IFN-l as a potential therapy for SARS-CoV-2 infection (O’Brien et al., Clinical Infectious Diseases, 2020; Prokunina-Olsson et al., Journal of Experimental Medicine, 2020). That suggestion was based on evidence that the IFN-l family provides important first-line immunological defense against viral respiratory tract infections and data indicating that SARS-CoV-2 induces weak expression of IFNs. There are no licensed IFN-l therapeutics, however, pegylated-interferon lambda 1, which was shown to be safe and effective in testing among >3,000 patients with chronic viral hepatitis infections, is available as an investigational agent through Eiger Biopharmaceuticals. Several phase 2 clinical trials have been launched to assess the safety and efficacy of pegylated-IFN-l1 for treatment or prevention of SARS-CoV-2 / COVID-19. Findings from two trials are now available.

Jordan Feld (University of Toronto) and colleagues conducted a double-blind, placebo-controlled randomized trial of pegylated-IFN-l1 among outpatients with mild-to-moderate COVID-19 (NCT04354259; Feld et al., The Lancet Respiratory Medicine, 2021). Patients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of 180 µg of pegylated-IFN-l1 or to a placebo injection within 7 days of either symptom onset or, for asymptomatic patients, the first positive swab. The investigators recruited 30 patients per arm. At day 7 after injection, findings in the active treatment group compared to those who received placebo were: a 2.42 log greater decline in SARS-CoV-2 RNA copies per mL (p=0·004); a 4-fold greater likelihood of having undetectable virus (p=0.03); 80% frequency of undetectable virus, compared with 63% in the placebo group (p=0·15). Among those with a baseline viral level >106 copies per mL, 79% of the treatment group had undetectable virus on day 7, compared with 38% of the placebo group (p=0·01). Treatment was well tolerated, and adverse events were similar between groups. Mild, but transient, increases in aminotransferase levels were more frequent in the pegylated-IFN-l1 group.

In a second trial, Prasanna Jagannathan (Stanford University) and colleagues enrolled 120 outpatients within 72 hours of diagnosis of mild-to-moderate COVID-19 (NCT04331899; Jagannathan et al., medRxiv, 2020). At enrollment, 41% of these subjects were SARS-CoV-2 IgG seropositive. Participants were randomized to receive a single injection of either pegylated-IFN-l1 or a placebo. In this study, neither median time to cessation of viral shedding (7 days in each arm) nor symptom duration (8 days with treatment, 9 days with placebo) differed significantly between groups. Treatment with pegylated-IFN-l1 was well-tolerated, however, elevated liver transaminases were more frequent in the active group (25%) compared to the placebo arm (8%; p=0.03).

While results of these two trials studies provide similarly encouraging results regarding the safety of a single injection of pegylated-IFN-l1 in patients with SARS-CoV-2 infection, the papers reached different conclusions regarding the efficacy of that treatment of early COVID-19. Feld and colleagues determined that pegylated-IFN-l1 accelerated viral clearance, especially in those with higher baseline viral levels, while Jagannathan et al concluded that this therapy did not shorten the duration of SARS-CoV-2 viral shedding. Clearly, more data are needed regarding the efficacy of pegylated-IFN-l1 for SARS-CoV-2 / COVID-19. Given the observed safety profile and the encouraging results from Feld et al, a larger, phase 3 trial to more fully assess the effect of pegylated-IFN-l1 on clearance of SARS-CoV-2 and the clinical course of infection would be welcome. Unfortunately, no such trial is currently in the works. Several additional phase 2 trials of pegylated-IFN-l1 are listed as active on the website. We look forward to those results.