Peginterferon-lambda for the treatment of COVID-19 in outpatients

Abstract

SummaryBackgroundThere are currently no effective treatments for outpatients with coronavirus disease 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens.MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection.FindingsThere were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group.InterpretationPeginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding.(NCT04354259)FundingThis study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma.Research in ContextTreatment trials for COVID-19 have largely focused on hospitalized patients and no treatments are approved for people with mild to moderate disease in the outpatient setting. A number of studies in ambulatory populations have been registered but no controlled studies in the outpatient setting have been reported to date (Pubmed Search October 20, 2020, COVID-19 treatment; controlled trials). Uncontrolled case series of hydroxychloroquine with or without azithromycin have been reported with mixed results but no clear signal of efficacy and some concerns raised about cardiac toxicity. Treamtent in the outpatient setting has potential to prevent infected individuals from deteriorating and perhaps more importantly, may shorten the duration of viral shedding, reducing the risk of transmission and the duration required for self-isolation, with significant public health and societal impact.Added value of this studyThis is the first study to show an antiviral effect in outpatients with COVID-19. After controlling for baseline viral load, those treated with peginterferon-lambda had a 4.12-fold (95%CI 1.15-16.7, p=0.029) higher odds of viral clearance by Day 7 compared to those who received placebo. The viral load decline was faster with pegterferon-lambda and the effect was most pronounced in those with high viral loads. In individuals with a baseline viral load of 10E6 copies/mL or higher, 15/19 (79%) in the peginterferon-lambda arm cleared by Day 7 compared to 6/16 (38%) (p=0.012) in the placebo arm (OR 6.25, 95%CI 1.49-31.1, p=0.012), translating to a median time to viral clearance of 7 days (95%CI 6.2-7.8 days) with peginterferon-lambda compared to 10 days (95%CI 7.8-12.2 days) with placebo (p=0.038). Those with low viral loads (<10E6 copies/mL) cleared quickly in both groups. Peginterferon-lambda was well-tolerated with a similar side effect profile to placebo and no concerning laboratory adverse events.Implications of all available evidenceThere is no currently approved therapy for outpatients with COVID-19. This study showed that peginterferon-lambda accelerated viral clearance, particularly in those with high baseline viral loads, highlighting the importance of quantitative viral load testing in the evaluation of antiviral agents for COVID-19. Treatment early in the course of disease may prevent clinical deterioration and shorenting of the duration of viral shedding may have important public health impact by limiting transmission and reducing the duration required for self-isolation. Additional trials of peginterferon-lambda and other antiviral strategies in the outpatient setting are required.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial

“…Our results differ somewhat from those seen in a similar, but smaller, randomized controlled trial of Lambda at the same dose in COVID-19 outpatients in Toronto 34 . In the Toronto study, Feld and colleagues randomized 60 outpatients to a single subcutaneous injection of 180 μg Lambda (n = 30) or placebo (n = 30) within 7 days of symptom onset or first swab if asymptomatic.…”

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

“…Together, our work demonstrates that many of the factors associated with the clinical trajectory following SARS-CoV-2 infection may stem from initial host-viral encounters in the nasopharyngeal epithelium. Further, it suggests that there may be a clinical window in which severe disease can be subverted by focusing preventative or therapeutic interventions early within the nasopharynx 115–118 , thereby bolstering anti-viral responses and curbing pathological inflammatory signaling prior to development of severe respiratory dysfunction or systemic disease.…”

Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection

“…Recombinant interferon blocks SARS-CoV-2 replication in vitro, and genetic deficiencies in the Type I interferon response as well as anti-interferon autoantibodies have been linked to greater COVID-19 disease severity (Bastard et al, 2020; Lokugamage et al, 2020; Pairo-Castineira et al, 2020; Vanderheiden et al, 2020; Zhang et al, 2020). Furthermore, early data from trials of recombinant Type I or Type III interferon for COVID-19 indicate a therapeutic benefit, particularly when patients are treated early in disease(Feld, 2020; Monk, 2020; Wang, 2020). However, elevated interferon responses later in infection are linked to worse outcomes and may drive immunopathology in severe COVID-19, which generally begins at week two to three of infection, after peak viral replication (Lee and Shin, 2020; Lucas et al, 2020).…”