CERC-002, a human anti-LIGHT mAb reduces respiratory failure and death in hospitalized COVID-19 ARDS patients

  1. David S. Perlin
  2. Garry A. Neil
  3. Colleen Anderson
  4. Inbal Zafir-Lavie
  5. Lori Roadcap
  6. Shane Raines
  7. Carl F. Ware
  8. H. Jeffrey Wilkins

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Abstract

Background

Severe COVID-19 infection is associated with dysregulated immune response which, in a substantial minority of patients, results in cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS). Inhibition of cytokines or cytokine-associated signal transduction is a promising strategy to ameliorate ARDS associated with CRS. We and others have previously shown that serum free LIGHT (TNFSF14) levels are markedly elevated in patients with COVID-19 pneumonia/ARDS 10,11 , suggesting that LIGHT neutralization may offer therapeutic benefit to COVID-19 ARDS patients.

Methods

We conducted a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept clinical trial of CERC-002 in adults with mild to moderate ARDS associated with COVID-19 (n=83). Enrolled patients received a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroids. The primary efficacy endpoint was alive and free of respiratory failure status through Day 28. Secondary outcomes included alive status at Day 28, free of invasive ventilation through Day 28, and serum free LIGHT levels.

Results

In patients hospitalized with COVID-19 associated pneumonia and mild to moderate (ARDS), CERC-002 increased the rate of alive and free of respiratory failure status through Day 28 as compared to placebo (83.9% vs 64.5%; p=0.044). Efficacy was highest in the prespecified subgroup of patients 60 years old and older (76.5% vs 47.1%; p=0.042), the population most vulnerable to severe complications and death with COVID-19 infection. Through both the initial 28-day and 60-day follow-up periods, reductions of approximately 50% in mortality were observed for CERC-002 compared to placebo (7.7% vs 14.3% at Day 28 and 10.8% vs 22.5% at Day 60). Importantly, this improvement was incremental to standard of care including high dose steroids and remdesivir 88.0% and 57.8%, respectively). In addition, serum LIGHT levels but not IL-6 levels were markedly reduced in patients treated with CERC-002.

Conclusions

The data presented herein demonstrate that CERC-002 markedly reduces the risk of respiratory failure and death incremental to standard of care including high dose corticosteroids and reduces LIGHT levels in patients with COVID-19 ARDS. (ClinicalTrials.gov number NCT04412057 ).

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    SciScore for 10.1101/2021.04.03.21254748: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Inclusion criteria for enrollment were as follows: Subject was ≥18 years of age at the time of informed consent and assent (as applicable); subject was male or non-pregnant, non-lactating female; subject had a diagnosis of COVID-19 infection through an approved testing method; subject had been hospitalized due to clinical diagnosis of pneumonia with acute lung injury defined as diffuse bilateral radiographic infiltrates and mild to moderate ARDS defined as PaO2/FiO2 >100 and <300 subject had an oxygen saturation at rest in ambient air <93%.
    RandomizationEligible patients were randomly assigned in 1:1 ratio to receive either CERC-002 or placebo.
    Blindingnot detected.
    Power AnalysisThis sample size was selected to provide greater than 80% power to detect a difference of 0.25 in the proportion of subjects alive and free of respiratory failure using a one-sided significance level of 0.05.
    Sex as a biological variableInclusion criteria for enrollment were as follows: Subject was ≥18 years of age at the time of informed consent and assent (as applicable); subject was male or non-pregnant, non-lactating female; subject had a diagnosis of COVID-19 infection through an approved testing method; subject had been hospitalized due to clinical diagnosis of pneumonia with acute lung injury defined as diffuse bilateral radiographic infiltrates and mild to moderate ARDS defined as PaO2/FiO2 >100 and <300 subject had an oxygen saturation at rest in ambient air <93%.

    Table 2: Resources

    Antibodies
    SentencesResources
    , serum free LIGHT levels and inflammatory biomarker patterns, plasma concentrations of CERC-002 over time and measurement of anti-drug antibody (ADA).
    anti-drug
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04412057CompletedClinical Trial to Evaluate CERC-002 in Adults With COVID-19 …

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.04.03.21254748v1 on medRxiv