Orally administered epeleuton inhibits SARS-CoV-2 viral load, replication and pathology in the Syrian Hamster model

  1. John Climax
  2. Moayed Hamza
  3. Adam Lafferty
  4. Kate Guilfoyle
  5. Geert van Amerongen
  6. Konrad Stadler
  7. Peter Wohlsein
  8. Wolfgang Baumgärtner
  9. Markus Weissbach
  10. David Coughlan

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Abstract

Early treatment of patients with confirmed COVID-19 presenting mild symptoms can reduce the number that progress to more severe disease and require hospitalization. Considering the potential for the development of drug resistance to existing therapies and the emergence of new SARS-CoV-2 variants, there is a need for an expanded armamentarium of treatment options for COVID-19. Epeleuton is a novel orally administered second-generation n-3 fatty acid with potential direct antiviral and immunomodulatory actions, and a favourable clinical safety profile. In this study we show that epeleuton inhibits SARS-CoV-2 infectious viral load, replication and disease pathology in the lungs and upper airways in the Syrian hamster model of SARS-CoV-2 infection. These data support the potential utility of epeleuton in the early treatment and prevention of SARS-CoV-2 infection. Clinical trials are needed to evaluate the efficacy of epeleuton as an outpatient treatment and prevention of COVID-19.

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    SciScore for 10.1101/2021.12.07.471588: (What is this?)

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

    Table 1: Rigor

    EthicsEuthanasia Agents: The animals were then humanely sacrificed by CO2 narcosis and the following tissues removed, weighed, snap frozen in liquid nitrogen and stored in a freezer set to maintain a temperature of −80°C until analysis: Lungs (perfused with phosphate buffer saline), heart, brain, eyes, liver, kidney, spleen, colon and skin (shaved).
    Sex as a biological variable15-HEPE Tissue distribution Study: Compliance with Ethical Standards: Ten male Sprague Dawley rats were used in this study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationAuthentication: Plasma extraction procedure: 15(S)-HEPE and its internal standard 15(S)-HETE-d8 were determined from rat plasma by enzymatic digestion followed by protein precipitation using validated bioanalytical method.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Detection of replication competent virus: Quadruplicate, 10-fold serial dilutions of throat swabs and tissue homogenates were transferred to 96 well plates with confluent layers of Vero E6 cells and incubated for one hour at 37°C.
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Tissue distribution study protocol: Eleven male Sprague Dawley rats (n=5/group) received a once daily oral dose of 500mg/kg Epeleuton or vehicle for 7 days.
    Sprague Dawley
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis: One-way ANOVA followed by Dunnett’s multiple comparisons tests were performed using GraphPad Prism version 9.0.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: We detected the following sentences addressing limitations in the study:
    A limitation of the present study is that treatment was initiated pre-infection to account for potential pharmacokinetic differences between hamsters and other species used in previous studies of epeleuton, and to ensure steady state levels are achieved early in the course of infection. Polyunsaturated fatty acids may take days to reach therapeutic concentrations in plasma and desired tissues. Consequently, while the observed results indicate that epeleuton exerts protective effects against SARS-CoV-2 infection and end-organ outcomes, the study design leaves some uncertainty regarding the potential treatment window. However, the marked effects of epeleuton on lung and upper airway pathology are consistent with previous findings that direct acting antivirals including for SARS-CoV-2 tend to improve disease outcome when administered early in the course of infection31, 32. To overcome the pharmacokinetic challenge posed by the acute course of SARS-CoV-2 infection, Cardiolink-9, a recent small exploratory phase 2a clinical trial of icosapent ethyl, an ethyl ester formulation of EPA, in patients with COVID-19 employed a loading dose. This trial provided the first human experience with a 4g BID (8 g/day) loading dose of a fatty acid therapy. The trialled treatment regimen demonstrated favourable short-term safety and tolerability, comparable to usual care, and resulted in significant improvements in inflammatory markers and patient symptom scores from baseline17. Since EPA is the m...

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

    IdentifierStatusTitle
    NCT04365400RecruitingTRIgyceride And Glucose Control With Epeleuton in Metabolic …

    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.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.12.07.471588v1 on bioRxiv