COVID-19: A need for new rather than repurposed antiviral drugs

  1. Dory Kovacs
  2. Chris Davis
  3. Paul Cannon
  4. Melanie McFarlane
  5. Stephanie M Rainey
  6. Rute Pinto
  7. Meredith E Stewart
  8. Agnieszka M Szemiel
  9. Aislynn Taggart
  10. Alain Kohl
  11. Fiona Marra
  12. Emma C Thomson
  13. Janet T Scott

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Abstract

Background

SARS-CoV-2 infection, the causative agent of COVID-19, has resulted in over 2,500,000 deaths to date 1 . Although vaccines are becoming available, treatment options remain limited. Repurposing of compounds could reduce the time, cost, and risks associated with the development of new drugs and has been the focus of many clinical studies.

Here, we summarise available evidence on 29 FDA-approved compounds, from in vitro results to clinical trials, focussing on remdesivir, galidesivir and favipiravir, and test 29 antiviral compounds’ activity in vitro .

Methods

A comprehensive search strategy was used to retrieve trials and publications related to antiviral compounds with potential efficacy to treat coronaviruses. These data were used to prioritise testing of a panel of antiviral drugs in vitro against patient isolates of SARS-CoV-2. An in vitro screen was carried out to determine the activity of 29 FDA-approved compounds.

Results

625 clinical trials investigated 16 repurposed antiviral candidate compounds for the treatment of COVID-19. In vitro studies identified ten drug candidates with demonstrable anti-SARS-CoV-2 activity, including favipiravir, remdesivir, and galidesivir. To validate these findings, a drug screen was conducted using two cell lines and wildtype isolates of SARS-CoV-2 isolated from patients in the UK. While eight drugs with anti-SARS-CoV-2 activity were identified in vitro, activity in clinical trials has, as yet failed to demonstrate a strong effect on mortality.

Conclusions

So far, no repurposed antiviral has shown a strong effect on mortality in clinical studies. The urgent need for novel antivirals in this pandemic is clear, despite the costs and time associated with their development.

Research in Context

Evidence before this study

Repurposing of existing compounds for the treatment of COVID-19 has been the focus of many in vitro studies and clinical trials, saving time, costs and risks associated with the research and development of new compounds.

Added value of this study

We reviewed the literature for 29 FDA-approved compounds with previously reported (or suspected) anti-SARS-CoV-2 activity and found 625 clinical trials that have been undertaken on 16 different drugs. We determined if repurposed antivirals are suitable for clinical trials based on previously published data, and conducted an additional in vitro screen using locally circulating strains in the UK (PHE2 and GLA1). We report the difference in IC 50 from published data using Wuhan1/Wash1 strains with PHE2 and GLA1, including IC 50 values below 100μM for galidesivir in wild-type virus. Given the limited success of repurposed compounds in the treatment of COVID-19, we comment on the urgent need for new antivirals specifically targeting SARS-CoV-2.

Implications of all the available evidence

Our data show that most prospective compounds for repurposing show no anti-SARS-CoV-2 activity, and antiviral activity in vitro does not always translate to clinical benefit. So far, no repurposed compound has shown a strong effect on mortality in clinical studies. Drugs, including monoclonal antibody therapies, that have been developed to target SARS-CoV-2 virus itself have shown most promise.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.25.436935: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The method was adapted from that recommended in the Cochrane Handbook for Systematic Reviews of Interventions13 for identifying trials.
    Cochrane Handbook
    suggested: None
    This process was repeated by searching medRxiv and bioRxiv simultaneously through bioRxiv in the title or abstract fields, and for ChinaRxiv across all fields.
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    Results were filtered for relevance before being exported and analysed in EndNote X9.
    EndNote
    suggested: (EndNote, RRID:SCR_014001)

    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
    NCT03891420RecruitingA Study to Evaluate the Safety, Pharmacokinetics and Antivir…
    NCT04280705CompletedAdaptive COVID-19 Treatment Trial (ACTT)
    NCT04257656TerminatedA Trial of Remdesivir in Adults With Severe COVID-19
    ISRCTN31062548NANA

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.03.25.436935v1 on bioRxiv