Identify and validate potential drug candidates from known antivirals and build translational understanding to support prediction of efficacy based on data from in vitro and in vivo pre-clinical models
current phase of drug development
updated 16 Feb 2023
DNDi is supporting the ANTICOV clinical trial by identifying and validating repurposed drug candidates, beginning with the in vitro and in vivo experimental work needed to provide supporting pre-clinical evidence. We are focusing mainly on compounds that have a direct-acting antiviral profile and on combinations of antivirals and anti-inflammatories.
COVID-19 is a new disease and has several phases – from an initial viral stage to a later inflammatory stage – which contributes to a lack of consensus understanding of the translational value of in vitro and in vivo experimental models. To help overcome this knowledge gap, our discovery team is also working to expand the translational understanding of how data generated in pre-clinical in vitro and in vivo models can help to predict the future efficacy of investigational drug candidates in patients.
Translational studies supporting the selection of new ANTICOV trial treatment arms continued with 19 compounds with different modes of action thoroughly investigated in in vitro and in vivo SARS-CoV2 infection models. In addition to repurposed drugs, several experimental or recently approved drugs were investigated. Of the compounds assessed, including MPro inhibitors (nirmatrelvir and ensitrelvir) and RdRp inhibitors (favipiravir and molnupiravir), very few showed a significant antiviral effect against SARS-CoV2 infection in in vivo models. Key data and conclusions from the translational studies supporting the selection of ANTICOV arms have been summarized in public disclosures and peer-reviewed publications, including a key publication summarizing data for all compounds included in the translational study. In parallel, initial data from the fluoxetine arm of the trial – showing compound efficacy – are being confirmed by additional studies at the University of Toulouse and the University of Liverpool.
DNDi continued to offer pre-clinical support for the selection of new treatment arms in the ANTICOV trial. Additional compounds were assessed based on clinical and pre-clinical literature, including the new RdRp inhibitors (molnupiravir, AT-527) and MPro inhibitors (PF-07321332), with clinical data now being published. This project is both providing support to ANTICOV with pre-clinical evidence for the selection of clinical trial arms, as well as helping to define a clear path forward from in vitro data to in vivo efficacy assessment based on clear pharmacokinetic data and modelling.
In vivo experiments to obtain pre-clinical data on several known antivirals (ritonavir-boosted atazanavir, nitazoxanide, favipiravir, sofosbuvir, and daclatasvir) were started in November 2020 in collaboration with the Katholieke Universiteit Leuven, the Unité de Virus émergents at the Université d’Aix-Marseille, and the University of Liverpool. At least three more potential treatments will be investigated in 2021.
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