project

The consortium will implement a strategic, multi gear R&D and clinical roadmap for the identification, optimisation, preclinical and clinical investigation of broad spectrum antivirals against pathogens with epidemic or pandemic potential.

In particular, the consortium will design compounds library with increased diversity to be tested in high-throughput assays against highly pathogenic viruses. Hits coming from this exercise, as well as assets that have demonstrated antiviral activity in previous exercises, will be assessed against a larger virus panel. Validation of the antiviral efficacy of the hits will be done in state-of-the art ex vivo models to prioritize compounds going to in vivo proof of concept studies. Mode of action and target will be also interrogated.

Additionally, the implementation of an adaptive platform trial will enable early clinical investigation of 3 antivirals and will pave the way for clinical testing of other antivirals

Finally, the project will investigate new innovative and improved delivery systems of antivirals through nano conjugation. Ultimately, this project will deliver a pipeline of broad-spectrum antiviral candidates and in the longer term contribute to European preparedness for emerging threats.

The project is organized into the following Work Packages:

WP1 (Lead: Joel LELIEVRE, GSK): Generation of chemical diversity and phenotypic high throughput screening (HTS):

To establish a tailored library of 125k compounds from GSK internal database and other outsourced databases (to be tested for Filovirus, Henipavirus and Flavivirus infection)
To perform phenotypic high throughput screening on these libraries and generate dose-response data for hits
To explore structure-activity relationship of validated primary hits

WP2 (Lead: Urtzi GARAIGORTA, CSIC): Primary hit validation and definition of the antiviral spectrum of antiviral candidates:

To assess the spectrum of activity of the primary hits using the full panel of NAVIPP priority viruses (Broad spectrum vs. Family-selective vs. Virus-specific, etc.) in conventional 2D models
To assess the spectrum of activity of the primary hits using the full panel of NAVIPP priority viruses (Broad spectrum vs. Family-selective vs. Virus-specific, etc.) in ex vivo models
To start exploring the step of the viral cycle impacted by the hits

WP3 (Lead: Claudia FILIPPONE, ERINHA): Preclinical evaluation:

To evaluate drug metabolism and pharmacokinetics (DMPK) properties
To evaluate safety and tolerability in silico and in vitro
To perform Physiologically based Pharmacokinetic / Pharmacokinetic Pharmacodynamic Modeling (PBPK /PKPD)
Structure Activity Relationship (SAR) definition for selected series to generate tool compounds for in vivo pre-clinical proof of concept (PoC)
In vivo evaluation of the antiviral effect in different infection models.

WP4 (Lead: Sonia SEVERS, MPI): Mode of Action (MoA) and target identification

To define the molecular target of a selected group of antiviral candidates identified by phenotypic screening (WP1) and sent to WP2 for validation.
Generate target engagement data to support mechanistic modeling and simulation (M&S) to inform Phase 2a clinical trial design

WP5 (Lead: Olivier KITTEN, AFFILOGIC): Enabling antivirals’ implementation

Explore innovative delivery systems for the administration of broad-spectrum antivirals (BSAV)
Develop a draft generic target product profile (TPP) for Nipah virus antivirals for submission to World Health Organization (WHO) for endorsement
Develop a draft TPP for dengue virus antivirals for submission to WHO for endorsement

WP6 (Lead: Sophie YACOUB, UOXF): ADAptive Platform Trial for antiviral screening in patients with early symptomatic dengue (ADAPT)

To develop methodology for PK/PD assessment of candidate antiviral drugs in early dengue.
To conduct a Phase 2a randomised, adaptive, open label trial in patients with early symptomatic dengue infection in Vietnam
To provide proof of concept for the rapid assessment of in-patient antiviral activity for repurposed and novel therapeutics for dengue using the rate of viral clearance as the primary virological endpoint

WP7 (Lead: Théophile TURBOUST, ERINHA): Coordination, project management, communication & dissemination

This WP, led by the coordinator ERINHA through the project management team (PMT), will ensure effective and efficient coordination and management of the project, as well as proper internal and external communication and dissemination, and exploitation.