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Neurotoxicity De-Risking in Preclinical Drug Discovery

Periodic Reporting for period 1 - NeuroDeRisk (Neurotoxicity De-Risking in Preclinical Drug Discovery)

Reporting period: 2019-03-01 to 2020-08-31

"NeuroDeRisk is an “Innovative Medicines Initiative” (IMI2) project aiming to provide novel validated integrated tools for improving the preclinical prediction of adverse effects of pharmaceuticals on the nervous system and thus help to de-risk drug candidates earlier in the Research and Development phases.

The adverse effects of pharmaceuticals on the central or peripheral nervous systems are poorly predicted by the current in vitro and in vivo preclinical studies performed during Research and Development (R&D) process. Therefore, increasing the predictivity of the preclinical toolbox is a clear need, and would benefit to human volunteers/patients (safer drugs) and Pharmaceutical Industry (reduced attrition). By combining top level scientists in neurobiology/toxicology with successful software developers, the NeuroDeRisk Consortium will aim at tackling three of the most challenging adverse effects: seizures, psychological/psychiatric changes, and peripheral neuropathies.

Our approach will be global, starting with an in-depth evaluation of knowledge on mechanisms of neurotoxicity (biological pathways as well as chemical structures and descriptors, using in particular historical data). Then we will search for innovative tools, assays and studies covering in silico, in vitro and in vivo approaches. This will include in particular:
- a molecular design platform,
- use of human induced pluripotent stem cells,
- establishing new blood-brain-barrier models,
- pharmacokinetics
- immunohistochemistry,
- transcriptomics,
- RNA editing biomarkers,
- video-monitoring and
- Non-invasive in vivo technologies (ultra high resolution video-monitoring, telemetry, actimetry)

The last step will aim at combining these tools in an integrated platform for improved risk-assessment and decision-points throughout R&D process, aiming at prediction of adverse effects by drug candidates based on potential neurotoxicity.

Thus, we shall deliver increased knowledge on mechanisms of nervous system modulation and toxicity, as well as a better understanding of molecular interaction factors that favor neurotoxicity risks for drug candidates.

All the results feed into an integrated risk assessment approach for providing better decision points throughout the preclinical drug discovery process.

The NeuroDeRisk consortium positively impacts IMI2 KPI 2 and 3, Regulation Objective b6 ""improve the current drug development process by providing the support for the development of tools, standards and approaches to assess efficacy, safety and quality of regulated health products”.

By investigating the molecular basis of drugs and/or drug candidate related adverse outcomes on the central and peripheral nervous system, the consortium lays the ground work for the development of better and safer drugs. By providing information on new biomarkers related to such adverse outcomes, and making available software tools for prediction of off-target interactions, the consortium contributes to replacement, reduction, and refinement of animal experiments (i.e. the 3R paradigm)."
"Work performed towards reaching the objectives of the NeuroDeRisk project within the first 18 months resulted in a considerable amount of deliverables obtained. So far, the consortium deposited 11 deliverables on time. Due to the COVID-19 pandemics, two deliverables, which were related to extensive lab work prohibited because of shut down measures, could not be deposited on time.

The consortium has worked towards the definition of molecules with ictogenic risk, with psychological/psychiatric adverse effects (with a particular focus on immune-modulation), and peripheral neuropathy risk in drug development candidates, and to identify and evaluate safety biomarkers to monitor CNS/PNS-related toxicity with creating a resource/database that contains all available information for potential risk compounds in a single searchable format.

Drug prioritization was based on a ""Disproportionality and Information Component Analysis"" approach. This enabled the identification of true safety signals for CNS/PNS AEs of drugs. In a chemo-informatic approach, 3D interaction models (pharmacophores) were built based on data retrieved using this approach in order to predict risk potentially associated with anti target related outcomes. The blood-brain barrier passage was investigated using assessment of contributive role of CNS barriers in achievement of extracellular and intracellular unbound compound exposure in brain regions of interest in rats in relation to the seizurogenic activity of the compounds. Seizure-risk predicting RNA-signatures were determined.

The work will make it possible to deploy the NeuroDeRisk Toolbox to project partners for in house use that will impact the progress of the NeuroDeRisk project initiatives, as the models can be used to profile in house compounds in 'real-life' use case scenarios, providing another level of validation on a much wider range of data that is not accessible to the project partners. New methods involving AI enhanced pharmacophore technology being developed allows the expansion of the validated methodology to make use of novel innovative approaches to address difficult challenges and make use of emerging new data and provide quantitative outputs to predictions.

Overall the outcome of work from the consortium directly impacts the objectives of the NeuroDeRisk project towards improving preclinical predictivity of adverse effects of pharmaceuticals on the CNS and PNS, as well as impacting causality networks to provide improved decision support at the preclinical stages of development."
The experimental models exceeding state-of-the-art developed as well as the data generated by the consortium additionally based on databases from EFPIA partners and the public domain, all put together in the NeuroDeRisk tool box, will be used to make predictions for novel compounds entering into clinical development, thus de-risking them for potential neurotoxic effects.

The collaboration within the NeuroDeRisk consortium will ensure both significant benefits for society by helping patients by delivering safer, better medicines, protecting human volunteers in clinical trials, and finally making the R&D process more efficient by helping industry with top level science to de-risk the discovery of new drugs with high unmet medical need, as still exist across all therapy areas.
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Location of NeuroDeRisk Consortium Partners