In silico predictive toxicology new disruptive technology

Transcription

1 Romain GUIDON Business Development In silico predictive toxicology new disruptive technology Enabling Predictive and Personalized Medicine Provide the right drug, to the right patient at the right dose

2 > Company Profile Enabling Predictive and Personalized Medicine Provide the right drug, to the right patient at the right dose

3 BioQuanta Team A multidisciplinary team : 26 employees + Consultants An independent group : 80% held by founders (3 scientists + 1 entrepreneur) SCIENTIFIC ADVISORY BOARD Dr. Marc Conti PhD, Pharm D Hospital practitioner at AP-HP, Biology, Biochemistry Pr. Sylvain Loric PhD Pasteur, Pharm D, Head of Biology Dept. at AP-HP, specialized in genetics Pr. Philippe Manivet PhD Polytechnique, Pharm D Hospital practitioner at AP-HP Biology, Bioinformatics Jean-Michel Mauclaire ESCP Europe, CPA CEO Thierry Gérardi MBA IAE Sorbonne Marketing, Comm., HR Remi Rabeuf MBA Managing Director MANAGEMENT Pr. Flavio Toma PhD Univ. Evry, structural biology CSO Thierry Delvienne Pharm D Admin., Sr. Mgmt., Business Dev. Europe LGC François Hamon Pharm D Finance advisor for biotech and pharma. Academic partnerships Copyright BioQuanta 03/2010. Tous droits réservés. 3

4 BioQuanta group BioQuanta SA is listed on NYSE-EURONEXT Paris, Marché libre BioQuanta Corp. Compagnie Holding BioQuanta SA Science as a service Kits de Diagnostic TheraQuanta Therapeutical molecules design & repositioning Bioinsignis Tracking and anticounterfeiting solution Copyright BioQuanta 03/2010. Tous droits réservés. 4

5 Our business model : 3 complementary pillars BioQuanta SA Therapeutics Services Diagnostic Pipeline 8 programs Scientific expertise Technological platfoms 1 patented kit : ADNc1 2 patents under submission R R R Cancer angiogenesis Antidepressant Alzheimer primary tumor cancer Infertility Anti-infectious/ HIV Malaria Chemokines ADME-Tox Prediction of molecule efficacy and toxicity Metabolic exploration Effects of exogen compound on cells or organism ADME-Tox Effects of a molecule on living organism UNDER DEVELOPMENT ADME-Tox Effects of a molecule on a programmed stem cell DIAGNOSTIC KITS ADNc1 MDA ADNc3 NMI ANGIM Standardisation PCR/Arrays COMPANION DIAGNOSTIC Ability to design and develop on demand companion Dx tests Traçabiliy / Anti-counterfeiting solution Copyright BioQuanta 10/2010. Tous droits réservés. 5

6 > Novel integrated approach Enabling Predictive and Personalized Medicine Provide the right drug, to the right patient at the right dose

7 Enabling predictive and personalized medicine to take place 1 Predictive Toxicity 2 Predictive ADME 3 Patient Categorization 4 Drug prescription & Monitoring Copyright BioQuanta 10/2010. Tous droits réservés. 7

10 Scalable modules for selecting the best compounds Nb. compounds 1000 Rapid screening 100 Prediction and ranking 10 Characterization 1 Toxicity check Copyright BioQuanta 10/2010. Tous droits réservés. 10

11 Enpoints list Carcinogenicity Mutagenicity Reproductive organs toxicity PBT, vp, vb Endocrine disruptor Cytotoxicity Genotoxicity Teratogenicity Cardiotoxicity (herg blockers) Hepatotoxicity Renal toxicity Gastrointestinal toxicity Lungs toxicity Neurotoxicity Irritancy Ocular Toxicity Respiratory Sensitization Skin Sensitization Ecotox: Algae Ecotox: Bird Ecotox: Daphne Ecotox: Fish Copyright BioQuanta 10/2010. Tous droits réservés. 11

12 3 unique technology components MultiDIP provides accurate and reliable toxicity predictions and characterizations based on : 1. A pharmacophore that represents isomeric and conformational variants of molecules 2. An extensive pharmacophore database of toxic compounds ( >1.7 million pharmacophores) 3. An extensive bibliographic system for an expert understanding of the biological context 03/01/2011 Copyright BioQuanta 10/2010. Tous droits réservés. 12

15 Molecular predictions from molecular models MultiDIP Toxicity Screening Based on a multidimensional representation of the entire molecule No pre-grouping required pharmacophores are directly compared for overlap in multiple dimensions No training set All relevant conformers and isomers can be screened Accurately represents geometric and electronic structure features important for binding Existing QSARs Mainly based on 2D fragments of an entire molecule Fragments are analyzed for statistical correlations with toxicity Require laborious pre-categorization of molecules to find the right QSAR Highly dependent on the training set Does not represent molecular flexibility (conformational contribution to binding) Does not capture whole-molecule electronic structure Copyright BioQuanta 10/2010. Tous droits réservés. 15

16 Shortcomings of 2D similarity 2D Versus 3D : Enantiomers Differentiation Example: Thalidomide (anxiolotic) Teratogenic Enantiomers S t a n d a r d A p p r o a c h B i o Q u a n t a s A p p r o a c h Thalidomide Classical 2D Structure (R)-Thalidomide (R) Enantiomer Mirror (S)-Thalidomide (S) Enantiomer 2D Structure It s not possible to differentiate enantiomers properties of molecules (R)-Thalidomide Pharmacophore 3D Pharmacophores Enantiomers properties differentiation is possible (S)-Thalidomide Pharmacophore Copyright BioQuanta 10/2010. Tous droits réservés. 16

17 Databases Application Reference compounds, targets Multidimensional models TOXICITY DSS TOX compounds 1,7 Million natural / non-toxic 1 million+ natural/non toxic ADME 120 relevant targets 1 million+ SAFETY PHARMACOLOGY 50 relevant targets 0,5 million+ PROFILING 2930 GPCR 500 ion channels and other targets 7,5 million+ Copyright BioQuanta 10/2010. Tous droits réservés. 17

18 DATA WHAREHOUSE : OLAP cube for fast analysis of data Extract, transform, and load data into the repository, and manage and retrieve metadata Allows manipulating and analyzing data from multiple perspectives Overcomes a limitation of relational databases Near instantaneous analysis and display of large amounts of data ZonoCube Copyright BioQuanta 10/2010. Tous droits réservés. 18

19 Toxicity Screening Process Virtual screening based on geodesic pharmacophore 1 2 Screening against database Data warehouse 2D/3D Pharmacophore 3 Screening Résults Copyright BioQuanta 11/2010. Tous droits réservés. 19

21 Scoring and analysis Compound input & parameter selection Pharmacophore screening Scoring and analysis Sample Hits from Screening: comparison of hit toxicity scores Screening Strategy : screen a compound on a single endpoint Screening Strategy : screen a compound on a several endpoints Copyright BioQuanta 10/2010. Tous droits réservés. 21

22 Bibliographic system Compound input & parameter selection Pharmacophore screening Scoring and analysis An automatically updated bibliographic system Hits from the screening are cross referenced to bibliographic entries on compounds with similar pharmacophores. The bibliographic references give the likely biological context of toxicity, helping you see the bigger picture. You get access to the studies that have already been published. You have decision guidance to efficiently design any additional testing required for the REACH dossier. Our database can also provide basic physicochemical data required by REACH in the IUCLID 5 XML format. BioQuanta, January All right reserved. 22

23 Sensitivity: true positive predictions World s highest level of reliability A benchmark study against major applications on the market shows a clear advantage for MultiDIP ROC Space : Mutagenicity prediction n= 501 compounds MultiDIP Tox benchmark results ; n=556 Nb. tested compounds 100% 80% 60% 40% 20% MultiDIP DEREK MC4PC 100% 80% 60% 40% 20% Specificity: true negatives Selectivity: true positives Nb comp. 0% 0% 20% 40% 60% 80% 100% Specificity: false positive 0% MLA (+) In Vitro Cytogenetics - Mutagenicity Carcinogenicity +: Mouse Lymphoma assay Actual and comparative results for this study are extracted from the following publication: Snyder. An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to in silico predictivity..environ. Mol. Mutagen. (2009) vol. 50 (6) pp

25 Toxicity Screening Process 1. Pharmacophore géodésique - technologie brevetée de modélisation - empreinte biologique 2. Entrepôt de données toxicologiques - criblage virtuel - recherche bibliographique sur les molécules similaires criblage virtuel 3. Expertise scientifique - analyse et interprétation des résultats - rapport d évaluation de toxicité - signature des résultats AIDE A LA DECISION Rapport signé Copyright BioQuanta 11/2010. Tous droits réservés. 25