Predicting Drug Candidates Safety : the Role and Usage of Knowledge Bases

Make the right decisions with data you can trust

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Predicting Drug Candidates Safety :
the Role and Usage of Knowledge Bases
03/12/2010 CS du 3 décembre 2010

Agenda
Aureus Sciences
Build Knowledge Base for Safety Prediction
General Approach
Quality
Examples :
Drug drug interactions
Safety Pharmacology
Usage of Knowledge Base for Safety Prediction
Prediction of Drug Drug Interactions
Prediction of Off target effect

Aureus at a Glance
Aureus is a knowledge and information management solutions provider for the Life Science industry located in Paris.
Over the past 10 years the company has developed a unique knowledge production platform which stores, indexes and organizes critical chemical and bioactivity information including experimental vitro and vivo protocols from the public or private literature.
Aureus employees 20 high level scientists (PhD and MSc) including scientific and IT project leaders and documentation analysts
Aureus is funded by institutional investors like CDC Entreprise, AXA Provate Equity, OTC Asset Management and is part of the OSEO Excellence innovation team.

To help our customers in the Life Science Industry to develop new innovative and safe drugs
by providing
Solutions which enable them to take the best advantage of the existing scientific knowledge
and therefore
Optimize processes, predict new opportunities as well as new risks of their R&D projects
AUREUS Mission 03/12/2010 Webinar « Make the right decisions with data you can trust »

Aureus Value Proposition
We offer a unique combination of scientific, IT, and knowledge management assets and experience to :
Assist companies in the Life Science Industry to define the scope and scientifc context of their information needs
We ensure the development of high level scientific databases focusing on experimental data in the areas of medicinal chemistry, drug biologics, drug safety, ADME/TOX, pharmacovigilance
We assist on the integration of such databases in customers IT infrastructure or other software applications for further analysis, predictions or simulations
We develop applications to mine and visualise the data

Aureus Selected Customers & Main projects « KnowTox »

Safety and Adverse Effects 31/03/11 Cliquez ici pour changer le texte Every year about 2 million patients in the United States are affected by a serious adverse drug reaction. This results in approximately 100,000 fatalities, making ADRs the fourth leading cause of death in the U.S. The consequence is a huge burden on national economies, which is estimated to be $136 billion annually in the U.S. Over the past 10 years, 19 broadly used marketed drugs were withdrawn after presenting unexpected severe side effects, with Rofecoxib and Cerivastatin.

DDI and Safety Problem? We need Predictive tools for safety assessment Examples of drugs withdrawn because of CYP-related DDIs See the US Food and Drug Administration (FDA) site ( http://www.fda.gov/medwatch/safety.htm ) for an updated list QTC Prolongation QTC Prolongation QTC Prolongation QTC Prolongation Toxicity Toxicity Toxicity Toxicity

Aureus Approach for Safety Prediction 31/03/11 Cliquez ici pour changer le texte

Standardization ≠

Unstructured date vs Structured knowledge base
Articles Patents
Simulation studies
Experimental studies

Quality Control: cross validation CHEMICAL MANUAL QUALITY CONTROL BIOLOGICAL MANUAL QUALITY CONTROL SCORE >5% NO NEW CROSS VALIDATION <5% YES Knowledge Database BATCH SAMPLE 50%

Quality Control : Statistical Approach Sql request: Definition of the set of data responding to specific criteria (parameter, protocol, substance, target…) Robust Grubbs Test ISO 5725-2 OUTLIERS Decreased number of false positives Multiplication factor to median

Outlier detection: publication error Test 4 Unit discrepency ERROR DETECTION AND CORRECTION

AurSCOPE Knowledge Databases Target Pharmacological Space 2002 2004 2005 2008 2009
Aureus Terminology, Glossary, Thesaurii
>70 glossaries and dictionaries, 5-10 taxonomies, >65,000 terms and synonyms, I UPHAR, SwissPROT
GPCR Biological Protocols Unique Ligands Biological Activities Publications Analyzed Kinase Ion Channel Nuclear Receptor Protease 146,426 354,323 670,407 1,243,793 10,206 including 6,806 patents 13,303 including 6,966 patents 32,588 including 15,281 patents 4,668 including 2,484 patents 98,439 275,044 4,226 including 1,060 patents 418,202 124,313 186,047 48,500

AurSCOPE Knowledge Databases ADME/DDI & TOX Biological Protocols Unique Ligands Biological Activities Publications Analyzed hERG ADME/DDI Hepatotox
Aureus Terminology, Glossary, Thesaurii
>100 glossaries and dictionaries, 5-10 taxonomies, >65,000 terms and synonyms, I UPHAR, SwissPROT
13,887 34,872 compounds including 4,050 metabolites 33,210 462,785 2,291 including 547 Patents 12,165 including 200 FDA Reviews 3,600 Articles (67 patents, 75 FDA Studies) 70,035 845 Drugs

31/03/11 Cliquez ici pour changer le texte Usage of Knowledge Base for Safety Prediction

Prediction Of DDIs : Approach DDI? AurSCOPE ADME/DDI Laboratory Marketed and Preclinical drugs In vitro Data Metabolism Inhibition PK Data Animal Human In vitro Data Metabolism Inhibition PK Data Human My drug IND Phase 1 Phase 2 Phase 3 NDA Phase 4 Discovery DDI Predict Profile of DDI (~100) In (2-3 minutes)

Aureus Pharma Confidential All CYPs Data Needed for DDI predictions Competitive inhibition Metabolism by different pathways (fm(E)) Mechanism-based inactivation (MBI) Inhibitor concentration [I] at the enzyme active site : - [I]in,max, [I]in,avg, Cmax, Cavg - fraction unbound in plasma (fu b ) - Non equilibrium conditions (Kp,Kb, C/M) CYP3A Inhibition of gut « first pass » metabolism (F’g/Fg) Competitive inhibition Metabolism by different pathways Mechanism-based inactivation (MBI)

Biological diversity for CYP3A and CYP2D6 inhibitors 31/03/11 Needs of structured data for retrieving in vitro and in vivo parameter values

31/03/11  f m : Contribution of a particular enzyme to the overall clearance AUC ratio Sensitivity fm(E) Variability impact on DDI Predictions

Prediction Accuracy 31/03/11 MSM : DDI Predict 2009 Edition MSM DDI predict 2009 Percent Correct (>2 fold DDI <2 fold no DDI) 81 Percent within two fold 76 Percent under predict 4 Percent over predicted 20 MFE 1.69 RMSE 5

Safety Pharmacology 31/03/11 Cliquez ici pour changer le texte Off Targets are unwanted pharmacology activity of drug candidate on various targets related to adverse effects . The hERG-related K+ channel, the 5-HT2B receptor, or the PXR nuclear hormone receptor are typical examples which fall into this category. Extensive in Vitro Safety Pharmacology Profiling can be quite expensive (in the order of about $3000-$10,000 for a panel of 50-100 targets. To offset this there is increasing interest in in silico methods, which do not require any underlying functional knowledge, to predict possible ADRs

Predicting Safety Pharmacology
AurPASS® is a ready-to-use software tool running with several SAR bases extracted from the Aureus knowledge bases. These include GPCR, Kinase, Ion Channel 3 , Nuclear Receptor, Protease, and hERG. Aureus specialists extract the SAR cases continuously and finetune them with the PASS algorithms to provide the highest quality predictions.
PASS : P rediction of A ctivity S pectra for S ubstances

Chemical Processing Biological Processing
No Peptides
No mixtures
Inorganic and metalo-organic removal
Charge standardization
Biological protocols
Target hierarchy
Target species, cell lines and tissues
Biological activity parameters
Ligand action on target
Added value of structured data for safety prediction

Predicting Safety Pharmacology on 82 Selected Drugs 277 Ion Channels 82 Selected Molecules

Prediction Accuracy using AurPASS Training Set: 47 938 molecules 517 Activity Types Mean Accuracy of Prediction: 98% Test Set: 2244 molecules 113 Activity types Mean Accuracy of Prediction: 90%

Prediction Accuracy using AurPASS

Aureus Services & New Projects
On demand database and searching systems
Immunogenicity
Biologics
Hepatotox
Cardiotox
Transporters, etc…
On demand Reports and Studies
Target & Compound Reports: Extract and provide specific datasets
Drug Repositioning Studies (Pharmacology Profiles)
Drug Drug Interaction Reports
Strengths
Great reputation for high quality products and scientific excellence
“ Data that you can trust”
Oncology Database
Inflammation/Allergy/Immunology

Thank you for your attention Aureus Sciences [email_address] 174, Quai de Jemmapes 75010 Paris, FRANCE www.a ureus-sciences.com

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Predicting Drug Candidates Safety : the Role and Usage of Knowledge Bases

by Aureus Sciences on Mar 31, 2011

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Predicting Drug Candidates Safety : the Role and Usage of Knowledge Bases — Presentation Transcript