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Make the right decisions with data you can trust
Instructions  for  attendees   ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],03/12/2010 CS du 3 décembre 2010
Agenda ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Aureus at a Glance ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],AUREUS Mission 03/12/2010 Webinar « Make the right decisions with data you can trust »
Aureus Value Proposition ,[object Object],[object Object],[object Object],[object Object],[object Object]
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which is estimated to be $136 billion annually in the U.S.  Over the past 10 years, 19 broadly used marketed drugs were withdrawn after presenting unexpected severe side effects, with Rofecoxib and Cerivastatin.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 We need Predictive tools for safety assessment Examples of drugs withdrawn because of CYP-related DDIs See the US Food and Drug Administration (FDA) site ( http://www.fda.gov/medwatch/safety.htm ) for an updated list QTC Prolongation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 ,[object Object],[object Object],[object Object]
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 ,[object Object],[object Object],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 ,[object Object],[object Object],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 ,[object Object],PASS :  P rediction of  A ctivity  S pectra for  S ubstances
Chemical Processing Biological Processing ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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

  • 1. Make the right decisions with data you can trust
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  • 8. Aureus Selected Customers & Main projects «  KnowTox  »
  • 9. 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.
  • 10. 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
  • 11. Aureus Approach for Safety Prediction 31/03/11 Cliquez ici pour changer le texte
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  • 14. 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%
  • 15. 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
  • 16. Outlier detection: publication error Test 4 Unit discrepency ERROR DETECTION AND CORRECTION
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  • 19. 31/03/11 Cliquez ici pour changer le texte Usage of Knowledge Base for Safety Prediction
  • 20. 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)
  • 21. 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)
  • 22. Biological diversity for CYP3A and CYP2D6 inhibitors 31/03/11 Needs of structured data for retrieving in vitro and in vivo parameter values
  • 23. 31/03/11  f m : Contribution of a particular enzyme to the overall clearance AUC ratio Sensitivity fm(E) Variability impact on DDI Predictions
  • 24. 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
  • 25. 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
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  • 28. Predicting Safety Pharmacology on 82 Selected Drugs 277 Ion Channels 82 Selected Molecules
  • 29. 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%
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  • 32. Thank you for your attention Aureus Sciences [email_address] 174, Quai de Jemmapes 75010 Paris, FRANCE www.a ureus-sciences.com

Hinweis der Redaktion

  1. Confidential
  2. Confidential