International SAE Consortium, Ltd An Int ernat ional Indust rial Biomedical Consort ium Researching t he Genet ic Basis of Drug Relat ed S erious Adverse Event s JPDSC Meeting October 16, 2009 SAE Consortium 1
Introduction � Thank you for the invitation to speak � There exist both global and local opportunities for SAE research collaboration � My hope � to lay the seeds for greater Japanese collaboration with the International SAE consortium SAE Consortium 2
Presentation Overview � Perspective on ADR genetics � SAEC Overview � Results to Date: • DILI GWAS • Severe skin reactions GWAS • Initial PQT/TdP GWAS � SAEC Future directions SAE Consortium 3
4 Overview of ADR Genetics SAE Consortium
Many Factors May Influence ADR Risk Genetics Disease Age Other ADR Dose Meds Diet Environment Compliance SAE Consortium 5
Genetic Influence on ADR Risk Selected Examples Adverse Drug Reaction Genetic Risk Factor Drug Freq. 1 Effect 2 Reaction Prevalence Risk Allele Cardiovascular events 0.13 0.03 3 CYP2C19*2/ 3/ 4/ 5 Clopidogrel Diarrhea 0.28 ABCG2 Q141K 0.07 5 Gefitinib Hepatotoxicity 0.15 CYP2E1*1 & NAT2 0.13 3 7 Isoniazid Hepatotoxicity <0.001 0.20 10 Co-amoxiclav HLA-DRB1*1501 Neutropenia 0.20 0.32 28 Irinotecan UGT1A1*28 Hepatotoxicity (cholestatic) <0.001 0.14 36 Ticlopidine HLA-A*3303 Hyperbilirubinemia 0.12 0.30 48 Tranilast UGT1A1*28 Hepatotoxicity <0.001 0.04 81 Flucloxacillin HLA-B*5701 Severe cutaneous reaction <0.001 0.15 678 Allopurinol HLA-B*5801 Hypersensitivity reaction 0.08 0.04 >1000 Abacavir HLA-B*5701 Stevens-Johnson <0.001 0.04 >1000 Carbamazepine HLA-B*1502 SAE Consortium 6
Relevance of ADR Pharmacogenetics � Improve our understanding of the ADR mechanism � Better characterize ADR risk � Identify patients with higher ADR risk • Reduce dose • Increase monitoring • Prescribe alternative drug � Improve benefit:risk ratio SAE Consortium 7
8 SAEC Introduction SAE Consortium
SAEC’s Mission “ The S AEC will ident ify and validat e DNA- variant s useful in predict ing t he risk of drug induced serious adverse event s.” SAE Consortium 9
SAEC – Phase 1 Goal s � Support international network[s] in obtaining well phenotyped cases and controls for SAE PGx research [ discovery and validat ion ] � Develop optimal genotyping and sequencing approaches for SAE research � Evolve the computational methods necessary for effective GWAS analysis � Create a publicly available “knowledge base” of PGx markers predictive key SAEs � Manage IP relating to PGx markers useful in predicting SAEs to ensure broad and open access SAE Consortium 10
Current SAEC’s Membership [11] Spanish DILI EUDRAGENE Top 5 SAEs External Collaborators/Contributors Spanish DILI SAE Consortium 11
SAEC – Phase 1 ( S ept ` 07- June` 10 ) � Genotyping Core ( Expression Analysis, Lt d. ) � Data Analysis & Coordinating Center ( Columbia Universit y ) � Serious skin rash GWAS I � DILI network development & GWAS I � DILI cohort 2 GWAS I ( Abbot t ) � PQT/TdP cohort 1 GWAS ( DARE Net work ) � Angioedema cohort 1 GWAS ( S anofi-Avent is ) � DILI & agranulocytosis WG Sequencing Pilot � SAEC website & SAE GWAS public data releases (3) � Electronic health record ADR/SAE identification pilots (2) � Phase 2 planning SAE Consortium 12 12
SAEC Phase 1 Operational Perspective Core Investment SSR GWAS, Paper & DR1 DILI GWAS, Phase 1 Execution Papers (3) & DACC development � Dividends! DRs 2 & 3 SJS characterization & analysis � � DILI network expansion TdP GWAS, � DILI characterization & Paper (1) & A-E DRs 4 analysis GWAS, � Data release[s] Paper (1) & DRs 6 Phase 2 planning � Myopathy GWAS, Paper (1) & DILI & DRs 5 Agranulocytosis 09/07-12/09 Sequencing Pilots SAE Cohorts Members Pilots (3) EMR SAE Case Sourcing SAE Consortium Pilots (3) 13
SAEC Web Site � ht t p:/ / www.saeconsort ium.org SAE Consortium 14 14
SAEC Data Portal – Access & Size • Available: SSR1, DILI1, and POPRES • 79 requests for data access • 70 yes & 9 no [ research purpose not stated or no institutional affiliation/sign-off ] • 48% company scientist requests [top requesters] SAE Consortium
Pharmacos Sourced SAE Cohorts Pharma PMS & Clinical Trials Agranulocytosis Clinical SAEC Sponsored Trial Academic Research Clinical Clinical Networks [e.g. PQT] Pharma Safety Trial Trial Pharmaco Clinical Groups EMR Collaborations via HMO Trial Knowledg Control Clinical Clinical Research Network, VA Cerner Health Facts, etc SAER 1 Cohort Trial Trial GALT dsCapture Cohorts (2) • -Enrollment EMR Systems • -SAEC CRF EDC • -Informed Consent SAE SAER • -Sample Mgmt • -Other Central Lab DILI AHSS Pharmaco Pharma 5 Potential ? Cohorts Cohorts Columbia Database S A E C onsortium Ltd PQT/TDP Angio-Edema Pharmaco SSR Pharmaco 1 Cohort 1 Cohort Pharmaco 1 Cohort SAE Consortium 16
Sourcing SAE cases via Providers & EMRs Phase 1 Feasibility Project EMR SAE Case Sourcing � 2009-10 Feasibility Projects � Focus: Using EMR and associated VA Health System [7 million pts.] research systems to determine the feasibility of yielding high quality SAE cases. � SAE targets/3/collaboration [ of joint Cerner Health Facts interest ] [15 million pts.] Cerner � Hepatotoxicity, TdP/PQT, and • SSR VA � Hepatotoxicity and • Rhabdomyolosis/Myopathy HMORN HMORN � Hepatotoxicity, EWG, and SSR • 25 million pts. SAE Consortium 17
HMORN Sourced SAE Cohorts (Pilot) Pharma PMS & Clinical Trials Clinical SAEC Sponsored Trial Academic Research Clinical Clinical Networks [e.g. PQT] Pharma Safety Trial Trial Clinical Groups EMR Collaborations via HMO Trial Knowledg Clinical Clinical Research Network, VA Cerner Health Facts, etc SAER Trial Trial GALT dsCapture • -Enrollment EMR Systems • -SAEC CRF EDC • -Informed Consent SAE SAER • -Sample Mgmt • -Other Central Lab Health Partners Geisinger Columbia Database S A E C onsortium Ltd DILI EWG-Anti Psych Group Health Marshfield Cooperative Kaiser SAE Consortium SSR 18
19 Drug Induced Liver Injury Study #1 Phase 1 Results to Date [ DILI] SAE Consortium
Phase 1 DILI Discovery Project –as of 06/09 Clinical Cohort Sourcing Global DACC Diligen EUDRAGENE Columbia University 214 105 Cases Cases & Global SAEC GT Core SAEC Members Spanish DI LI Scotland 53 46 ~70 ~700 EA, Inc. Cases Cases Cases Controls Sweden (Bjornsson) Japan 4800 WTCCC Texas (Lee) 60+ (Takikawa ) 46 Controls 30 WGGT to date France Singapore ( Larrey) (Gee ) � Discovery Cases � ~ 500 50 25 � Population Controls � ~ 700 � WTCCC Controls � ~ 4800 SAE Consortium 20 20
21 SAEC DILI case profile (Sept-09) Total cases 505 % Female 296 (59%) Sex % Male 219 (41%) White/European 473 Race Other 32 UK 208 Spain 93 Country/ USA 65 origin for Scotland, UK 44 Europeans France 42 Italy 21 SAE Consortium
Total Phase 1 DILI Case Recruitment Samples genotyped through August 2009 Drug (group) Diligen EUDRA Scotlnd Malaga Abbott T otal Coamoxiclav 78 25 13 58 0 174 Flucloxacillin 70 0 6 0 0 76 Coamoxi or Fluclox 8 0 0 0 0 8 Zileuton 0 0 0 0 71 71 Diclofenac 25 3 0 0 0 28 IRPE 25 1 0 0 0 26 NSAIDs 0 33 0 0 0 33 Other 20 44 25 0 0 89 Total 226 106 44 58 71 505 SAE Consortium 22
DILI Controls Strategy � Country (or PCA) and sex-matched population controls at ~2:1 (control:case) ratio • Drawn from GSK Population Reference Sample (POPRES) � Draw on publicly available Illumina whole- genome genotype data to supplement • WTCCC (UK) ~4800 controls • Improve statistical power for modest effects SAE Consortium 23 23
Genetic structure of Caucasian subjects: 384 cases, 650 controls (after QC) UK Spain Italy SAE Consortium 24 24
Overview of DILI GWAS Analysis Drug / Number of cases Pending action Major Results Drug groups /controls items 77 UK cases / 282 1. HLA-B*5701 (OR ~ 80) is a major risk factor Flucloxacillin POPRES 2. Paper published in Nat ure Genet ics DR2 Tag SNP is associated, with genome- 1. wide significance (OR=2.5) 1. HLA 142 Caucasian cases / 2. Top associated SNP (OR=2.9) is in HLA class II sequencing 651 POPRES / 4900 Coamoxiclav region, and indicates a signal independent of cases WTCCC of DR2 2. Publication 3. Independent association in class I (OR=2.1) 14 Caucasian cases / Interesting association in chr 8 (OR=8; p=10^-6), Ant i-TB 282 POPRES close to gene NAT1 22 cases/282 controls None Diclofenac 10 cases/40 controls None COXIBS 12 cases /48 controls None NIMESULIDE 1. Publication Interesting association in chr 6 (OR=4; p=4x10^- All NS 57 cases/228 controls AIDs 6), close to genes IL22RA2 and IL20RA All cases not SAE Consortium Interesting but not genome-wide significant 151 cases / 650 caused by association of a SNP from chr 4 (OR=3; p=9x10^- controls flucloxacillin or 8), close to gene S LC34A2 coamoxiclav
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