JPDSC Meeting October 16, 2009 SAE Consortium 1 Introduction - - PowerPoint PPT Presentation

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JPDSC Meeting October 16, 2009 SAE Consortium 1 Introduction - - PowerPoint PPT Presentation

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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

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SLIDE 1

SAE Consortium

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

1

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SLIDE 2

SAE Consortium

2

Introduction

Thank you for the invitation to speak There exist both global and local

  • pportunities for SAE research

collaboration My hope to lay the seeds for greater Japanese collaboration with the International SAE consortium

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SLIDE 3

SAE Consortium

3

Presentation Overview

Perspective on ADR genetics SAEC Overview Results to Date:

  • DILI GWAS
  • Severe skin reactions GWAS
  • Initial PQT/TdP GWAS

SAEC Future directions

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SLIDE 4

SAE Consortium

4

Overview of ADR Genetics

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SLIDE 5

SAE Consortium

5

Many Factors May Influence ADR Risk

Environment

ADR

Genetics Age Dose Compliance Diet Disease Other Meds

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SAE Consortium

6

Genetic Influence on ADR Risk

Selected Examples

Drug Adverse Drug Reaction Genetic Risk Factor

Reaction Prevalence Risk Allele

  • Freq. 1

Effect2

Clopidogrel Cardiovascular events 0.13

CYP2C19*2/ 3/ 4/ 5

0.03 3 Gefitinib Diarrhea 0.28

ABCG2 Q141K

0.07 5 Isoniazid Hepatotoxicity 0.15

CYP2E1*1 & NAT2

0.133 7 Co-amoxiclav Hepatotoxicity <0.001

HLA-DRB1*1501

0.20 10 Irinotecan Neutropenia 0.20 UGT1A1*28 0.32 28 Ticlopidine Hepatotoxicity (cholestatic) <0.001

HLA-A*3303

0.14 36 Tranilast Hyperbilirubinemia 0.12 UGT1A1*28 0.30 48 Flucloxacillin Hepatotoxicity <0.001 HLA-B*5701 0.04 81 Allopurinol Severe cutaneous reaction <0.001

HLA-B*5801

0.15 678 Abacavir Hypersensitivity reaction 0.08 HLA-B*5701 0.04 >1000 Carbamazepine Stevens-Johnson <0.001

HLA-B*1502

0.04 >1000

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SLIDE 7

SAE Consortium

7

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

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SLIDE 8

SAE Consortium

8

SAEC Introduction

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SLIDE 9

SAE Consortium

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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.”

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SLIDE 10

SAE Consortium

10

SAEC – Phase 1 Goals

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

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SAE Consortium

11

Current SAEC’s Membership [11]

Top 5 SAEs

External Collaborators/Contributors

EUDRAGENE Spanish DILI Spanish DILI

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SLIDE 12

SAE Consortium

12

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

12

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SAE Consortium

SAEC Phase 1 Operational Perspective

Phase 1 Execution

  • DACC development
  • SJS characterization & analysis
  • DILI network expansion
  • DILI characterization &

analysis

  • Data release[s]
  • Phase 2 planning

09/07-12/09

13

SSR GWAS, Paper & DR1 DILI GWAS, Papers (3) & DRs 2 & 3 TdP GWAS, Paper (1) & DRs 4 Myopathy GWAS, Paper (1) & DRs 5 A-E GWAS, Paper (1) & DRs 6

Dividends!

EMR SAE Case Sourcing Pilots (3) SAE Cohorts Members Pilots (3)

Core Investment

DILI & Agranulocytosis Sequencing Pilots

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SLIDE 14

SAE Consortium

14 14

SAEC Web Site

ht t p:/ / www.saeconsort ium.org

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SAE Consortium

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]

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SLIDE 16

SAE Consortium

Pharmacos Sourced SAE Cohorts

S A E C

  • nsortium Ltd

SAE Clinical Trial Clinical Trial Clinical Trial Clinical Trial Clinical Trial Clinical Trial

Pharma Safety Groups

Central Lab Columbia Database GALT dsCapture

  • -Enrollment
  • -SAEC CRF EDC
  • -Informed Consent
  • -Sample Mgmt
  • -Other
SAER SAER EMR Collaborations via HMO Research Network, VA Cerner Health Facts, etc SAEC Sponsored Academic Research Networks [e.g. PQT] EMR Systems Knowledg

Pharma PMS & Clinical Trials

DILI Pharmaco 5 Potential Cohorts PQT/TDP Pharmaco 1 Cohort Angio-Edema Pharmaco 1 Cohort SSR Pharmaco 1 Cohort AHSS Pharma ? Cohorts

16

Agranulocytosis Pharmaco 1 Cohort Control Cohorts (2)

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SLIDE 17

SAE Consortium

Sourcing SAE cases via Providers & EMRs Phase 1 Feasibility Project

EMR SAE Case Sourcing

Cerner Health Facts [15 million pts.]

2009-10 Feasibility Projects Focus: Using EMR and associated

research systems to determine the feasibility of yielding high quality SAE cases.

SAE targets/3/collaboration [of joint

interest]

  • Cerner Hepatotoxicity, TdP/PQT, and

SSR

  • VA Hepatotoxicity and

Rhabdomyolosis/Myopathy

  • HMORN Hepatotoxicity, EWG, and SSR

17

VA Health System [7 million pts.] HMORN 25 million pts.

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SLIDE 18

SAE Consortium

HMORN Sourced SAE Cohorts (Pilot)

S A E C

  • nsortium Ltd

SAE Clinical Trial Clinical Trial Clinical Trial Clinical Trial Clinical Trial Clinical Trial

Pharma Safety Groups

Central Lab Columbia Database GALT dsCapture

  • -Enrollment
  • -SAEC CRF EDC
  • -Informed Consent
  • -Sample Mgmt
  • -Other
SAER SAER EMR Collaborations via HMO Research Network, VA Cerner Health Facts, etc SAEC Sponsored Academic Research Networks [e.g. PQT] EMR Systems Knowledg

Pharma PMS & Clinical Trials

Group Health Cooperative Marshfield Kaiser

18

Health Partners Geisinger

DILI SSR

EWG-Anti Psych

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SAE Consortium

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Phase 1 Results to Date Drug Induced Liver Injury Study #1 [ DILI]

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SAE Consortium

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Phase 1 DILI Discovery Project –as of 06/09

EUDRAGENE

&

105 Cases SAEC Members ~70 Cases ~700 Controls Clinical Cohort Sourcing Global DACC Global SAEC GT Core

EA, Inc. Columbia University

Diligen

4800 WTCCC Controls Spanish DI LI

53 Cases

Scotland

46 Cases

Texas (Lee) 46 Sweden

(Bjornsson)

60+ Japan

(Takikawa)

30 Singapore

(Gee)

25 France

(Larrey)

50

20

WGGT to date

Discovery Cases ~ 500 Population Controls ~ 700 WTCCC Controls ~ 4800 214 Cases

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SAE Consortium

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SAEC DILI case profile (Sept-09)

Total cases 505 Sex

% Female 296 (59%) % Male 219 (41%)

Race

White/European 473 Other 32

Country/

  • rigin for

Europeans

UK 208 Spain 93 USA 65 Scotland, UK 44 France 42 Italy 21

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SAE Consortium

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Total Phase 1 DILI Case Recruitment

Samples genotyped through August 2009

Drug (group) Diligen EUDRA Scotlnd Malaga Abbott T otal Coamoxiclav 78 25 13 58 174 Flucloxacillin 70 6 76 Coamoxi or Fluclox 8 8 Zileuton 71 71 Diclofenac 25 3 28 IRPE 25 1 26 NSAIDs 33 33 Other 20 44 25 89 Total 226 106 44 58 71 505

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SAE Consortium

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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
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SAE Consortium

24 24

Genetic structure of Caucasian subjects: 384 cases, 650 controls (after QC)

UK Spain Italy

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SAE Consortium

Overview of DILI GWAS Analysis

Drug / Drug groups Number of cases /controls Major Results Pending action items Flucloxacillin

77 UK cases / 282 POPRES 1. HLA-B*5701 (OR ~ 80) is a major risk factor 2. Paper published in Nat ure Genet ics

Coamoxiclav

142 Caucasian cases / 651 POPRES / 4900 WTCCC

1. DR2 Tag SNP is associated, with genome-

wide significance (OR=2.5) 2. Top associated SNP (OR=2.9) is in HLA class II region, and indicates a signal independent

  • f DR2

3. Independent association in class I (OR=2.1) 1. HLA sequencing

  • f cases

2. Publication

Ant i-TB

14 Caucasian cases / 282 POPRES Interesting association in chr 8 (OR=8; p=10^-6), close to gene NAT1 1. Publication

Diclofenac

22 cases/282 controls None

COXIBS

10 cases/40 controls None

NIMESULIDE

12 cases /48 controls None All NS

AIDs

57 cases/228 controls Interesting association in chr 6 (OR=4; p=4x10^- 6), close to genes IL22RA2 and IL20RA

All cases not caused by flucloxacillin or coamoxiclav

151 cases / 650 controls Interesting but not genome-wide significant association of a SNP from chr 4 (OR=3; p=9x10^- 8), close to gene S

LC34A2

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SAE Consortium

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Flucloxacillin DILI (51 Northern European cases)

Top SNP: rs2395029 Case genotypes 4/39/8 P-value 10-30 Allelic OR 14 Dominant OR 35 MAF in controls 0.05 Tags HLA-B*5701 r2 = 1 Daly et al. (2009) Nat. Genet. 41:816-9

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SAE Consortium

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Coamoxiclav DILI: All Caucasians from four cohorts

  • 142 cases, 651 POPRES controls
  • MHC II: the association of top SNPs from are

genome-wide significant

  • Previous data: Association to

DR2 (HLA-DRB1*1501-DQA1*0102-DQB1*0602)

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SAE Consortium

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Coamoxiclav DILI: MHC region

HLA-A HLA-DRB1 ~ DQB1

Representative SNP @ MHC II Position chr:Mb OR P-value Genome-wide adjusted P-value P-value conditioned

  • n rs3135388 (DR2)

rs9274407 6:32.74 2.9 1.2e-10 < 0.0003 0.0004 rs3135388 (DR2) 6:32.52 2.5 4.8e-8 0.022 NA

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SAE Consortium

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MHC region: conditioned on rs9274407

HLA-A HLA-DRB1 ~ DQB1

Class I SNP Position Chr:Mb Logistic regression Conditioned on Class II (rs9274407) P OR P OR Adjusted-P in MHC rs2523822 (A* 0201) 6:29.9 2.7e-7 2.1 6.0e-7 2.1 0.001 rs1632933 6:29.9 2.6e-6 0.5 4.3e-5 0.55 0.048

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SAE Consortium

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Anti-TB: 14 UK cases, 282 controls

Inter-genic, between ASAH1 and NA T1

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SAE Consortium

Zileuton-DILI: summary of genotyped cases (77) leukotriene synthesis inhibitor -- Asthma

Ethnicity White 70 Black 5 Other 2 Gender Female 48 Male 29 Age 48 ± 15 Max ALT (xUNL) 7.8 ± 6

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SAE Consortium

Zileuton-DILI: selecting controls based

  • n PCA (66 cases, 235 controls)

Northern- Central EU (57 cases, 203 controls)

Italian s??

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SAE Consortium

Zileuton-DILI: Results: All Caucasians

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SAE Consortium

Zileuton-DILI: Top associated SNPs

All Caucasians (66 cases, 235 controls) NC-EU (57 cases, 203 controls) Updated cohort (58 cases, 207 controls) MAF in WTCCC 2 (~4800) MAF in UK POPRE S (282) SNP Chr: Mb Gene P-value MAF contr

  • ls

OR P-value MAF contr

  • ls

OR P MAF OR rs12464471 2: 63.5 C2orf86 / MDH1 / UGP2 etc 5.4e-8 0.14 4.3 1.9e-7 0.15 4.3 9.9e-8 0.14 4.6 0.22 0.18 rs12470478 2: 63.6 1.1e-7 0.16 3.9 2.1e-7 0.16 4.2 2.7e-7 0.16 4 0.24 0.20 rs7671181 4: 21.3 KCNIP4 2.3e-6 0.17 3.1 2.0e-6 0.18 3.5 2e-5 0.18 2.9 0.24 0.23 rs12600361 17: 72.6 C17orf86 / SCARNA1 6 5.8e-6 0.043 5.1 2.5e-6 0.04 6.7 5.9e-6 0.048 5.3 0.066 0.059 rs10915448 1: 4.1 None 5.5e-6 0.25 3.1 2.4e-6 0.24 3.5 0.00015 0.25 2.7 0.28 0.26

Note: all SNPs are nominally associated with the second eigen vector

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SAE Consortium

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Phase 1 Results Serious Skin Rash Study #1 [ SJS/TEN]

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SAE Consortium

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Phase 1 SSR Discovery Project – June` 09

GSK Cohorts 73 Cases

RegiSCAR

&

400 Cases Japan NI HR ~69 Clinical Cohorts Global DACC Global SAEC GT Core

EA, Inc.

Discovery Cohort 81

Columbia University

140 Controls Small Collabs 18 Cases

EUDRAGENE

Italy 20 GATC 19 8 Cases

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SAE Consortium

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SSR Case Summary

Samples provided from GSK SJS/TEN & Italian study 91 case & 141 control subjects enrolled [independent adj udicat ion 275 pot ent ial t o 73

act ual cases]

Mean age of subjects: 41.2 yrs Female (68.5%), Male (31.5%) Ethnicity: White (79.5%), Black (9.6%), Hispanic (5.5%), Asian (2.7%) >40 different drugs cited as being associated with onset of SJS/TEN

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SAE Consortium

SJS Caucasians: Population Structure

Southern European Population Northern/Western European Population

  • PGX40001 SJS (52 cases, 96 controls),
  • Italian (19 cases)
  • HapMap TSI (88 controls)
  • POPRES southern EU (21 controls)
  • LAM30004 (5 cases, 52 controls),
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SAE Consortium

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SSR n-EU group: 49 cases /4980 controls (6/09)

chr 7, position 7767212, p-value = 5.8×10-8, OR: 3.7; MAF in cases vs controls: 0.32 vs 0.11 Adjusted p-value = 0.11

39

SNPs chr Position Genes Function of the genes rs17137412

7 7767212

RP A3

cellular response to replication stress and DNA damage. immunoglobulin diversification

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SAE Consortium

SJS/TEN population structure

Previously:

40

More precisely:

evec 1 evec 2

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SAE Consortium

Updated 10/09 SSR top associated SNPs

41

SNP Chr: Mb Type closest gene Overall cases (71 vs 417 ) n-EU cohort (46 vs 4250) s-EU cohort (22 vs 80) logistic Fisher Exact test logistic Controls MAF p-value OR Controls MAF p-value OR Controls MAF p-value OR

rs981946 Chr 6: 3.3 Intronic SLC22A23 0.32 8.6E-07 2.7 0.36 0.002 1.9 0.29 0.0065 2.8 rs1079284 Chr 6: 3.3 Intronic SLC22A23 0.32 8.6E-07 2.7 0.36 0.002 1.9 0.29 0.0065 2.8 rs17137412 Chr 7: 7.8 Intronic RPA3 / GLCCI1 0.12 0.00022 2.3 0.11 1.3E-08 4.0 0.12 0.52 0.66 rs4532807 Chr 5: 162 Intronic ATF6 0.046 0.00003 2.7 0.036 2.8E-05 4.5 0.056 0.31 0.32

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Recent Associations -- SCAR and HLA Variants

Patients Drugs Diseases SNPs Odds etc. 56 White Carbamazepine DIHS HLA-B*1502 All neg. 8 White Carbamazepine SJS/TEN HLA-B*1502 All neg. 4 Asian Carbamazepine SJS/TEN HLA-B*1502 All pos. 60 Han Carbamazepine SJS HLA-B*1502 1357 51 Han Allopurinol SCAR HLA-B*5801 580 31 White Allopurinol SJS/TEN HLA-B*5801 80 (61%)

3 Japanese Allopurinol SJS/TEN/DIHS HLA-B*5801 All pos. 40 Japanese Multiple SJS/TEN HLA-A*0206 5.5 Genetic [HLA] marker variance across ethnicity & drug

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SAE Consortium

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Phase 1 Initial Results TdP/PQT Study #1 [ DARE]

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SAE Consortium

44

Initial SAEC TdP/PQT GWAS Study Goals

Complete a initial investigation into PGx markers

associated with TdP/PQT in Caucasians/three major drug groups [Q4` 09]

To identify potential genetic marker(s) of clinical

significance (i.e. which would be observable in relatively small numbers of patients).

Establish the foundation for an international network

(IDILQTC) to further study the genetics of TdP/PQT.

[Q4`09]

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SAE Consortium

DARE cohort: clinical attributes

45

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SAE Consortium

DARE: selecting genetically matched controls

  • 97 cases selected as UK
  • 282 POPRES UK

controls

46

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SAE Consortium

TdP GWAS: preliminary result

47

97 UK cases vs 282 controls Fisher’s exact test

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SAE Consortium

Top Associated SNPs

Regions

  • Chr 2: close to TPO
  • Chr 4: associated with AF (potential

confounding factor)

Similar p-values were acquired when including ~4K WTCCC2 controls

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SAE Consortium

49

Acknowledgments

Members

  • Brian Spear [Abbott]
  • Rick Scheyer [Daiichi Sankyo]
  • Lon Cardon [GSK]
  • Nadine Cohen [J&J]
  • Joanne Meyer [Novartis]
  • Aidan Power [Pfizer]
  • Klaus Lindpaintner [Roche]
  • Robert Dix [Sanofi-Aventis]
  • Leonardo Sahelijo [Takeda]
  • Michael Burczynski [Wyeth]
  • Janet Woodcock [FDA]
  • ShaAvhree Buckman [FDA]
  • Michael Dunn [Wellcome Trust]

SMC

  • Ann Daly & DILIGEN [Newcastle]
  • Mariam Molokhia & EUDRAGENE [London]
  • Matt Nelson [GSK]
  • Sally John [Pfizer]
  • Yufeng Shen [Columbia]
  • Itsik Pe’er [Columbia]
  • Aris Floratos [Columbia]
  • Mark Daly [Harvard/Broad]
  • David Goldstein [Duke]
  • Eric Lai [ex-GSK]
  • Donald Halbert [Abbott]
  • Joe Walker [D-S]
  • Nadine Cohen, Quingqin Serena Li, & Adrian Thomas [J&J]
  • Joanne Meyer & Steve Lewitzky [Novartis]
  • Klaus Lindpaintner & Karen Wilcock [Roche]
  • Steven Kovacs [Sanofi-Aventis]
  • Leonardo Sahelijo [Takeda]
  • Ted Burczynski & Maha Karnoub [Wyeth]
  • Robert O'Neill & Steve Wilson [FDA]
  • Andrea Califano [Columbia]
  • Allen Roses [Duke]
  • Elijah Behr [St. George’s London]
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SAE Consortium

50

SAEC Phase 2 “The Future – 2010-2012”

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51

Future Directions

Complete pilot studies in

  • PQT/TdP
  • Agranulocytosis
  • Angioedema
  • Rhabdomyolisis

Expand SSR network Expand DILI network Develop Prolonged QT/Torsades de Pointes network Initiate acute hypersensitivity reaction network Support the Phenotype Standardization Project Leverage EHRs and health networks to recruit cases Incorporate member collections and external data

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SAE Consortium

SAE Research Priority Ranking [2/09] 1- Highest, 9- Lowest

52

Top Priority – Network Support

Medium Priority – Via Collabs/ Min. I nvestment

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SAE Consortium

Disease spectrum, with potentially important common genetic factors

Drug Induced Immunologic SAEs

An Integrated Model of Genetic Predisposition

Maculopapular eruption

SSR Tolerant

SJS and TEN Hypersensitivity syndrom e Death Extra-cutaneous

  • rgan involvem ent

( Liver, Kidney ,Lung)

Source: Munir Pirmohamed et al , modified by SAEC

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54

Genetic Influence on ADR Risk

Selected Examples

Drug Adverse Drug Reaction Genetic Risk Factor

Reaction Prevalence Risk Allele

  • Freq. 1

Effect2

Clopidogrel Cardiovascular events 0.13

CYP2C19*2/ 3/ 4/ 5

0.03 3 Gefitinib Diarrhea 0.28

ABCG2 Q141K

0.07 5 Isoniazid Hepatotoxicity 0.15

CYP2E1*1 & NAT2

0.133 7 Co-amoxiclav Hepatotoxicity <0.001

HLA-DRB1*1501

0.20 10 Irinotecan Neutropenia 0.20 UGT1A1*28 0.32 28 Ticlopidine Hepatotoxicity (cholestatic) <0.001

HLA-A*3303

0.14 36 Tranilast Hyperbilirubinemia 0.12 UGT1A1*28 0.30 48 Flucloxacillin Hepatotoxicity <0.001 HLA-B*5701 0.04 81 Allopurinol Severe cutaneous reaction <0.001

HLA-B*5801

0.15 678 Abacavir Hypersensitivity reaction 0.08 HLA-B*5701 0.04 >1000 Carbamazepine Stevens-Johnson <0.001

HLA-B*1502

0.04 >1000

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SAE Consortium

International DILI Consortium Phase 2 Network (Example)

&

SAEC Members / Pharmacos

Web Based Clinical Network

SAEC DACC

DNA Repository

TBD based

  • n RFP

Guru Aithal & Ann Daly

300 Cases

Spanish Network

VA HMORN SAEC Members / Pharmacos

DI LI I nvestigator Network [8] – Bjornsson, Takikawa, Gee, & Larrey, etc.

SAEC Genomics Core

TBD based

  • n RFP

TBD based

  • n RFP

Japanese NI HR Cerner 2b

DI LI N NI DDK

I nt. TB Study Menzies et al (Montreal)

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56

SAEC Phase 2 -- “Membership Targets” [Goal = 10]

Four Major SAEs

Potential + Phase 2 Members

Phase 1 Members

X

No

Yes Yes Yes

IP IP IP

Yes

IP

Yes

IP

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57

SAEC – Phase 2 Formation Timetable

3 months 6 Months

  • 1. Program Definition & Initial Organization
  • 2. Commitment of 10 funding members
  • 3. SRA/Research Collaborations Development and Consortium

Development

  • 4. Consortium Agreements: Finalization & Sign Off

SAEC Phase 2 Launch!

Dec ` 09

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SAE Consortium

58

Thank You