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New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies, Nice, April 11-12, 2013 Michael Merz, Novartis Institutes for BioMedical Research

New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

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Page 1: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury:First insights from clinical qualification

Joint Conference of European Human Pharmacological Societies, Nice, April 11-12, 2013

Michael Merz, Novartis Institutes for BioMedical Research

Page 2: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 20132

Outline

DILI background

Shortcomings of current liver safety biomarkers, requirements for advanced markers

Biomarker qualification in the IMI SAFE-T consortium

Initial findings for new liver safety biomarkers

Biomarker discovery

Page 3: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

3

Kola et al. (2004), Nat Rev Drug Discovery; 3: 711-15

Development phase

Suc

cess

ra

te [

%]

Drug safety: room for improvementAttrition in drug development

• Around 90% of compounds entering clinical development fail

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

• 30% of these failures are due to clinical safety and toxicology

Page 4: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 20134

Nat Rev Drug Discovery 2012; 11(1): 17-18

Probability of success by development phase

AbuseCarcinogenic

Cardiovascular

Dermatologic

Drug interaction

Hematologic

Hepatic

Neurologic

PsychiatricRenal

Reasons for withdrawals

Drug Info J 2001; 35:293

Attrition rate over timeA universal and eternal constant?

• Do we have to live with losing e.g. 1/3 of drugs in phase III and 1/6 during submission??

• For decades, drug-induced liver injury has been one of the key safety issues in drug development and post marketing

Page 5: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

5

Trovafloxacin

1984Methaqualon

1991Triazolam

2004Rofecoxib

1962 Thalidomide

Terfenadine

Fenfluramine

AlosetronCisapride

Cerivastatin

1970

2001

1998

1997

2000

2006

2003

Iproniazid

1967

1982 1985 1996

2005

2007

Withdrawals

1959

Oxyphenisatin

Ibufenac BenoxaprofenTicrynafen

Perhexiline Alpidem

TolcaponeTolrestat

Bromfenac

TroglitazoneAmineptine Nefazodone

Pemoline

Ximelagatran

Lumiracoxib

Withdrawals due to drug-induced liver injury (DILI)Reducing treatment options for key disease areas

Diabetes

Cardiovascular disorders

CNS disorders

RA/OA

ConstipationInfections

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 6: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

6

Drug-induced liver injury (DILI) Key challenges

DILI is the leading cause of acute liver failure in the United States

In the post-approval setting, DILI is a leading cause of regulatory actions, including drug withdrawals, label changes and boxed warnings

Across the industry, we regularly loose promising candidates due to DILI• A part of those may be false positives

Of predominant concern are idiosyncratic, hepatocellular types of DILI• Non-dose dependent (?)

• Not predictable (as yet)

• High rate of liver failure, often fatal outcome

• Rare

A major issue is the lack of suitable markers allowing for • Early signal detection

• Mechanistic assessment

• Robust prediction of clinically relevant effects

• Risk assessment in individual patients

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 7: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

7

Standard liver tests: ALT, AST, AP, gGT, bilirubin Some shortcomings

Inadequate sensitivity and specificity

Limited predictive value, both from a translational and clinical outcome perspective

Do not allow for differentiation between injury, upregulation, reduced clearance

Half life of aminotransferases too long to allow for close monitoring and assessment of rapid changes in liver status

Aminotransferase activities frequently confounded by e.g. effect of different diets and different levels of physical exercise

Not supporting mechanistic understanding

Focusing on liver only, not taking into account immune system involvement

Clear need for alternative biomarkers of drug related liver injury.

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 8: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

8

Specific liver test attributes of interest

Patient level – Lower injury threshold

– Earlier time to onset

– Larger extent of changes

– Improved liver specificity

– Better suited to monitor and predict clinical outcome

– Better suited to assess causality

Population level – Earlier and more specific liver signal detection in clinical development programs

– Improved mechanistic insight

– Superior in terms of identifying underlying pathology

– Better suited to predict human risk from animal toxicity

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 9: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

9

Key challenges for biomarker qualification

Substantial background variability in initial candidate markers

Biomarker response varies across different populations

Large initial number of biomarker candidates requires substantial sample volumes to be taken

Cases with key target response, i.e. DILI, suitable and accessible for qualification, are overall very rare

Large sample sizes are required

Multitude of patient populations need to be included

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Qualification cannot be achieved by one company alone

Page 10: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

10

IMI SAFE-T ConsortiumObjectives

To evaluate utility of safety biomarkers for detecting, assessing, and monitoring drug induced kidney, liver, and vascular injury in humans

To develop assays and devices for clinical application of safety biomarkers

To compile enough evidence to qualify safety biomarkers for regulatory decision making in clinical drug development and in a translational context

To gain evidence for how safety biomarkers may also be used in the diagnosis of diseases and in clinical practice

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 11: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

11

SAFE-T participants

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Academia

CollaboratorsAdvisors

SMEs

Page 12: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201312

DILI BM step 1 list

Submit to health authorities

Literature

SAFE-T sources

DatabasesEvaluation

DILI BM step 2 list

Healthy volunteers

Patients non-liver disease

Patients liver disease

Patients hepatotoxic drugs

Samples

Regulatory advice

DILI BM f inal list

DILI BM step 3 list

Assay / stat analysis / select BMs

Regulatory advice

Regulatory approval

Select

SelectE

xplo

rato

ryp

has

eC

on

firm

ato

ryp

has

e

Assay / stat analysis / select BMs

Background variability

Thresholds

Assay availability / development

DILI BM step 4 list

Qualification

Assay / stat analysis / select BMs

SAFE-T Biomarker qualification processElements and process flow

Q2 2009

Q1 2010

Q2 2011

Q2 2014

Status Q

4 2012

Page 13: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

13

Background variability

Response to DILI

Response to non-liver disease

Response to non-DILI liver disease

High

Yes

No

Low Bad

Good

Exploratory phase Confirmatory phase

Drop

Drop

DropPathology?

Mechanism?

Disease severity?

Drug-relatedness?

Clinical outcome?

Information on...

DILI biomarker selection processTwo (& a half) stage approach

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Stage gate analysis

Page 14: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

14

Ongoing prospective clinical studiesPopulations and (some) key objectives

Multi-center international study in patients with suspected drug-induced liver injury• Sensitivity, specificity, predictive value (outcome), association with standard markers, time profiles

Single-center study in rheumatoid arthritis patients• Specificity, association with standard markers

Single-center study in patients with acute or myeloid lymphoblastic leukemia on chemotherapy• Sensitivity, specificity, predictive value (outcome), association with standard markers, time profiles

Multi-center study in patients after liver transplantation• Link to histopathology, association with fibrosis progression

Multi-center study in patients on antituberculosis treatment• Differentiation of susceptible patients from adaptors and tolerators

Multi-center Swiss study in patients with suspected drug-induced liver injury• Specificity, predictive value, association with genetic suspectibility markers

Single-center study in nevirapine-treated HIV patients • Differentiation of susceptible patients from adaptors and tolerators

Single-center study in acetaminophen-overdose patients• Predictive value (outcome), association with standard markers, time profiles, mechanistic understanding

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 15: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

15

Biomarker candidatesInitial selection

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Candidate markers Liver specificity Pathology

microRNA 122 Highly specific Hepatocellular injury

albumin mRNA Highly specific Hepatocellular injury

Microglobulin precursor (Ambp) mRNA Highly specific Hepatocellular injury

High mobility group (HMGB-1), hypo- and hyperacetylated forms Not specific Hepatocellular injury, inflammation

Cytokeratin 18, full length and caspase cleaved fragment Not specific Hepatocellular injury, necrosis vs apoptosis

Conj./unconj. bile acids Highly specific Cholestatic injury

Urocanic Acid Not specific Cholestatic injury, biliary hyperplasia

ALT1 & 2 Highly (ALT1) Hepatocellular injury

Glutamate dehydrogenase (GLDH) Specific Hepatocellular injury

Purine nucleoside phosphorylase (PNP) Specific Hepatocellular injury

Malate dehydrogenase (MDH) Not specific Hepatocellular injury

Glutathione S-Transferase (GST-alpha) Specific Hepatocellular injury

F-protein (HPPD) Highly specific Hepatocellular regeneration

Arginase 1 Highly specific Hepatocellular injury

alpha-fetoprotein Specific Hepatocellular injury

Regucalcin Specific Hepatocellular injury

alpha2,6-sialyltransferase (ST6gal) Specific Inflammation

Osteopontin Not specific Inflammation

Colony stimulating factor receptor (CSF1R) Not specific Inflammation

Paraoxonase 1 (PON1)/Prothrombin Specific Hepatocellular function

Leucocyte cell-derived chemotaxin2 (LECT2) Not specific Inflammation

Page 16: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

16

mir-122mir-192ALT

APAP/mouse

APAP/mouse

miR-122miR-192ALT

Blood-based microRNA biomarkers for DILIEvidence from preclinical models

miR-122

Liver tissue specific

Translatable to human

Earlier detection than ALT; greater sensitivity; less variability...

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Wang et al, PNAS, 2009Yi Zhang et al, Clin Chemistry, 2010

Courtesy Ina Schuppe Koistinen, Astra Zeneca

Page 17: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

17

He

alt

hy

Co

ntr

ols

AP

AP

NO

AL

I

CK

D

NO

N-A

PA

P A

LI

AP

AP

AL

I

He

alt

hy

Co

ntr

ols

AP

AP

NO

AL

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CK

D

NO

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PA

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LI

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alt

hy

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ols

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AP

NO

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CK

D

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PA

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LI

AP

AP

AL

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ols

AP

AP

NO

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CK

D

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LI

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NO

AL

I

CK

D

NO

N-A

PA

P A

LI

AP

AP

AL

I0.0001

0.01

1

100

10000

1000000 ****** ******

***

****

ALT miR-122 miR-192 miR-1 miR-218

non-APAP ALI:- autoimmune- HBV- HCV- Clarithromycin DILI

ALI: acute liver injuryCKD: chronic kidney diseaseAPAP: acetaminophen

Serum microRNAs as human DILI biomarkersSpecificity of miR-122 for liver injury

Starkey-Lewis et al., (2011)Hepatology 54:1767

Courtesy Jonathan Moggs, Novartis

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 18: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201318

Adapted with permission from Kaplowitz N, Nat Rev Drug Discov. 2005 Jun; 4(6): 489-99

Drug

Standard liver tests: focus on liver onlyNeed to account for mechanistic background

Hepatocyte/cholangiocyte markers

Immune system markers

Page 19: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

19

HMGB1 and Cytokeratin 18Mechanism based biomarkers

Apoptosis:• Keratin-18 – intermediate filament

protein / structural integrity• Is cleaved by caspases• Fragment released into blood• Full length K18 passively released

during necrosis

Necrosis and Inflammation:• HMGB1 – chromatin binding protein• Passive release by necrotic cells• Active release by activated immune cells

(hyper-acetylated (Lys NLS))• Cytokine activity (TLR/RAGE)

Antoine DJ et al., 2010 Mol MedAntoine DJ et al., 2009 Toxicol Sci

Slide courtesy Neil French, MRC CDSS

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 20: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

20 New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

KCC met

LogV

alue

5

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

-0.5

-1

-1.5

-2

AcetHMGB1

N Y47 31

-1.39794 0.382886CountMedian

Alpha level = 0.05Root MSE = 0.861sqrt(2)q* = 2.817

NecrK18

N Y47 31

4.35994 4.87509

Alpha level = 0.05Root MSE = 0.573sqrt(2)q* = 2.817

%Apoptosis

N Y47 31

1.24047 0.745432

Alpha level = 0.05Root MSE = 0.539sqrt(2)q* = 2.817

ALT (U/l)

N Y47 31

3.52969 3.66285

Alpha level = 0.05Root MSE = 0.498sqrt(2)q* = 2.817

Patients post acetaminophen overdose Markers for inflammation, necrosis, and apoptosis

Association with King‘s College Criteria for prognosis of acute liver failure

Based on Antoine DJ et al., 2012 J Hepat

Acetylated HMGB1 may be a prognostic DILI marker, indicating extent of inflammation

Caspase cleaved cytokeratin 18 may have value as a prognostic DILI marker, indicating involvement of apoptosis as protective mechanism

Page 21: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

21

Diagnostic value of Glutathione S transferase a (aGST)

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Glutathione S transferase a (aGST): • Inducible phase II detoxification enzyme

• Four isozymes of GST expressed in human and other mammals; aGST is a liver specific dimer expressed in human hepatocyte cytosol

• High concentration in centrilobular cells: may be more sensitive than ALT and AST

• Half life ~1 h in humans: may be useful for close monitoring

• Low molecular weight: release into plasma may occur earlier than for ALT and AST

Meta-analysis of four Novartis phase 1 studies using aGST for liver monitoring• 150 healthy subjects (108 m, 42 f), age 18 - 60, BMI 18 -32, duration 1-4 weeks

• Key objectives: o Analyse correlation of aGST levels with age, BMI, and aminotransferases at baseline, and with

aminotransferases during treatment (active drug and placebo)

o Characterize time profiles of aGST as compared to ALT and AST

o Explore to which extent aGST levels may be able to support causality assessment in case of elevated aminotransferases.

Page 22: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

22

Diagnostic value of Glutathione S transferase a (aGST)Preliminary results from Novartis meta-analysis

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Day corrected

Max

(ALT

n),

Max

(GS

Tn)

0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40

450

400

350

300

250

200

150

100

50

0

450

400

350

300

250

200

150

100

50

0

A-5105 A-5136

B-5110 B-5114

Color by

Max(ALTn)Max(GSTn)

Horizontal Line:

ULN

Vertical Line:

LastTreatment Day

• Time to onset of enzyme elevations may be marginally shorter with aGST

• In some patients, aGST returns to baseline faster , possibly supporting causality assessment

ALTnGSTnASTn

Treatment end

• Earlier onset and faster resolution?

• Helpful for causality assessment in a subset of cases?

Page 23: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201323

Initial, preliminary results of stage gate samplesCK18 full length and fragment, MCSF-R: DILI association

Population

Val

ue

50000

45000

40000

35000

30000

25000

20000

15000

10000

5000

0

ccKeratin 18 [U/L]

DILI HV RA54 91 30

752.409 207.692 146.87110 6 3

CountMedianOutliers

Alpha level = 0.05Root MSE = 2000.366sqrt(2)q* = 3.343

Keratin 18 [U/L]

DILI HV RA54 91 30

1236.05 127.338 120.0010 0 4

Alpha level = 0.05Root MSE = 10487.122sqrt(2)q* = 3.343

MCSF-R [ng/mL]

DILI HV RA30 24 30

3535.6 1101.37 1949.344 4 1

Alpha level = 0.05Root MSE = 3169.398sqrt(2)q* = 3.377

*MCSF-R=CSF1R: cytokine receptor, controlling macrophage proliferation and function

*

Significant associations with DILI

Page 24: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201324

Initial, preliminary results of stage gate samplesCK18 full length and fragment, MCSF-R: DILI (and gender?) association

Population

Va

lue

DILI HV RA DILI HV RA DILI HV RA

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

ccKeratin 18 [U/L]

50000

45000

40000

35000

30000

25000

20000

15000

10000

5000

0

Keratin 18 [U/L]

22000

20000

18000

16000

14000

12000

10000

8000

6000

4000

2000

MCSF-R [ng/mL] Color byGender

FM(Empty)

MCSF-R: association with DILI and gender?

Page 25: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201325

Initial, preliminary results of stage gate samplesCK18 full length and fragement, MCSF-R: absence of age dependency

Age

Va

lue

10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

ccKeratin 18 [U/L]

50000

45000

40000

35000

30000

25000

20000

15000

10000

5000

0

Keratin 18 [U/L]

22000

20000

18000

16000

14000

12000

10000

8000

6000

4000

2000

MCSF-R [ng/mL] Color byPopulation

DILIHVRA

Straight Line Fit:

DILI - Straight lineHV - Straight lineRA - Straight line

No associations with age

Page 26: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201326

Initial, preliminary results of stage gate samplesCK18 full length and fragement, MCSF-R: absence of BMI dependency

BMI

Va

lue

20 25 30 35 40 20 25 30 35 40 20 25 30 35 40

11000

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

ccKeratin 18 [U/L]

50000

45000

40000

35000

30000

25000

20000

15000

10000

5000

0

Keratin 18 [U/L]

22000

20000

18000

16000

14000

12000

10000

8000

6000

4000

2000

MCSF-R [ng/mL] Color byPopulation

DILIHVRA

Straight Line Fit:

DILI - Straight lineHV - Straight lineRA - Straight line

No associations with BMI

Page 27: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

27

Parallel to qualification: DILI biomarker discovery

Why?

Biomarker candidates do not cover all objectives of SAFE-T DILI WP

• Lack of susceptibility markers

• Lack of sensitive functional markers, some pathologies poorly represented

• Most markers identified in pre-clinical models

How?

Based on human DILI cases from SAFE-T clinical studies

Characteristic changes in serum proteome and metabolome expected

• Mass spec and protein antibody array analyses of plasma samples ongoing

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Page 28: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

28

Watkins Study: early predictive DILI markersStudy design and initial output

Healthy men and women (18-55 years) were treated with 4g acetaminophen/day for 7 days

17 subjects: responders (ALT >2.0 x baseline level)

15 subjects : intermediate responders (ALT 1.5-2.0 x baseline level)

18 subjects: non-responders (ALT <1.5 x baseline level)

Results Urine metabolite profiles prior or at start of

treatment not predictive of DILI

Urine profiles at day 5-6 (prior to raised ALT)

could distinguish responders from non-

responders

Predictive metabolites include APAP and

endogenous metabolites

Winnike JH, Li Z, Wright FA, Macdonald JM, O'Connell TM, Watkins PB. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther. 2010;88(1):45-51

O'Connell TM, Watkins PB. The application of metabonomics to predict drug-induced liver injury. Translational Medicine, 2010, 88(3): 394-99

New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

Courtesy Ina Schuppe Koistinen, AstraZeneca

Page 29: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201329

Watkins Study: early predictive DILI markersAdditional benefit of serum proteomics and metabolomics

Courtesy Ina Schuppe Koistinen, AstraZeneca

Day 12

Day 5 and 6

Day 8 and 9

Pre-dose

PLS-DA 1 PLS-DA 1

PLS-DA 1PLS-DA 1

PLS

-DA

2

PLS

-DA

2

PLS

-DA

2

PLS

-DA

2

ProteomicsMetabolomics

• LC-MS based profiling for compound and endogenous metabolites

• Suspension bead protein array (antibody based)

• Endogenous metabolites and protein profiles identified, that:

• Predict ALT elevations at baseline (susceptibility markers)

• Predict ALT elevations early during treatment

• Pathways involved

• Pyruvate and glutamate metabolism at baseline

• Cell death pathways activated at the time of ALT elevations

• Overlap with ximelagatran candidate biomarkers

Page 30: New biomarkers for drug-induced liver injury: First insights from clinical qualification Joint Conference of European Human Pharmacological Societies,

New biomarkers for drug-induced liver injury - M Merz - April 11, 201330

Conclusions

Advanced safety biomarkers for prediction, detection, and assessment of drug-induced liver injury (DILI) are urgently needed.

Due to the low incidence of DILI, large sample sizes across a range of different populations are required for clinical qualification of new markers.

Large scale public private partnerships involving industry, academia, small to medium sized enterprises, and regulators such as the IMI SAFE-T consortium may be the most efficient way to successful biomarker qualification.

A list of promising DILI biomarker candidates has been selected by the SAFE-T consortium for clinical qualification.

Preliminary data on a subset of markers offer first insights into potential predictive and diagnostic value.

Regulatory approval of new DILI biomarkers with defined contexts of use is expected by 2015.

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31 New biomarkers for drug-induced liver injury - M Merz - April 11, 2013

AcknowledgementsNeus Prats Marc Walton Axel Kretschmer Denise Robinson-Gravatt Martin Shaw Elisabetta Cargnello Ralf Schindler Ofer Eyal

Anna Domènech Hüseyin Firat Thomas Krahn Bernard Souberbielle Cormac Kilty Nicole Schneiderhan-Marra Ahmed Sheriff Ina Naumov

Eric Massana Kaïdre Bendjama Nicolas von Behr David Reynolds Vicky McGrath Hugo Hämmerle Rolf Seeland Ronni Gamzu

Pere Berga Marti Peter Thomann Heidrun Ellinger-Ziegelbauer Robin Privman Barry Hayes Günter Beck Theresa Klein Bernd Stowasser

Mariona Auli Attila Garami Matthias Gottwald Dominique Brees Rory Connolly Thomas Schweikert Thomas Berg Isabelle Clavier

Silvia Lopez Béatrice Molac Susanne Schwenke Ceri Collins Mark Pinches Jens Göpfert Florian van Bömmel Frederic Galli

Jose-Luis Diaz Fuat Firat Katja Matheis Erik Kuja David Brott Stefanie Rimmele Stefanie Frank Joachim Tillner

James Matcham Stella Suzanne Christine Rentzsch Andrew Zehner Ina Schuppe Koistinen Hannes Planatscher Sabine Boas-Knoop Xavier Benain

Alexandre Mencik Brice Suire Uwe Bamberger Shelli Schomaker Håkan Andersson Frank Dieterle Lina Badimon Joost Dwerhagen

Simon Gibbs Barbara Fischer Birgit Stierstorfer Cornelia Ciorciaro Anders Samuelsson Peter Hoffmann Teresa Padro Isabelle Pirani

Patrice Cacoub Dorina Bratfalean Arno Kalkuhl Laura Suter Dick Sally Price Michael Merz Xavier Sánchez-Vallve Catherine Lunven

David Saadoun John Haselden Joachim Stangier Piotr Szczesny Jesper Hedberg Robert Schmouder Nuria Nadal Olivier Pasquier

Damien Sene Andrew Nicholls Kristiane Wetzel Barbara Lenz Björn Glinghammar Ursula Knauf Gemma Vilahur Jean-Charles Gautier

Michel Buchert Elaine A. Irving Dr. Volker Mahlbacher Jacky Vonderscher Pierre Dönnes John Prince Silvia Gómez Nathalie Piton

Anne Skrobot Vincent Mooser Dorothee Schwall-Rudoph Lucette Doessegger Terry Reed Jeffrey Donohue Sandrine Schwartz Marie-Hélène Pascual

Florence Ghrenassia Fiona J McClure Marcus Kostka Manfred Argast Ann-Cathrine Jonsson-RylanderFrancois Legay Daniel Sanchez Muriel Breitbach

Thierry Poynard Aubrey Swain Nadine Erne Christoph Wandel Li-Ming Gan David Laurie Thomas Joos Sylvie Brohier

Mona Munteanu Theo Dare Andreas Port Rodolfo Gasser Jenny McKay Alexandre Avrameas Martina Kahnert Jean-François Gallas

Hugo Perazzo Ian Roman Ulf Neumann Bernhard Risse Jonas Bergström Marie Anne Valentin Jessica Mittelstädt Reinhold Stockbrugger

Servane de Penquer Federica Crivellente Maximilian Schmeding Rosemarie Kientsch-Engel Marcus Gry Philip Bentley Manfred Schmolz Bernard Levin

Laurent Becquemont David Howe Eveline Fräßdorf Thomas Schindler Harry Southworth Gerd Kullak-Ublick Thomas Knorpp Ali Yağız ÜRESİN

Benoit Labarthe Landry Cochard Janine Heyder Isabelle Gilet Scott Adler Franck Meyer Derek Leishman Hugh Laverty

Anne Gysembergh-Houal Marc Loher Volker Schmitz Nadir Arber Sif Ormarsdottir Steve Hall Sarah Chatham Kevin Park

Joe Keenan Christiane Andriamandroso Eckart Schott Sara Kraus Stephen Furlong Stefan Sultana Simon Harper Munir Pirmohamed

Camilla Stephens Maribel Lucena Patrick Murray Colin Green Magnus Nord Michael Lawton Paul Commander Neil French

Brooke Bergeron Jean-Marc Vidal Marisa Papaluca Raúl Andrade

SAFE-T consortium, in particular DILI work package

Kevin Park

Neil French

Daniel Antoine

Björn Glinghammar

Ina Schuppe Koistinen

Thomas Joos

Thierry Poynard

Hannes Planatscher

Jens Goepfert

Nicole Schneiderhan-Marra

Teresa Padro

Lina Badimon

Gerd Kullak-Ublick

Jonathan Moggs