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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 - 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
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
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
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
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
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
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
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
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
11
SAFE-T participants
New biomarkers for drug-induced liver injury - M Merz - April 11, 2013
Academia
CollaboratorsAdvisors
SMEs
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
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
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
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
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
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
I
CK
D
NO
N-A
PA
P A
LI
AP
AP
AL
I
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
I
CK
D
NO
N-A
PA
P A
LI
AP
AP
AL
I
He
alt
hy
Co
ntr
ols
AP
AP
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
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
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
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
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.
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?
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
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?
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
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
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
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
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
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.
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