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Translation of Safety Biomarkers in the Clinical Setting
Michael MerzNovartis Institutes for BioMedical Research
Ina Schuppe KoistinenGlobal Safety Assessment, AstraZeneca R&D, Sweden
Coordinators IMI SAFE-T consortium
24th AnnualEuroMeeting
26-28 March 2012Copenhagen, Denmark
DisclaimerThe views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.
These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.
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Outline
• IMI SAFE-T Consortium: brief overview
• Status 2012
• Clinical biomarker qualification program
• Focus drug-induced liver injury: biomarkercandidates
• Initial experimental results
• Collaborations
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The IMI SAFE-T* ConsortiumScope
Three organs needing better clinical monitoring ofdrug-induced injuries:
Kidney: current standards increase only once 50-60% of kidney function is lost.
Liver: current standards are not sufficiently sensitive and specific and do not adequately discriminate adaptors from patients at high risk to develop liver failure.
Vascular System: currently no biomarkers available for drug-induced vascular injury in human.
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*Safer And Faster Evidence-based Translation
• Patient level – Lower injury threshold
– Earlier time to onset
– Larger extent of changes
– Improved specificity
– Better suited to monitor and predict clinical course
– Better suited to assess causality
• Population level – Earlier and more specific 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
Biomarker attributes of interest
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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
• Key target responses, i.e. specific adverse drug reactions, suitableand accessible for qualification are overall very rare
Large sample sizes are required
Multitude of patient populations need to be included
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Qualification cannot be achieved by one company alone
SAFE-T participantsAcademiaAcademia
CollaboratorsCollaboratorsAdvisorsAdvisors
SMEs
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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 safetybiomarkers
• 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
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Funding and timing
Financing• IMI funding: 13.9 mio EUR• EFPIA contribution, mainly in kind: 17.7 mio EUR• Contribution academia/SME: 4.1 mio EUR
• Total project cost: 35.7 mio EUR
Timing:• Starting date: June 15, 2009• Duration: Five years
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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
Select
Expl
orat
ory
phas
eCo
nfirm
ator
yph
ase
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
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Biomarker identification
Assay identification
Required sample sizes
Target populations
Biomarker qualification
Pathologies of interest
Assay development
Database costs
Investigative sites
Number and design of clinical studies
Capabilities
EFPIA studies with add-on sampling
Prospective studies Retrospective samples
Incidence of target disease
Sampling and shipment processes
Sample matrices and volumes
Drug selection
Data capture, management, analysis
Number of study sites needed
Number of patients needed
Biomarker submission
Recruitment ratesData management resources
Extent of in-kind support required
Type of in-kind support required
Biomarker qualification processInitial challenges
Technology platform
Data entry resources
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Key achievements at project half-time
• Biomarker candidates prioritised, assay development well advanced
• Central biobank for sample storage up and running
• Database and data capture system up and running
• Academic sites: 17 prospective clinical studies initiated
• EFPIA partners:
– Completed SAFE-T studies: 2
– Retrospective samples: >6500 patients from 4 studies
– Ongoing add-on sampling: 3 studies
– Submitted or under preparation: 5 studies
• Initiated regulatory interactions via briefing meetings with EMA/FDA
• Established collaboration with Predictive Safety Testing Consortium (PSTC)
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Clinical partners • Patient / sample codes
• Guidelines for sample collection and processing, shipment instructions
Samples
Biomarker assay group
Sample request
Sample approval team
Data analysis group
Patient – sample information
Regulatory requirements group
29 studies planned
1538 aliquots
SOPs, informed consent
10 studies, >60,000 aliquots
Samples
SAFE-T biobank: up and running
Approval of sample release
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SAFE-T database: up and running
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DILI biomarkers – status of assay developmentCandidate biomarker
miRNA 122albumin mRNAMicroglobulin precursor (Ambp) mRNA
High mobility group box 1 (acetylated vs. non-acetylated)Conjugated/unconjugated bile acids
High mobility group box 1 (acetylated vs. non-acetylated)ALT 1 & 2, isoform specificF-protein (HPPD)Arginase 1Keratin 18 (caspase cleaved & intact)Alpha fetoprotein (AFP)Regucalcin (RGN)Glutathione S-Transferase (GST-alpha)ST6gal IOsteopontinColony stimulating factor receptor (CSF1R)Paraoxonase 1 (PON1)ProthrombinLECT2
Glutamate dehydrogenase (GLUD, GLDH)Purine nucleoside phosphorylase (PNP)Malate dehydrogenase (MDH)Sorbitol dehydrogenase (SDH)ALT1/2, isoform specificAc
tivity
ass
ayRN
ALC
MS
Imm
unoa
ssay
Status
Ready for sample screeningReady for small sample sizesOptimization phaseIn developmentDevelopment necessary
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HMGB1 and Cytokeratin 18Mechanism based biomarkers
Apoptosis:• Keratin‐18 – intermediate
filament protein / structural integrity
• Is cleared by caspases• Fragment released into blood• Full length K18 passively released
during necrosis
Necrosis and Inflammation:• HMGB1 – chromatin binding protein• Passive released by necrotic cells• Active released 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
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Patients post acetaminophen overdoseMarkers for inflammation, necrosis, and apoptosis
Association with King‘s College Criteria 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
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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 planned
• Genetic analysis not planned, but possible collaboration with iDILIC
IMI SAFE-
T
CollaborationKey to success
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PSTC
SAFE-T
Biomarker qualification
fNIH
SAEC
DILIN
? ? ? ?
• SAFE-T is collaborating closely with C-Path‘s Predictive Safety TestingConsortium (PSTC), utilizing synergies and preventing overlaps
• There may be more opportunities to expand collaboration, helping toincrease efficiency and maximize output
Conclusions
• Qualification of new safety biomarkers can best be done in a setting of large scale pre-competitive collaborations such as the IMI-SAFE-T consortium, PSTC, and others alike
• The IMI SAFE-T consortium has made significant progress during thepast 2.5 years
• Consortium systems and processes for sample collection, processing, storage, shipment, and analysis have been set up and are running well
• Data capture, storage, management, and analysis tools are in place
• Seventeen prospective clinical studies have been initiated, but need toincrease recruitment
• SAFE-T may serve as an encouraging example to establish furtherprecompetitive collaborations focusing on drug safety
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Kevin ParkNeil FrenchDaniel Antoine
Thomas Joos
Hannes PlanatscherJens GoepfertNicole Schneiderhan-Marra
Teresa PadroLina Badimon
AcknowledgementsEric 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- Francois 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
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