hypothesis: “basket trials” using pathology based outcome953b2c3f-fffb-4305-88d9... · synovium...
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Birmingham (BEACON, OASIS)
Oxford (NOC, TGU)
Coventry and Warwick
4 Disease Indications
(RA, SS, SpA and IBD)
Established cohorts
M40 A-TAP Clinical Research Network
New Cohorts
7 Million Patients
The Arthritis Therapy Acceleration Programme:
Hypothesis: “Basket Trials” using pathology based outcome measures will aid go-no-go decisions in IMIDs
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Pathological mechanisms (Pathway driven)
Rheumatoid arthritis Sjögren’s syndrome
IBD SpA
Cytokine Antigen Enzymes Signalling Cell death
Senescence
Clinical Diagnosis and management
(Organ based)
STRATIFIED PATHOLOGY
How to match clinical features to
underlying pathology
What is the problem ? “How to match right drug to the right disease
early in drug discovery”
Stratified medicine is about the right drug to the right patient Stratified pathology is about the right drug for the right disease
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The A-TAP “Right drug to the Right disease” In order to reveal new mechanistic insights
Salivary Gland
Enthesis synovium
Intestine
Organ-based Process-driven Pathway -focused
Basket Trials One drug
many indications (A-TAP)
Umbrella Trials One indication many therapies
“Umbrella trials : focus on a single disease or histo-type , but usually have multiple sub-trials within the umbrella framework, each testing a targeted therapy within a molecularly defined subset”
“Basket trials are an efficient way for screening experimental therapeutics across multiple patient populations and diseases in an early-phase of development”
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How does the A-TAP add value and where does it position itself in the experimental medicine landscape ?
Phase 1 (safety)
Phase 3
Phase 2
Current Approach
(3.6%)
Drug Discovery
Experimental
Pivotal/Regulatory
5 assets per year
1 asset per year
1:20 £20M per
study
Phase 1b
Phase 3
Phase 2a
Future Approach
(15%)
Time
Time
Process Driven-pathway focussed
19 assets fail: Why?
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The Arthritis Therapy Acceleration Programme
Birmingham (BEACON, OASIS)
Oxford (NOC, TGU)
Coventry and Warwick
4 Disease Indications
(RA, SS, SpA and IBD)
Established cohorts
Clinical Research Network
New Cohorts
7 Million Patients
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The Arthritis Therapy Acceleration Programme Outline Structure
Basket Basket
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Mean aggregate area and distribution
FDC, plasma cells presence
T/B cell segregation
T/B cell composition
Quantitative mRNA analysis
Vascular redistribution
Cell proliferation / Apoptosis
Change in pathology as the end point for “basket” trials
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Clinical outcomes.
18 months
Ultrasound
Guided Biopsy
Frozen Sections
Paraffin Sections
Cultured Fibroblasts
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Validation of Liquid Histology cassette: RA synovium at one time point has 16 cell subsets
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Validation of Liquid Histology Cassettes Three fibroblast subsets: Different in OA
Cluster 2 CD90+
Cluster 1 CD90+
Cluster 3 CD90-
Cluster 4
Cluster 5
Cluster 6
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What about Lymphocytes in histoflow ?
Sero Positive Sero Negative
Synovium Tonsil
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Dendritic cell
Stromal cell
T cell
B B
B
B
B
Epithelium
Time
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Focus score=No of foci/4mm2/Total area
Average Focus area =Total foci area/No of foci
Volume Fraction= Total focus are/Total area
Percentage of segregation= No segregated foci/No of foci
CD3 CD20
H&E Digital Histology: Sjogrens
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Liquid Histology : Sjogrens
On single cell suspension:
Flow cytometry
CyTOF
Functional experiments in vitro
Transcriptomics
Mass Spectrometry
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Malignant clone selection
MALT lymphoma (5% of the cases)
Oligo/Monoclonal proliferation
LESA
Polyclonal activation
GC-LS (20% of the cases)
Lymphocytic Infiltrate
Non specific activation
Good pathology outcome measures “Treat to Target: Treat to Pathology”
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Towards consensus and regulatory approval
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Eye, skin, enthesis in SpA
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Translational Gastroenterology Unit
Kennedy Institute
Oxford IBD Biobank
TGU
John-Radcliffe Hospital
Dr. Satish Keshav
Prof. Holm Uhlig
Prof. Simon Travis Animal Facilities
CyTOF
Botnar Institute
FACS facility
Wellcome Trust Centre
for Human Genetics
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The Arthritis Therapy Acceleration Programme Future Directions: The Goldilocks paradox ?
• Enable clinical research in four related IMIDs to be co-ordinated in a unified, systematic manner, taking shared and unique pathogenic processes into account for the first time. This will transform how future clinical studies are designed, approved by regulatory bodies and reimbursed by payers.
• A focus on process-driven-pathology rather than organ-based-disease will
bridge current knowledge gaps in disease aetiology and allow future research to match therapy to underlying disease pathology; a major “blind-spot” in current research strategies in IMIDs.
• Explore endorsement from patient partners, specialist societies, industry
and regulatory bodies to ensure rapid and widespread uptake and dissemination of our A-TAP Programme.
• Facilitate future collaborations and exchange of personnel across the
Experimental Arthritis Treatment Centre networks in the UK