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

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

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”

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?

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

The Arthritis Therapy Acceleration Programme Outline Structure

Basket Basket

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

Clinical outcomes.

18 months

Ultrasound

Guided Biopsy

Frozen Sections

Paraffin Sections

Cultured Fibroblasts

Validation of Liquid Histology cassette: RA synovium at one time point has 16 cell subsets

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

What about Lymphocytes in histoflow ?

Sero Positive Sero Negative

Synovium Tonsil

Dendritic cell

Stromal cell

T cell

B B

B

B

B

Epithelium

Time

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

Liquid Histology : Sjogrens

On single cell suspension:

Flow cytometry

CyTOF

Functional experiments in vitro

Transcriptomics

Mass Spectrometry

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”

Towards consensus and regulatory approval

Eye, skin, enthesis in SpA

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

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