Using Advanced Imaging Biomarkers

to understand if your drug works

Dr. Olga Kubassova, Founder and CEO of Image Analysis 15/05/2013

Clinical Trials Today Competition

Baminnercept (BG9924), Biogen,

an agent in development for rheumatoid arthritis (RA) and lupus , which targets lymphotoxin-beta, a component on the surface of cells that signals the inflammatory process to begin.

Denosumab (AMG 162), Amgen

erosions in osteoporosis .

Ofatumumab (HuMax-CD20), GSK

disease activity in , which targets RANK ligand, a protein involved in the development of bony Rheumatoid Arthritis and bone loss in an infused biologic designed to reduce the number of B cells, which may decrease Rheumatoid Arthritis

Belimumab (Benlysta), Human Genome Sciences/GSK

antibodies. Belimumab is in development for , which inhibits the activity of B-lymphocyte stimulator (BLys), a protein that causes B cells to grow in number and perhaps produce lupus as well as RA .

Canakinumab (Ilaris), Novartis,

in clinical trials for which targets the proinflammatory cytokine interleukin-1 beta (IL-1β). Approved for a rare autoimmune disorder called cryopyrin-associated periodic syndrome (CAPS), canakinumab is currently Rheumatoid Arthritis and Juvenile Arthritis.

Fostamatinib disodium, AZ

Rheumatoid

Masitinib, AB Science,

Arthritis.

, an agent that works by blocking the effects of a protein called syk kinase, which helps B-cells to mature. Fostamatinib disodium is in clinical trials for which inhibits the activity of mast cells, which become activated and contribute to joint inflammation in RA . Masitinib is taken orally and has been in clinical trials for RA.

……Lexicon Genetics, Pfizer,Galapagos, Vertex, Morphosys, Lilly, Rigel/AstraZeneca, Takeda, Abbvie….

Time Pressure Budget Cuts Regulatory

Late Phase Trials Fail:

‘Trial with HuMax-CD4 in Patients With Rheumatoid Arthritis Failing Treatment With Methotrexate and a TNF-alpha Blocker’, Celltrion terminates European Phase III trial of Rituxan biosimilar, April 2013

Head to Head Trials don’t always succeed:

‘AZ's fostamatinib inferior to Humira in mid-stage RA trial, 2012

2-12-

’

http://www.pharmatimes.com/article/1 13/AZ_s_fostamatinib_inferior_to_Humira _in_mid-stage_RA_trial.aspx

‘AstraZeneca has suffered another clinical setback after its investigational rheumatoid arthritis pill fostamatinib failed to match the efficiency of Abbott's blockbuster Humira.’

•

Why Clinical Trials Fail?

The compound is ineffective.

• The dose or the dosage schedule administered is ineffective • The compound is administered at the wrong time in the disease process .

• The trial population group may be inappropriate for demonstrating the effect of the agent.

• The outcome measures used to determine drug effect may lack the sensitivity to detect a change

.

X-ray

• Use of X-ray will only allow seeing late manifestations of the inflammatory disease (such as bone erosions in Rheumatoid arthritis studies) • Markers extracted from X-rays will certainly not make your drug efficacy competitive

Use of Advanced Imaging - MRI

MRI allows seeing early disease

manifestations:

-synovitis or oedema in Rheumatoid Arthrits, which precede erosions. Erosions themselves will be shown on X ray up to 2 years after they were seen in MRI -Tumors at earlier stages in MRI of breast patients

Quantification of MRI with sensitive metrics However, application of insensitive or qualitative metrics to quantify MRI will not make the full use of the information provided by MRI

If tumours are quantified using simplistic RESIST criteria (in effect measuring tumour diameter) gives a very crude measure of tumour shrinkage but doesn’t assess inflammatory activity synovitis is measured by visually making a judgement of how much activity there is in the joint or using manual placement of Region of Interest, the measurements done by 2 people will have up to 25% variation

Solution:

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Sensitive Imaging to visualise the effect of treatment

•

Quantitative Imaging Methods to show the effect of treatment

•

Appropriate Infrastructure for multi-centres trials

Dr Omer Aras, Phd Sloan Kettering Cancer Centre, NY, USA Dr. Mikael Boesen, MD Parker Inst.

Copenhagen, Denmark Prof. Peter Taylor, Kennedy School of Rheumatology, Oxford, UK Nikolay Tzaribachev, MD

Tuebingen,

Germany

IA team and Independent Clinical Advisory Board have worked in close collaboration with clinical specialists and radiologists specialising in MSK, Oncology, Neurology and Cardiology focusing on

quantification of inflammation and perfusion.

Olga is a CEO of IA, which she founded in 2007 after completing her PhD on ‘Development of Algorithms for Dynamic MRI Data Analysis’ UK. Olga co authored of over 40 papers, 5 book chapters and books. Olga and the Clinical Board oversee each clinical trial design to ensure

the most effective use of imaging Dr. Olga Kubassova

Quantitative Imaging + Infrastructure

Computer-aided Detection of tumors, lesions, inflamed tissues to speed up and

standardize image reading

Metrics are

quantified and objective

Data Management

Computer support allows for over 95% reproducibility

of the results Ability to detect even slightest changes to

analyse the impact of treatment early

Image Assessment /Biomarker Reading Quality Control

Comprehensive set of imaging markers to build

competition treatment response profile to it differentiate from the

Validation: over 40 papers Used: world-wide, over 25 installations in clinics and support of major clinical trials Regulatory: Class Iia, CE, ISO13485, CRF21-11 (pending), FDA510K (pending)

Earliest Efficacy Indication, RA:

Radiological Assessment of the Rheumatoid Arthritis knee with DEMRIS, Dynamika:

imaging remission on Day 2

Baseline Day 1 Day 2 Day 7 Radiological Assessment of the Rheumatoid Arthritis knee with RAMRIS: Synovitis: Baseline: 1; Day 1: 1; Day 2: 1, Day 7: 1: no response to treatment Boesen, M; Kubassova, O et al, Arthritis 2011

Automated Detection and Quantification

iMAPs with Dynamika, Image Analysis Fully Automated Detection of tumor in DCE-MRI of breast using Dynamika’s pixel-by-pixel iMAPs approach: - In colours, active inflamed tissues, redder colours show less activity, bright, yellow colours more Brain Tumors

Comprehensive assessment of DCE-MRI dataset from RA patient

GD – Contrast Uptake Pattern

highlights regions where contrast was absorbed, retained and was quick to diffuse out of tissues over time.

Contrast Absorption

Time highlights the initial time point where contrast was absorbed into tissues

– TWASHOUT – Time of Washout

highlights the start point where contrast diffuses out of tissues

ME – Maximum Enhancement

highlights tissues that retain contrast where red indicates low or no inflammatory activity and white/yellow high activity.

IRE- Initial Rate IRW of Enhancement

highlights the how quickly contrast was absorbed

– Initial Rate of Washout

highlights how quickly contrast diffuses out of tissues

Automated mapping of inflammatory activity with Dynamika’s parametric maps

Automated Detection and Quantification

Cardiac Perfusion Nail bed inflammation in PsA Osteoarthritis Brain Tumors Prostate Cancer Imaging Data Analysis

Use of Dynamika in a Clinical Trial

In a Trial Operations

Analysis and interpretation of medical images is to accomplish.

more reliable, less reader-dependent, and easier Faster data allow better patient monitoring and coordination between sponsor and sites Lower variability and bias across readers Less training is needed Reduction of missing, lost or incomplete data leading to stronger statistical power and reduction of number of patients to enrol

Marketing

Increased reliability of the quality of the imaging data to support regulatory filings .

Robust dossier to support approval from Health Authorities Better evaluation of the drug candidate / new therapeutic strategy efficacy . Improved go/no go decisions Technology support allows immediate cost saving less patients, faster data lock and Direct access to retrospective data set to perform additional analysis for therapy assessment Full transparency activities near real time information, rapid feed –backs to the sites.

over project Supportive evidence to Pricing and reimbursement committees Seamless translation of results into clinical practice

Summary

• Dynamika is a powerful tool used to support superior image analysis • We provide full support for imaging trials and improve the accuracy, objectivity and standardization of the image reading allowing for – Detection of even slightest changes, which otherwise might have been missed – Automating routine reading and saving time and costs • • Platform validated in over 40 publications and by major pharma, KOLs and physicians CE mark granted by BSI in 2011, FDA510K pending @OlgaKubassova or @ImageAnalysisUK E: [email protected]

www.ImageAnalysis.org.uk