Using Advanced Imaging Biomarkers to understand if your drug works

1. Using Advanced Imaging Biomarkers to understand if your drug works Dr. Olga Kubassova, Founder and CEO of Image Analysis 15/05/2013

2. Clinical Trials Today Time Pressure 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, which targets RANK ligand, a protein involved in the development of bony erosions in Rheumatoid Arthritis and bone loss in osteoporosis.  Ofatumumab (HuMax-CD20), GSK an infused biologic designed to reduce the number of B cells, which may decrease disease activity in Rheumatoid Arthritis Belimumab (Benlysta), Human Genome Sciences/GSK, which inhibits the activity of B-lymphocyte stimulator (BLys), a protein that causes B cells to grow in number and perhaps produce antibodies. Belimumab is in development for lupus as well as RA. Canakinumab (Ilaris), Novartis, 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 in clinical trials for Rheumatoid Arthritis and Juvenile Arthritis. Fostamatinib disodium, AZ, an agent that works by blocking the effects of a protein called sykkinase, which helps B-cells to mature. Fostamatinib disodium is in clinical trials for Rheumatoid Arthritis. Masitinib, AB Science, 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…. • 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 Rituxanbiosimilar, April 2013 • Head to Head Trials don’t always succeed: ‘AZ's fostamatinib inferior to Humira in mid-stage RA trial, 2012’ http://www.pharmatimes.com/article/12-12-13/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.’

3. 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.

4. 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

5. 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

6. 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 • synovitisis 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

7. Solution: • Sensitive Imaging to visualise the effect of treatment • Quantitative Imaging Methods to show the effect of treatment • Appropriate Infrastructure for multi-centres trials

8. 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

9. Quantitative Imaging + Infrastructure • Computer-aided Detection of tumors, lesions, inflamed tissues to speed up and standardize image reading • Metrics are quantified and objective • Computer support allows for over 95% reproducibility of the results • Ability to detect even slightest changes to analyse the impact of treatment early • Comprehensive set of imaging markers to build treatment response profile to it differentiate from the competition Data Management Image Assessment / Biomarker Reading Quality Control 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)

10. 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

11. Automated Detection and Quantification 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 iMAPs with Dynamika, Image Analysis Brain Tumors

12. Comprehensive assessment of DCE-MRI dataset from RA patient TONSET – 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 GD – Contrast Uptake Pattern highlights regions where contrast was absorbed, retained and was quick to diffuse out of tissues over time. IRE- Initial Rate of Enhancement highlights the how quickly contrast was absorbed IRW – Initial Rate of Washout highlights how quickly 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. Automated mapping of inflammatory activity with Dynamika’s parametric maps

13. Automated Detection and Quantification Osteoarthritis Cardiac Perfusion Nail bed inflammation in PsA Brain Tumors Prostate Cancer Imaging Data Analysis

14. Use of Dynamika in a Clinical Trial

15. 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: info@imageanalysis.org.uk www.ImageAnalysis.org.uk