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Using Advanced Imaging Biomarkers to understand if your drug works
Dr. Olga Kubassova, Founder and CEO of Image Analysis
15/05/2013
Clinical Trials TodayCompetitionBaminnercept (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 syk kinase, 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….
RegulatoryLate 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’ 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.’
Budget Cuts
Time Pressure
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:
• Sensitive Imaging to visualise the effect of treatment
• Quantitative Imaging Methods to show the effect of treatment
• Appropriate Infrastructure for multi-centres trials
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.
Dr. Mikael Boesen, MD
Parker Inst.
Copenhagen, Denmark
Dr. Olga Kubassova
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
Prof. Peter Taylor,
Kennedy School of Rheumatology,
Oxford, UK
Nikolay Tzaribachev, MD
Tuebingen, Germany
Dr Omer Aras, Phd
Sloan Kettering
Cancer Centre, NY, USA
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
StudyReporting
QualityAssurance
DataAnonymization
Upload
Centralization
Quality Control
AssessmentImage
/ BiomarkerReading
DataManagement
Validation: over 40 papersUsed: world-wide, over 25 installations in clinics and support of major clinical trials
Regulatory: Class Iia, CE, ISO13485, CRF21-11 (pending), FDA510K (pending)
Baseline Day 1 Day 2 Day 7
Boesen, M; Kubassova, O et al, Arthritis 2011
Earliest Efficacy Indication, RA:
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
Radiological Assessment of the Rheumatoid Arthritis knee with DEMRIS, Dynamika: imaging remission on Day 2
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
Brain Tumors
iMAPs with Dynamika,
Image Analysis
Comprehensive assessment of DCE-MRI dataset from RA patient
ME – Maximum Enhancement
highlights tissues that retain
contrast where red indicates low
or no inflammatory activity and
white/yellow high activity.
GD – Contrast Uptake Pattern
highlights regions where contrast was
absorbed, retained and was quick to diffuse out of tissues over
time.
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
IRE- Initial Rate of
Enhancement highlights the how quickly contrast was
absorbedIRW – 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
Prostate Cancer Imaging Data Analysis
Cardiac Perfusion
Brain Tumors
Osteoarthritis
Nail bed inflammation in PsA
Use of Dynamika in a Clinical Trial
In a Trial Operations Marketing
Analysis and interpretation of medical images is more reliable, less reader-dependent, and easier to accomplish.
Faster data allow better patient monitoring and coordination between sponsor and sites
Increased reliability of the quality of the imaging data to support regulatory filings.
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
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 less patients, faster data lock and immediate cost saving
Supportive evidence to Pricing and reimbursement committees
Direct access to retrospective data set to perform additional analysis for therapy assessment
Full transparency over project activities near real time information, rapid feed –backs to the sites.
Seamless translation of results into clinical practice
@OlgaKubassova or @ImageAnalysisUK
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
