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, 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….
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’
http://www.pharmatimes.com/article/1
2-1213/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 Xray 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
Dr Omer Aras,
Phd
Dr. Mikael
Boesen, MD
Sloan Kettering
Parker Inst.
Cancer Centre,
NY, USA
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 coauthored 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
Data
Management
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
Image
Assessment
/ Biomarker
Reading
Quality Control
Comprehensive set of imaging
markers to build treatment response
profile to it differentiate from the
competition
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
Brain Tumors
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
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
Automated Detection and Quantification
Osteoarthritis
Cardiac Perfusion
Nail bed inflammation in PsA
Brain Tumors
Prostate Cancer Imaging Data Analysis
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
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
Less training is needed
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