fshd: clinical trial preparedness - treat-nmd tawil... · 2018. 10. 10. · fshd clinical trial...
TRANSCRIPT
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FSHD: Clinical Trial Preparedness
Rabi Tawil, MD
University of Rochester Medical Center
FSHD Clinical Trials Readiness Workshop
Newcastle, October 31, 2013
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Developing an FSHD Clinical Trial Toolkit
Why now?
Establishment of a unifying molecular
mechanism with potential therapeutic targets
Possible early phase human trials in 3-5 yrs.
Establishing and optimizing outcome measures
takes time
Old methods not good enough for regulatory
agencies: increasing emphasis on clinical
relevance
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FSHD: Genetic defect
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Molecular Mechanism: De-repression of DUX4 Gene Expression
SMCHD1-
DUX4
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Effects of DUX4 Expression
DUX4 is a transcription factor: activates genes
normally expressed only in the germline: cancer
testis antigens, genes involved in protein
degradation and muscle atrophy, genes involved
in the innate immune system
Highly toxic causes apoptotic cell death
Interferes with myogenic differentiation
Makes cells more susceptible to oxidative stress
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FSHD Trial Preparedness Workshop
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Thirty participants from five countries: US, UK, France, The Netherlands, Italy and Denmark
Advocacy groups: FSH Society (USA), FSH Europe and whil Research Foundation (Canada)
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FSHD Clinical Trial Toolkit: Workshop Goals
Immediate Workshop goals:
Discuss ways of optimizing patient access to
clinical trials
Reach consensus on the most promising clinical
and biomarker outcome measures to pursue.
Other:
Establish whether different outcome measures for FSHD2
are needed.
Establish whether different outcome measures for
childhood onset FSHD are needed.
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FSHD Clinical Trial Toolkit: Workshop Goals
Long Term Workshop Goals:
Validate/qualify selected outcome measures
Establish an FSHD clinical trials network with the
following aims:
More efficient testing and validation of outcome measures
in FSHD
Establishing the infrastructure for future FSHD trials: an
asset in NIH or pharma sponsored studies.
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Patient Access to Clinical Trials
Little difficulty in recruiting FSHD patients in prior
trials.
Multiple trials may make more difficult to recruit subjects
FSHD is very slowly progressive: unless one is expecting large
therapeutic effects, large numbers will be needed for trials.
Optimizing patient access to trials is still crucial:
USA: National Registry for FSHD Patients and Family Members
Europe: A number of European registries either already in place or in
the process of development using TREAT-NMD’s Registry Toolkit
and established FSHD minimal dataset.
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National Registry for FSHD and Family Members
Facilitate contact between researchers and patients
interested in participating in translational research
Researchers apply to the registry with proposals:
Anonymized data
Access to patients for in clinical research studies.
Detailed questionnaire then shorter yearly questionnaire to
assess changes in health and functional status
Medical records curated to insure accuracy of diagnosis
Over 700 FSHD patients followed over >10 years.
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Factors that Influence Disease Severity
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Clinical Outcome Measures
Measurement of strength:
QMT and MMT were used in the FSHD Natural history study (1996)
This established rate of disease progression and the variability of the
measures allowing estimation of sample size and power calculations.
The validity of these measures were recently reinforced by looking at
the combined data from all clinical trials in FSHD:
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Neuromuscular Disorders Volume 23, Issue 4 , Pages 306-312, April 2013
Revaluating measures of disease progression in facioscapulohumeral
muscular dystrophy. Jeffrey M. Statland, Michael P. McDermott, Chad Heatwole,
William B. Martens, Shree Pandya, E.L. van der Kooi, John T. Kissel, Kathryn
R. Wagner, Rabi Tawil
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Extended Natural History Data
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Placebo is not Natural History
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Clinical Outcome Measures
Problems with strength measurements:
It is a measurement of disability not function: hard to make clinical
sense of changes in overall measured strength
It takes 180 patients per treatment group followed for a year to
measure arrest of progression.
Activity rating scales are needed:
Prior studies used variations of the Brooks and Vignos rating scales
but these proved less sensitive the strength testing.
Need to develop activity scale that is at least as sensitive as strength
testing.
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Clinical Outcome Measures
Patient reported outcome measures:
Neuromuscular specific: INQoL validated in a number of neuromuscular
conditions including FSHD
FSHD specific PRO: FSH Health Index (FSH-HI) recently developed at
the University of Rochester.
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Tissue and Serum Biomarkers
There are no validated serum and tissue biomarkers at
present
Existing hurdles:
No FSHD specific histopathologic markers
DUX4 expression is considered the causative event in FSHD but it is
expressed in very few nuclei at any one time making quantitative
measurement of DUX4 difficult
DUX4 Activated genes:
A set of DUX4 regulated genes have been identified that seemed to be
a more easily measurable sign of DUX4 activation
Some are secreted proteins that could also potentially provide
measurable serum biomarkers. 18
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Imaging Biomarkers
DEXA (Dual Energy X-ray Absortiometry):
Useful for measurement of regional or overall changes in muscle mass
MRI:
Provides multimodal measurements of skeletal muscle anatomy
especially in a disease with heterogeneous muscle involvement.
Recent association of T2 STIR+ muscle in FSHD with inflammation and
the presence of DUX4 induced targets and circulating inflammatory
markers make this MRI sequence of particular interest in FSHD
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FSHD Clinical Trial Toolkit: Where Things Stand
Patient Access to trials: Multiple mechanisms exist or being
developed, not likely to be a hindrance early in trial recruitment.
Clinical Outcome Measures:
Strength measures: validated, QMT useful for early phase trials but not
phase III trials.
Activity impairment scales:
Presently an FSHD composite impairment scale made up of items
from validated scales is being studies prospectively.
Another FSHD impairment scale is being developed in Newcastle
Patient reported outcome measures:
Neuromuscular scale: INQoL validated in FSHD and ready for use
FSHD-specific PRO: FSH-Hi developed and presently being tested.
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FSHD Clinical Trial Toolkit: Where Things Stand
Imaging biomarkers:
MRI: Utility and significance of STIR+ muscles in FSHD needs further
study in a longitudinal study.
Exploring the utility of EIM, electrical impedance myometry.
Tissue and serum biomarkers:
Perhaps the most significant bottleneck in FSHD trial preparedness
especially for trials targeting the underlying disease mechanism.
The set of DUX4 induced target genes first reported in human
myoblasts transduced with DUX4 expressing lentivirus has now been
replicated by several labs confirming their potential utility as
biomarkers
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FSHD Clinical Trial Network
Establishing a FSHD clinical trials network would
have provided us with the critical mass to:
Run a large prospective study to efficiently test the variability,
reliability and responsiveness of the various outcome measures
and correlate the biomarkers to the clinical outcome measures.
To have trial-ready sites with experience with FSHD and access
to patients ready to participate in FSHD trials.
No funding for a large network at this point.
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