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

FSHD: Genetic defect

Molecular Mechanism: De-repression of DUX4 Gene Expression

SMCHD1-

DUX4

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

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.

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

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

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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