FSHD: Clinical Trial Preparedness

Transcription

1 FSHD: Clinical Trial Preparedness Rabi Tawil, MD University of Rochester Medical Center FSHD Clinical Trials Readiness Workshop Newcastle, October 31, 2013

2 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 2

3 FSHD: Genetic defect

4 Molecular Mechanism: De-repression of DUX4 Gene Expression SMCHD1- DUX4

5 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

6 FSHD Trial Preparedness Workshop 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) 6

7 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. 7

8 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. 8

9 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. 9

10 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. 10

11 Factors that Influence Disease Severity 11

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13 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: Neuromuscular Disorders Volume 23, Issue 4, Pages , 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 13

14 Extended Natural History Data 14

15 Placebo is not Natural History 15

16 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. 16

17 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. 17

18 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

19 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 19

20 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. 20

21 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 21

22 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. 22

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