GM2 Gangliosidosis: Getting the Most out of Patient Surveys · GM2 Gangliosidosis: Getting the Most...
Transcript of GM2 Gangliosidosis: Getting the Most out of Patient Surveys · GM2 Gangliosidosis: Getting the Most...
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GM2 Gangliosidosis: Getting the Most out of Patient Surveys
NIH Natural History Workshop
May 17, 2012
Florian S. Eichler, MD Massachusetts General Hospital
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GM2 Gangliosidosis – What we know
• AR inherited lysosomal beta-hexosaminidase deficiency
• ganglioside accumulation in brain • neurodegeneration in children but also adults
• no effective treatments • failed systemic delivery of enzyme • promising data on intracranial gene delivery in
animals
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GM2 Gangliosidosis – What we know
Striking pathology but little data on rate of clinical progression
Infantile GM2
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GM2 Gangliosidosis – The Challenges
• rate of functional decline unknown • factors affecting survival not systematically
described • heterogeneous clinical spectrum
– infantile form: most severe and progressive – juvenile form: rarer and more variable – adult form: chronic, slow
• biomarkers of neurodegeneration unknown
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GM2 Gangliosidosis – The Challenges
• literature mostly case reports • low prevalence and incidence • most patients far advanced by time of diagnosis
– risks of travel – risks of intubation
• limited ability for large prospective cohort • limited resources
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Begin with the end in mind
• plan for intracranial AAV-mediated gene delivery – significant survival advantage in animal models
• does the current animal work justify moving
towards a human clinical trial? • what patient population is the first one to test? • is the target of administration appropriate? Is the
level of risk justified in light of the known rate of disease progression?
• what endpoints should be studied?
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GM2 Gangliosidosis – The Opportunities
• well organized patient advocacy group • prospect of intervention • motivated families and advocates • collaborative team of investigators (young + old) • “collective memory” of the disease
• rapid disease progression in infants may be
most quantifiable and homogeneous…
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The Strategy for Infantile GM2
• develop patient surveys to – estimate survival and – quantify gain and loss of specific developmental
milestones
• identify and recruit patients through advocacy organization
• collect anonymized surveys (waiver of written consent)
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The Surveys for Infantile GM2
12 sections, 18 pages 70 “yes/no” questions followed by requests to time events options to state uncertainty or “not applicable” validation questions prior to send-out we had test-runs:
– physicians of different specialties – patient advocates – family members
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Bley et al. Pediatrics 2011
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The Surveys for Infantile GM2
• initial skepticism • poor first response • follow-up emails from advocacy group • plug at annual meetings • visible presence at fundraiser events • work to create “buy-in”
• 237 families contacted, • 97 surveys received (5 HSCT analyzed separately)
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The Strategy for Infantile GM2
we complemented surveys with life-span data from • patients whose families did not respond to
surveys • literature search dating back to 1881 (>2000
papers)
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Mortality data according to cohort and birth year for patients with infantile GM2 gangliosidosis
Bley et al. Pediatrics 2011
n=121 n=103 n=92
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Survival curves for patients with infantile GM2 gangliosidosis
Bley et al. Pediatrics 2011
47 months
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Disease progression of infantile GM2 gangliosidosis
Bley et al. Pediatrics 2011
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Bley et al. Pediatrics 2011
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Bley et al. Pediatrics 2011
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• caregivers can provide a detailed recollection of distinct clinical findings (baby books), but milestones may be tainted by subjective impression and cannot be objectively verified.
• details on the course of regression assist in choice of outcome measures and design trials for future interventions
• first draft of disease specific clinical scoring system
Bley et al. Pediatrics 2011
What did we learn?
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(max. 10 points)
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• retrospective nature • self-reporting by parents and other family
members • features harder to isolate (e.g.vocalizing) more
prone to misrepresentation • cannot exclude recall bias, ascertainment bias
and bias of potentially missing data
• need for prospective validation
Limitations
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Biomarkers: Brain MRI Abnormalities in GM2
• families also sent advocacy group brain MRIs • opportunity to develop MRI scoring system
– location of abnormalities – location of atrophy
GM2 control
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Biomarkers: Brain MRI Scoring System for GM2
(max. 20 points)
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Biomarkers: Brain MRI Scoring System for GM2
0
4
8
12
16
0 1 2 3 4 5
Age at MRI (years)
Juvenile
0
4
8
12
16
0 20 40 60 80
Age at MRI (years)
Adult
0
4
8
12
16
0 0.5 1 1.5 2
Age at MRI (years)
Tota
l MR
I sco
re
Infantile
11.1 points (range 9-15) 4.3 points (range 3-7) 1 point (range 0-2)
significant differences between subtypes but no serial data to suggest that MRI tracks progression
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choice of patient population: • most infantile patients are too advanced by time
of diagnosis to benefit from intervention • include only infantile patients who had gained
milestones • include juvenile patients that can still walk
independently
How does this influence clinical trial design?
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choice of outcome measures: • measure retention of clinical function • need prospective studies (6MWT, GMFS, etc.) • develop biomarkers (MRI, gangliosides in CSF) • correlate biomarkers with clinical course
How does this influence clinical trial design?
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• first rough sketch of the “GM2 landscape” – surveys chart clinical course – MRI scoring system describes anatomic burden
• many details need to be filled in • questions raised and room for growth • temporal and spatial benchmarks for future
studies • much can be learned from retrospective surveys
Summary
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Patient Surveys
Prospective Studies Literature
MR Imaging Biomarkers
Pathophysiology Trial Design
IND Enabling
Early Phase Clinical
Late Phase Clinical
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Aknowledgements
MGH: Annette Bley, Paul Caruso Ourania Giannikopoulos Doug Hayden NTSAD: Kim Kubilus, Susan Kahn
TSGT Consortium National Tay Sachs and Allied Diseases Association NIH UL1 RR 025758 NIH K08NS52550 Lysosomal Disease Network 5U54NS065768