GM2 Gangliosidosis: Getting the Most out of Patient Surveys

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Brook Dorsey
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1 GM2 Gangliosidosis: Getting the Most out of Patient Surveys NIH Natural History Workshop May 17, 2012 Florian S. Eichler, MD Massachusetts General Hospital

2 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

3 GM2 Gangliosidosis What we know Infantile GM2 Striking pathology but little data on rate of clinical progression

4 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

5 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

6 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?

7 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

8 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)

9 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

10 Bley et al. Pediatrics 2011

11 The Surveys for Infantile GM2 initial skepticism poor first response follow-up s 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)

12 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)

13 Mortality data according to cohort and birth year for patients with infantile GM2 gangliosidosis n=121 n=103 n=92 Bley et al. Pediatrics 2011

14 Survival curves for patients with infantile GM2 gangliosidosis 47 months Bley et al. Pediatrics 2011

15 Disease progression of infantile GM2 gangliosidosis Bley et al. Pediatrics 2011

16 Bley et al. Pediatrics 2011

17 Bley et al. Pediatrics 2011

18 What did we learn? 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

19 (max. 10 points)

20 Limitations 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

21 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

22 Biomarkers: Brain MRI Scoring System for GM2 (max. 20 points)

23 Biomarkers: Brain MRI Scoring System for GM2 Infantile Juvenile Adult Total MRI score Age at MRI (years) Age at MRI (years) Age at MRI (years) 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

24 How does this influence clinical trial design? 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

25 How does this influence clinical trial design? 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

26 Summary 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

27 Late Phase Clinical Early Phase Clinical IND Enabling Pathophysiology MR Imaging Trial Design Biomarkers Prospective Studies Literature Patient Surveys

Aknowledgements TSGT Consortium National Tay Sachs and Allied Diseases Association NIH UL1 RR 025758 NIH K08NS52550 Lysosomal

28 Aknowledgements TSGT Consortium National Tay Sachs and Allied Diseases Association NIH UL1 RR NIH K08NS52550 Lysosomal Disease Network 5U54NS MGH: NTSAD: Annette Bley, Paul Caruso Ourania Giannikopoulos Doug Hayden Kim Kubilus, Susan Kahn

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