GM2 Gangliosidosis: Getting the Most out of Patient Surveys

NIH Natural History Workshop

May 17, 2012

Florian S. Eichler, MD Massachusetts General Hospital

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

GM2 Gangliosidosis – What we know

Striking pathology but little data on rate of clinical progression

Infantile GM2

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

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

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?

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…

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)

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

Bley et al. Pediatrics 2011

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)

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)

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

Survival curves for patients with infantile GM2 gangliosidosis

Bley et al. Pediatrics 2011

47 months

Disease progression of infantile GM2 gangliosidosis

Bley et al. Pediatrics 2011

Bley et al. Pediatrics 2011

Bley et al. Pediatrics 2011

• 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?

(max. 10 points)

• 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

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

Biomarkers: Brain MRI Scoring System for GM2

(max. 20 points)

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

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?

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?

• 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

Patient Surveys

Prospective Studies Literature

MR Imaging Biomarkers

Pathophysiology Trial Design

IND Enabling

Early Phase Clinical

Late Phase Clinical

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