1. Use of Historical Control Data in the Approval of Myozyme®
Ron Knickerbocker, Ph.D.
Nancy Silliman, Ph.D.

2. Outline Background of Pompe Disease
Genzyme Sponsored Natural History Study
Primary Study
Design
Statistical Plan
Results
Issues/Results for Supportive Study
Further Exploration/Regulatory Questions
Summary
11/15/2018

3. Background
Genzyme has a background in developing Enzyme Replacement Therapies (ERTs) for Lysosomal Storage Disorders
Cerezyme® for Gaucher disease
Fabrazyme® for Fabry disease
Aldurazyme® for MPS-1
Pompe disease is a Lysosomal Storage Disorder involving a defect in the gene that makes the enzyme (acid alpha-glucosidase, GAA) which converts glycogen to glucose
11/15/2018

4. Background
Most progressive form of the disease strikes newborn infants and is characterized by:
Enlarged heart (cardiomyopathy)
Severe and progressive muscle weakness
Floppiness
Failure to meet development milestones (sitting, walking, crawling)
Difficulty breathing, respiratory infections
Feeding problems
Enlarged Tongue
Estimated Incidence (Infantile Onset)~1/138,000 live births
Most die of respiratory failure before age of 12 months
live births in US in 2003  < 30 cases
11/15/2018

5. Natural History Study
Genzyme Sponsored an Epidemiologic Study of the Natural History of Infantile Pompe Disease
Multinational, multicenter historical cohort study
Patients: Infantile-onset Glycogen Storage Disease Type II (GSD-II) or Pompe disease who have not received enzyme replacement therapy
Survival and clinical characteristics captured for 163 patients
11/15/2018

6. Pompe Is a Fatal Disease: Survival in Infantile-Onset Pompe Disease
Age (months) 6 12 18 24 30 36 42 48 54 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Proportion of Patients Alive
Survival at 12 mos.: %
Survival at 24 mos.: %
Survival at 36 mos.: %
Pompe is a fatal disease. In its most severe form, the infantile-onset form, 75% of the affected children die during the first year of life and 90% die by the age 2.
*Based on n=163 with available data (Genzyme Study; data on file)

7. Pivotal Study – AGLU01602
Due to mortality low incidence placebo-controlled study felt to be unethical/infeasible
Pivotal study to be conducted in infants under 6 months of age
Confirmed Pompe Disease
Cardiomyopathy
Not invasively ventilated
Patients to be randomized to 2 doses of enzyme, primarily to allow safety experience
Prior experience with ERT in other disease areas shows that early intervention may improve response
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8. Primary Endpoint
The hard endpoint that allows best comparison to historical data is survival
Feasible due to poor survival with disease
FDA had concern that in open label setting that survival could be “artificially improved” through invasive ventilation
Decided that primary endpoint would be time to death or “permanent” invasive ventilation
Primary endpoint conservatively to be compared to survival in natural history study
Ventilation data was collected in natural history, but not as reliable in historical setting
Treatment could change with time or the possibility of a new available treatment
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9. Statistical Issues
First, needed to subset historical control dataset to more closely match study populations
Data was not always available in historical control, in such cases take conservative choice,
eg, cardiomyopathy required in pivotal study, if data not available in historical control patient was included
Historical control subset should have less cardiac involvement thus better survival than pivotal study population
Led to a subset of 62 patients
Survival at 12 months of age: 16.8% (6.8%, 26.8%)
Survival at 18 months of age: % (0% , 5.5%)
Data from historical study available to regulatory agencies to evaluate sensitivity of choices
11/15/2018

10. Statistical Issues
Compare Time to Vent-Dependence or Death from Study to Death in Historical Control Reference Group
Primary Timepoint 18 months of age
Interim at 12 months of age
Criteria for Success – Conservative
Non-overlapping 95% Confidence Intervals from K-M estimates of “survival”
Sample Size 18 patients
LL Confidence Interval with 10 successes %
Also driven by practical considerations
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11. Statistical Issues
All issues discussed multiple times with FDA (before SPA process in place)
Conservative choices were made and analyses kept simple
Exception, reference population had many patients (approx 30%) that died prior to 6 months of age
Because patients could be enrolled at any age up to 6 months in pivotal study this creates bias in favor of drug (at least in early part of survival curve)
Simple solution – sponsor to perform sensitivity analysis to exclude patients who die early (prior to 3, 4, 5, and 6 months)
More elegant solution to be described later in presentation
11/15/2018

12. Sensitivity Analysis of Reference Population
Age Milestone Subset N
Estimate and 95% CI
All Patients 61
16.8 (6.8, 26.8)
4 months 57
18 (7.4, 28.6)
6 months 37
25.0 (10.9, 39.2)
1.9 (0.0, 5.5)
2.0 (0.0, 5.9)
2.8 (0.0, 8.2)
12 Month
18 Month
Modest Impact on 12 Month Survival
Trivial Impact on 18 Month Survival
11/15/2018

13. Survival Free of Invasive Ventilation at 18 Months of Age (Primary End Point)
15/18 trial patients
[83%; 95% CI: 66% - 100%]
1/62 untreated controls
[2%; 95% CI: 0% - 6%]
Clinical Trial Patients
Untreated Historical Cohort
95% Confidence Intervals

14. Pivotal Study-Secondary Endpoints
Reference Population could not be used for other endpoints
In most cases, data was described and when possible age matched to general population
Percentiles of height and weight
Z-scores for Cardiovascular parameters
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15. Changes in Heart Mass (Echocardiograms)
100% patients with decreased LVM from Baseline (n=15)
Mean decrease in LVM of 58% at Week 52
+7.1 Z-score 9 8 7 6
+3.2 Z-score 5
Mean LVM Z-score 4 3
Upper Limit of Normal 2 1 -1
Baseline
Week 26
Week 52

16. Supportive Study – AGLU01702
Prior to Initiation of Pivotal Study a Supportive Study with 21 patients was initiated
Similar in most fashions to Pivotal Study
Patients were 6-36 months at study entry
Patients were allowed to be ventilated as baseline
Primary hard endpoint would need to be survival not the same as pivotal study
No specification was made at protocol initiation for comparison to historical control
Group was felt to be heterogenous
A larger proportion of reference population did not survive much past 6 months
Note that hazard seems to decrease as age increases
11/15/2018

17. Pompe Is a Fatal Disease: Survival in Infantile-Onset Pompe Disease
Age (months) 6 12 18 24 30 36 42 48 54 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Proportion of Patients Alive
Survival at 12 mos.: %
Survival at 24 mos.: %
Survival at 36 mos.: %
Pompe is a fatal disease. In its most severe form, the infantile-onset form, 75% of the affected children die during the first year of life and 90% die by the age 2.
*Based on n=163 with available data (Genzyme Study; data on file)

18. Supportive Study
Proposed a summary of survival data using similar concept as pivotal study
Not statistically powered
Divide Study Population into two subgroups at interim analysis following 15 patients being treated for at least one year:
≤12 months at entry (n=6, med age=8.6 months)
>12 months (n=9, med age = 18.1 months)
Subset historical control to create reference population
Same process as for pivotal study (N=86)
Calculate conditional probability of surviving a year matched to median age for each of the 2 subgroups
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19. Comparison of Survival in AGLU01702 to Estimated Conditional Survival in AGLU01702 Reference Populations
AGLU01702
AGLU01702 Reference Population
Age Category at 1st Infusion
12 Month Survival Rate (95% CI)
Reference Age for Conditional Survival Estimate
Estimated 12 Month Conditional Survival Rate (95% CI)
≤ 12 months
3/6=50.0%
(11.8%, 88.2%)
n=6
8.1 months
16.2%
(6.6%, 25.9%)
n=60
> 12 months n=9
8/9=88.9%
(51.8%, 99.7%)
18.1 months
45.5%
(16.0%, 74.9%)
n=11
All Patients n=15
11/15=73.3%
(44.9%, 92.2%)
15.0 months
37.5%
(13.8%, 61.2%)
N=16
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20. Supportive Study Survival Results
Survival is directionally improved with ERT
Due to small subsets not possible to meet criteria of non-overlapping confidence intervals
Subsetting is ad-hoc to lead to easier presentation of results
Also proposed testing procedure that estimated conditional survival probability for each patient enrolled (based on age of initiation of treatment)
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21. Estimates of 6 month survival for AGLU01702 Patients
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22. Supportive Study Results
Results were generally encouraging (“p-values” < 0.05) but not highly conclusive
We were convinced that best approach was to introduce a model (Cox regression) including both treated and untreated patients
Treatment could be a time varying covariate which would credit reference population with survival prior to treatment initiation
Could allow for adding other covariates to the model
In the historical analysis had looked at covariates which impacted survival with some having modest effect
Reviewer from EU suggested this same approach to answer some questions (and to provide some inference for supportive study)
Never prospectively identified in protocol or SAP
Felt we needed pretty robust findings
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23. Results of Cox Model for 2 Studies
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24. More Results – Adjusting for Covariates
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25. Summary Myozyme® increases survival in infantile-onset Pompe disease
Prespecified analyses show clearly in pivotal study
Posthoc analyses appear to confirm in supportive study; however, effect may be less pronounced
Important to have access to historical data when possible
In rare diseases, have to get it yourself
Dialog with regulatory agencies very important
Greater role for exploratory analyses
Diseases not as well studied
11/15/2018