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

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

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

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 4000000 live births in US in 2003  < 30 cases 11/15/2018

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

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.: 26% Survival at 24 mos.: 9% Survival at 36 mos.: 7% 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)

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 11/15/2018

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 11/15/2018

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: 1.9% (0% , 5.5%) Data from historical study available to regulatory agencies to evaluate sensitivity of choices 11/15/2018

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 - 30.7% Also driven by practical considerations 11/15/2018

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

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

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

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 11/15/2018

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

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

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.: 26% Survival at 24 mos.: 9% Survival at 36 mos.: 7% 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)

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 11/15/2018

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 11/15/2018

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) 11/15/2018

Estimates of 6 month survival for AGLU01702 Patients 11/15/2018

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 11/15/2018

Results of Cox Model for 2 Studies 11/15/2018

More Results – Adjusting for Covariates 11/15/2018

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