Endocrinologic & Metabolic Drugs Advisory Committee Meeting

Fabrazyme® (agalsidase beta)

January 13, 2003

Alison LawtonSenior Vice President

Regulatory Affairs & Quality Systems

Agenda

Introduction A. Lawton

Fabry Disease & Fabrazyme® M. Goldbergclinical development

Rationale for renal pathology endpoint H. Rennke

Safety & Phase 4 clinical program M. Goldberg

Statistical methods for assessing clinical benefit D. Rubin

Points for consideration & summary A. Lawton

Participating Experts

Robert J. Desnick, MD, PhD - Prof. and Chair, Dept of Human Genetics, Mount Sinai School of Medicine of New York University

Gregory A. Grabowski, MD - Prof. of Pediatrics, Director, Division and Program of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH

Barry M. Brenner, MD - Director Emeritus, Renal Division, Brigham & Women’s Hospital and Samuel A. Levine Professor of Medicine, Harvard Medical School, Boston

Christine Eng, MD - Assoc. Prof. of Molecular and Human Genetics, Director, Storage Disease Clinic, Baylor College of Medicine, Houston, Texas

Dominique P. Germain, MD, PhD - Dept. of Genetics, Hopital European Georges Pompidou, Paris, France

Gillian Shepherd, MD - Clinical Associate Professor of Immunology, Weill Medical College of Cornell University

Ralph B. D'Agostino Sr. PhD - Professor of Mathematics, Statistics and Public Health, Boston University, Boston

Fabry

Renal

Phase 1/2, 3 & 4 Studies

Phase 3 Study

Immunology

Statistics

Fabrazyme® Regulatory History

• Orphan designation (approx. 3500 US patients)

• Fast Track Status

• BLA filed June 2000

– Accelerated approval (21 CFR 601 Subpart E)

– Priority review

• Approved in 26 countries– EU August 2001

Proposed Indication

Fabrazyme (agalsidase beta) is indicated for use

as a long-term enzyme replacement therapy in

patients with a confirmed diagnosis of Fabry

disease. Fabrazyme treats the underlying

pathology of Fabry disease by significantly

clearing globotriaosylceramide (GL-3) to normal

or near normal levels from the vascular

endothelium of the kidney, heart and skin.

Serious or life-threatening illnesses

Meaningful therapeutic benefit over existing treatments

Approval on the basis of adequate and well-controlled clinical trials

Surrogate endpoint that is reasonably likely based on pathophysiologic or other evidence to predict clinical benefit

Post-marketing studies would usually be studies already underway

Objectives of Meeting: Demonstrate Fabrazyme meets requirements for accelerated approval

FDA Questions to the Committee

1. Clinical outcome data

2. Histological endpoint of essentially normal renal capillary endothelium by light microscopy

3. Impact of anti-GAL A antibodies on long-term safety and efficacy of Fabrazyme®

4. Phase 4 clinical study for verification of clinical benefit

5. Conversion of Phase 4 study to blinded, matched-control active treatment

Mark A. Goldberg, M.D.

Senior Vice President

Clinical Research

Genzyme Corporation

Fabry Disease and Fabrazyme Clinical Development

Fabry Disease

• Rare, lethal, X-linked inborn error of metabolism

• Deficient -Galactosidase A (-GAL A) activity

• Deficient -GAL A activity leads to progressive

globotriaosylceramide (GL-3) accumulation in multiple

cell types and tissues culminating in end organ

impairment

Key pathology: vascular endothelial deposition

Fabry Disease

Age (years)

Pathological

Clinical

10 20 30 40 50 60

Fabry Disease or

Hypercholesterolemia?

Fabry Disease: Clinical Manifestations

CNS Disease

Pain Crises

Acroparesthesia

6010 20 30 40 50 70 80

Age

Classical Phenotype (< 1% activity)+++ endothelial accumulation

Cardiac Disease

Renal Failure

Fabry Disease: Clinical Manifestations

Cardiac Phenotype (> 1% activity)min. endothelial accumulation

Cardiac Disease

Proteinuria

Renal Failure

6010 20 30 40 50 70 80Age

Classical Phenotype (< 1% activity)+++ endothelial accumulation

CNS Disease

Pain CrisesAcroparesthesia

Cardiac Disease

Renal Failure

Female Heterozygotes: Manifestations

Corneal Dystrophy 70

Acroparesthesias 70

GI Symptoms 58

Angiokeratoma 35

Hypohidrosis 33

CNS Involvement (TIA/CVA) 22

Renal Failure 2

Manifestations % Carriers (n = 60)

MacDermot, et al ., J Med Genet. 2001

Clinical Pathological Correlation Fabry Renal Disease

GlomerularEpithelial cellinvolvement

VascularEndothelial cell

involvement

asymptomatic markedlysymptomatic

mildlysymptomatic

Clinical Status

- female heterozygotes- cardiac variants

- classical hemizygotes- female heterozygotes

Enzyme Replacement Therapy

• Fabrazyme is a recombinant form of human -Galactosidase A

• Fabrazyme replaces the deficient enzyme

• Enzyme replacement therapy has been proven effective in treating Gaucher disease

Clinical Pathological Correlation Fabry Renal Disease

GlomerularEpithelial cellinvolvement

VascularEndothelial cell

involvement

asymptomatic markedlysymptomatic

mildlysymptomatic

Clinical Status

- female heterozygotes- cardiac variants

- classical hemizygotes- female heterozygotes

Fabrazyme treatment

1998 1999 2000 2001 2002 2003

Phase 1/2 Studyn = 15

Phase 3 Studyn = 58

Phase 1/2 Extension Studyn = 15

Phase 3 Extension Studyn = 58

Phase 2 Japan Studyn = 13

Phase 4(n = 76 , 2:1 randomization)

Phase 2 JapanExtension Study

n = 13

French ATUn = 50

EU approval

Clinical Studies and Experience

> 350 patients

> 4,000 infusions worldwide

Phase 1/2 Clinical Study Design(FB9702-01)

• Open-label, single center, dose finding

• Objectives

– Safety - Pharmacokinetics

– Dose finding - Preliminary efficacy/pharmacodynamics

• 3 doses, 2 IV dose regimens

– 0.3, 1.0, and 3.0 mg/kg every 2 wks for 5 doses

– 1.0 and 3.0 mg/kg every 48 hours for 5 doses

• 3 patients/treatment group, 15 patients total

• 1.0 mg/kg every 2 weeks optimal for safety/efficacy

Phase 3 and Extension Study Design

+ 6 + 12 + 54+ 18

Fabrazyme (~ 1.0 mg/kg q 2 weeks)

Phase 3 Extension StudyAGAL-005-99

(19 sites in USA and EU)

Phase 3 Placebo-Controlled StudyAGAL-1-002-98

(8 sites, 4 countries)

Baseline

Randomization

Months: 1 2 3 4 5

Week 20Entry into Phase 3 Extension Study

Placebo

Fabrazyme (~ 1.0 mg/kg q 2 weeks)

Months Post-entry

n = 58

Primary Endpoint Selection

Primary Endpoints Considered Pain Reduction

• Pain is subjective, episodic, and wanes over time

• No validated pain instruments in Fabry disease

• Appropriate statistical power requires large trial

– To avoid false positive / false negative results

– >100 patients/group

Primary Endpoints Considered Cardiac and Cerebrovascular Events

• Determination of sample size and study duration not

feasible

– Event rates poorly documented

– Confounded by common concomitant conditions such as

hypercholesterolemia and hypertension

Primary Endpoints Considered Renal Function

• Atrophic and sclerotic damage is irreversible

• Renal function remains normal for many years before

declining

• Demonstrating a significant difference from placebo

requires

– Long period of time

– Large trial (relative to size of patient population)

• Developed to allow a clinical development

program to proceed based on a mutually agreed

upon surrogate endpoint reasonably likely to

predict clinical benefit

FDA Accelerated Approval Mechanism

Primary Efficacy Endpoint Chosen

• Percentage of patients with reduction of GL-3

inclusions in renal capillary endothelium to essentially

normal levels at Week 20

• Morphologic, light microscopy assessment by three

independent pathologists

– Blinded to pre/post biopsy sampling

– 0 (none/essentially normal) to 3 (severe) severity scale

Secondary Efficacy Endpoints

• Composite score of GL-3 accumulation in the capillary endothelium (vasculature) of the kidney, heart, and skin as measured by Light Microscopy

• Composite score of reduction of Urinary GL-3 and Kidney tissue GL-3 (ELISA)

– Reduction of Urinary GL-3 Baseline to Week 20

– Reduction of Kidney GL-3 Baseline to Week 20

• McGill Pain Questionnaire

Additional Exploratory Endpoints

Multiple exploratory endpoints including:

– Assessment of renal function

• Serum creatinine

• Glomerular Filtration Rate (GFR)

• Proteinuria

– Plasma GL-3

Efficacy Results

Phase 3 and Extension Studies

Phase 3 Study Patient DemographicsAs Treated Population

Placebo (n = 29) Fabrazyme (n = 29)

Age (yrs) 28.4 ± 11.0 32 ± 9.4

Weight (kg) 69.6 ± 13.4 67.3 ± 9.9

Height (cm) 175.6 ± 8.2 175.7 ± 8.3

GenderMale 29 27Female 0 2

RaceCaucasian 26 27Non-Caucasian 3 2

Primary Endpoint ResultKidney Histology: Capillary Endothelium Clearance

% Zero-Scores

0

20

40

60

80

100

P < 0.001 (2x2 Chi Square)

0/290%

20/2969%

Placebo Fabrazyme

Week 20*

Assessments were independent of:• site • pathologist• age

*As Treated Population, considered equivalent to Intent-To-Treat

Primary Endpoint ResultKidney Histology: Capillary Endothelium Clearance

% Zero-Scores

0

20

40

60

80

100

P < 0.001 (2x2 Chi Square)

0/290%

20/2969%

Placebo Fabrazyme

Week 20*

*As Treated Population, considered equivalent to Intent-To-Treat

23/2592%

24/24100%

PL / FZ FZ / FZ

+ 6 Months*

Secondary Efficacy Endpoints Mean Capillary Endothelium Scores

(Scale 0-3)

PlaceboFabrazyme

0

1

2

3

4

5

6

Baseline Week 20

0

1

2

3

4

5

6

Baseline Week 20

Skin

Composite

Composite

Heart Heart

Kidney

SkinKidney

P < 0.001

Skin Histology: Response of Superficial Endothelial Cells- As Treated Population

96%100%

91%95%

100% 100%96%

88%

100%

3%

0

20

40

60

80

100

Week 20 6 Months 1 Year 18 Months 30 Months

% Zero Scores

Placebo/Fabrazyme PL/FZ FZ/FZ PL/FZ FZ/FZ

Phase 3 Study Phase 3 Extension Study

1/29

29/2925/26

26/27 27/2727/28

20/2221/24

PL/FZ FZ/FZ

20/2119/19

PL/FZ FZ/FZ

Kidney Histology: Additional Renal Cell Types

At 6 Months of Open-Label Treatment with Fabrazyme

Placebo / Fabrazyme Fabrazyme / Fabrazyme

Renal Cell-Type n % “0” Scores n % “0” Scores

Non-CapillaryEndothelial Cells

22 86 23

Glomerular Endothelial Cells

18 100 17 100

96

Interstitial Cells 24 79 24 100

Mesangial Cells 18 94 17 100

Kidney Histology: Additional Renal Cell Types

At 6 Months of Open-Label Treatment with Fabrazyme Placebo / Fabrazyme Fabrazyme / Fabrazyme

Renal Cell-Type n % GL-3 ScoresReduced

n % GL-3 ScoresReduced

Distal ConvolutedTubules/CollectingDucts

24 75 24 50

Non-CapillarySmooth Muscle Cells

22 86 21 81

Podocytes 22 23 17 18

Score of Percent Change in GL-3 Accumulation (ELISA) in Urine and Kidney Tissue

Parameter Statistic Fabrazyme Placebo P-Value*

n 21 21Urine GL-3% Change Median -23.3 42.8 0.005

n 27 28Kidney Tissue GL-3 % Change Median -34.1 -6.2

0.256

n 20 21Rank Sum Score

Median 32.5 48.0

0.003

*P-value for Wilcoxon’s Rank Sum Test

Biochemical endpoint confirms histological endpoint.

Median Plasma GL-3 Levels

Median Plasma GL-3 Level

(ng/L)

0

2

4

6

8

10

12

14

upper limit of normal (2.9 ng/L)

Placebo / FZ Group

FZ / FZ Group

Study Timepoint

Visit 1 Visit 7 Visit 11 Entry 6 Months 12 Months

Entry into open-label extension study

Glomerular Filtration Rate as Determined by Inulin Clearance (mL/min/1.73 m2)

Treatment Group Placebo Fabrazyme

n Mean sd n Mean sd

Baseline 28 97.4 34.74 29 82.3 22.23

Placebo / Fabrazyme Fabrazyme / Fabrazyme

12 Months 22 100.7 32.53 28 79.8 25.81

Phase 3 Placebo-Controlled Study:

Phase 3 Extension Study:

Mean Serum Creatinine (mg/dL)As Treated Population

Placebo/Fabrazyme

Fabrazyme/Fabrazyme

Mea

n (+

/- S

td.D

ev.)

Cre

atin

ine

(mg/

dl)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Baseline Visit 4 Visit 7 Visit 10 Week 20 Entry 6 Months

12Months

18Months

24 Months

Study Timepoint

Summary of Urinary Protein(mg/dL): Urinary Creatinine (mg/dL) Excretion

Baseline 18 Months 24 Months

n 30 30

Median 0.225 0.220

Min, Max 0.02, 2.92 0.04, 6.95

30

0.211

0.05, 8.13

Patients with values at both Baseline and 24 months

Change in Urine Protein / Urine Creatinine from Baseline to 18 Months into the Extension Study

Placebo/Fabrazyme

Fabrazyme/Fabrazyme

Cha

nge

from

Bas

elin

e to

18

Mon

ths

-1

0

1

2

3

4

5

Baseline Urine Protein/Urine Creatinine0 1 2 3 4

Helmut G. Rennke, M.D.

Professor of Pathology Harvard Medical School

Director, Renal Pathology Laboratory Brigham and Women’s Hospital

Rationale for Renal Pathology Endpoint

Renal Pathology in Fabry Population

• As a result of ongoing ischemic damage due to vascular GL-3, Fabry patients develop progressive secondary renal pathology over time:

– Focal segmental glomerulosclerosis (FSGS)

– Global glomerulosclerosis

– Tubular atrophy

– Interstitial scarring

– Eventually lead to end stage renal disease

• Clearance of vascular GL-3 will prevent this permanent damage

Tubular atrophy and interstitial scarring

Globally sclerosed glomerulus

Patient 119: Baseline Biopsy (age 48)

20x obj.

No glomerulosclerosis

• Early on in the disease, there is little permanent renal damage• Scarring which occurs later in the disease is irreversible

Patient 102: Baseline Biopsy (age 18)

No interstitial scarringNo tubular atrophy

Pre-treatment Post-treatment

Primary EndpointGL-3 Clearance From Peritubular Capillary Endothelium

(Score = 3) (Score = 0)

Review of Other Cell Types

• Glomerular capillary endothelium

• Mesangial cells

• Interstitial cells

• Arteriolar endothelium and smooth muscle

• Distal tubular epithelium

• Podocytes

Pre-treatment Post-treatment

GL-3 Clearance From Mesangial Cells ( ) & Capillary Endothelial Cells ( ) of the Glomerulus

Pre-treatment Post-treatment

GL-3 Clearance From Interstitial Cells of the Kidney

Post-treatment

Pre-treatment

GL-3 Reduction in Podocytes

Example: Asymptomatic Female HeterozygoteApproved as Donor for Renal Transplant

- Corneal opacities present, -gal activity in leukocytes= 0.38mU/mg protein, GFR=120mL/min/1.73m2, no proteinuria - Podocytes laden with GL-3 but capillary endothelium relatively spared (similar to cardiac variant)Conclusion: marked podocyte pathology without clinical disease

Wuthrich et al., Nephrol Dial Transplant. 1998.

Endothelial Involvement in Clinical Disease

Classic Fabry patient no yes yes yes

Female heterozygote yes yes minimal minimal

Cardiac variant yes yes minimal minimal

Podocyte/tubuleinvolvement?

Endothelialinvolvement?

Renalfailure?

Residual enzyme?

Conclusion: Female heterozygotes and cardiac variants have residual

enzyme activity that keeps their vascular endothelium clear of GL-3

and protects them from end stage renal disease.

Mark A. Goldberg, M.D.

Senior Vice President

Clinical Research

Genzyme Corporation

Safety

Phase 3 Safety: Adverse Events

• No statistically significant difference in adverse events between Fabrazyme and placebo except mild/moderate events

*Skeletal pain was unrelated to Fabrazyme

• No patient discontinued

Fabrazyme Placebo (# of Patients)

Fever 14 5

Chills/Rigors 15 4

Skeletal Pain* 6 0

Infusion-Associated Reactions (IAR)

• Mild to moderate in severity

• Generally transient and managed conservatively

• Number of patients experiencing IARs decreases over time

• Majority of patients developed IgG antibodies

Percent Fever and/or Rigors and Seroconversion at each InfusionAs Treated Population - Placebo/Fabrazyme, n = 27 (at last visit)

Ent

ry in

to O

pen

Lab

el

Seroconversion

Fever and/or Rigors

% o

f Pa

tient

s w

ith I

AR

s de

fine

d as

Fev

er o

r R

igor

s

0

10

20

30

40

50

Visit

0 1 2 3 4 5 6 7 8 9 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

Cum

ulat

ive

% o

f Pa

tient

s w

ho S

eroc

onve

rted

0

10

20

30

40

50

60

70

80

90

100

IgG Seroconversion

• 52/58 patients developed IgG antibodies

• Median time to seroconversion was 6 weeks

• Median time to peak titer is 83 days

• IgG titers have declined over time in >50% patients

• 7 patients have tolerized (no detectable antibody by RIP)

• There is no evidence of immune complex disease

IgG Seroconversion Does Not Impact Efficacy

• Clearance of endothelial cell GL-3 independent of IgG seroconversion:

• Sustained clearance of tissue and plasma GL-3

• Stable renal function

Parameter Zero-Scores(GL-3 Clearance)

Non-Zero Scores

Total P-value

Seronegative

Seropositive

4 (80%)

16 (67%)

1 (20%)

8 (33%)

5

241.000

P-value based on Fisher’s Exact Test

Fabrazyme Patients with Reduction in AUC During Phase 3 Study

Kidney GL-3Skin GL-3Serum Creatinine

TiterVisitPatient

N/A00.7640018 months

0N/A0.532006 months

000.812800Visit 1176%

Reduction

220.6N/ABaseline706

000.9256006 months

000.825600Visit 11

83%

Reduction

320.9N/ABaseline705

N/A01.21280018 months

001.2256006 months

001.225600Visit 1162%

Reduction

221.1N/ABaseline801

N/A0N/A2560024 months

N/A21.02560018 months

IgE and Skin Test Positive*

• Primary symptoms included pruritis and urticaria

• 2 patients’ sera tested positive for IgE antibodies

– 2/2 have been successfully rechallenged

• 3 patients had skin test results consistent with a positive finding

– 1/2 has been successfully rechallenged

– 1 is awaiting rechallenge

• < 1.4% (5/350) patients have had IgE or skin test positive

• No patient experienced signs consistent with anaphylaxis* As of 01 July 2002

Serious Adverse Events

Serious Adverse Events (Phase 3):– 5 patients in each treatment group– None related to treatment – All attributed to underlying disease, accidents, or

protocol-required biopsy procedures

Deaths:– 1 “possibly related” report

• Patient with severe heart disease, known arrhythmia and pacemaker

• Died at home 10 days after Infusion 29

Safety Summary

• Most common adverse events:

– Primarily infusion-associated reactions

– Generally mild to moderate in severity, managed conservatively, and decrease over time

• Majority of patients develop IgG antibodies

• IgG seroconversion does not impact efficacy

• No patient experienced signs consistent with anaphylaxis

– < 1.4% incidence of positive IgE or skin test

• Long-term use is well tolerated

Phase 4 Program

Clinical-Pathologic Correlation: Potential Benefits

Age (years)

Clinical

10 20 30 40 50 60

Treat early and prevent pathological accumulations and avoid renal damage

Treat later andslow rate of

progression of renal disease

Phase 3 population

Phase 4 population

• Multi-national, multi-center, randomized, double-blind, placebo-controlled trial

• Target sample size of approximately 70 patients with mild to moderate renal disease

– Serum creatinine measurement of 1.2 to 3.0 mg/dL OR

– Estimated creatinine clearance < 80 mL/min

• 2:1 randomization

• Minimum ~35 months study duration (14 renal events)

Current Phase 4 Study: Design

To assess the effectiveness of Fabrazyme vs. placebo in

prolonging the time to clinically significant deterioration in:– Renal function

• 33% increase in serum creatinine

• Progression to dialysis

• Renal transplant

– Cardiac function• Myocardial infarction

• Unstable angina

• Requirement of surgical intervention

– CNS disease• Stroke

• Transient ischemic attack

– Death

Current Phase 4 Study: Objective/Endpoints

• Clinically significant arrhythmia• Progression of congestive heart failure

Current Phase 4 Study: Status

• 34 sites

• >235 patients screened

• 76 patients randomized and infused

Current Phase 4 Study: Design Issues

• Ethics of completing a long-term placebo-controlled,

post-marketing trial with an endpoint of irreversible

organ damage

• Feasibility of completing a long-term placebo-controlled

trial in a post-marketing setting

Decline in GFRAge (years)

0 6010 20 30 40 50

Pathologicalaccumulation

of GL-3

Compare toPhase 3 Population

Compare to Phase 4 Study (Historical Control)

Proposal for a Modified and Expanded Phase 4 Program

Develop Fabry Disease Natural History Database

32

1

• 27 sites enrolled 447 unique patients

– 19 US, 5 Canada, 1 Czech Republic, 1 Denmark, 1 The Netherlands

• The data were collected by an independent CRO

• Prospectively designed case report forms were used

• The data from the Historical Study is recent, with 71% of the serum creatinine measurements occurring after February 1996

Natural History Study Data Collection

Two-Year Renal Event Rate Estimates (33% Increase in Serum Creatinine) Phase 3

Extension Compared to Historical Control

Comparison of Matched Historical Controls (n=57) versus Phase 3 Patients (n=57)

Estimated Event Rate

Phase 3Extension

(Fabrazyme)

MatchedHistoricalControl

RiskReduction

5%

(3/57)

11%

(6/57)53%

Evolution of Phase 4 Program1. Randomized, double-blind, placebo-controlled trial

Concerns: ethics and feasibility

Advantages:

• All patients are treated

• No feasibility concerns

• No ethical concerns

FDA Concerns:

• Comparability of the groups

• Comprehensiveness of data

2. Single-arm, open-label treatment vs historical control study

3. Randomized, blinded, placebo-controlled trial supplemented

with matched historical control data

FDA concerns addressed

Use of Propensity Score Matching Algorithms and Imputation in the

Proposed Phase 4 Program

Donald B. Rubin, Ph.D.

John L. Loeb Professor of StatisticsChairman, Department of Statistics

Harvard University

Objectives

• Modify Phase 4 study from randomized double-blind, placebo-control design to blinded, two-control group design

– Placebo controls from Phase 4 double-blind study

– Appropriately matched group from Historical study

• Compare renal event rates of Fabrazyme treated patients with appropriate untreated controls

Stage 1: Propensity Score Matching to Select Historical Control Group

• Powerful technique used to select historical controls who match the randomized group, thereby eliminating/minimizing bias between groups

• Parallels design of a randomized experiment--blinded to outcome data, only criteria involves balancing baseline covariates

• Matching Covariates in this study:

– Gender, Age, Baseline Serum Creatinine;

– Race, Estimated Creatinine Clearance, Blood Group, Plasma -GAL, Height, Weight

• End result: sub set of Historical patients as comparable as possible to set of randomized patients

Propensity Score Matching: Examples of Clinical Applications

• Blocker Use / CABG Surgery (Ferguson, JAMA, 2002)

• Coronary Artery Bypass / Stroke (Stamou, Ann Thorac Surg, 2002)

• Aspirin Use / All Cause Mortality (Gum, JAMA, 2001)

• Right Heart Catheterization / Mortality (Conners, JAMA, 1996)

• In Utero Phenobarbital Exposure / Intelligence Deficits (Reinisch, JAMA, 1995)

Propensity Score MatchingReduces or Eliminates Biases in Data

• Propensity score defined as conditional probability of receiving a treatment given pre-treatment characteristics:

p(Xi) = Prob.{Wi = 1 | Xi}

• Principal theorem:

– If group of treated and control patients are matched relative to

their propensity scores, differences between the two groups, on

average, cannot be due to the observed covariates.

Propensity Scores Matching Randomized Double-Blind Phase 4 Patients and Chosen Historical

Controls

Randomized Patients n=69

Chosen Historical Patients n=85

Linear Propensity Score

Propensity Scores Matching Randomized Double-Blind Phase 4 Patients and Chosen Historical

Controls with Sub-Classifications

Randomized Patients n=69

Chosen Historical Patients n=85

Linear Propensity Score

Stage 2: Multiple Imputation

• There are two control groups:

1) Historical controls who never had access to treatment

2) Placebo controls while on placebo in current Phase 4 study

– Both have missing serum creatinine data

• The imputation of missing serum creatinine data for the two control groups will utilize data from each other:

– The Phase 4 placebo group, prior to open-label, provides uniform short-term measurements

– The Historical control group provides longer term data (> 2 years)

Chosen Historical Controls (n=85) Pattern of Missing Data

Ind

ivid

ua

l Pa

tien

t

-2 -1 0 1 2 3 4 [pre-Qualification] ------------Time (Years)-----------------

Historical Study Datan=85 Chosen Historical Controls

Ind

ivid

ua

l Pa

tien

t

-2 -1 0 1 2 3 4 [pre-Qualification] ------------Time (Years)-----------------

Multiple Imputation

• Before the blind is broken, an acceptable model for disease progression will be defined, e.g. 1/creatinine vs time

• Each set of multiple imputations will create one "complete" data set

• Multiple imputation is a standard technique for dealing with missing data, e.g. available in SAS

Illustration of Imputation MethodHistorical Patient Data

Cre

atin

ine

(mg/

dL)

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Time (years)-1 0 1 2 3 4

Illustration of Imputation MethodPlacebo Randomized Patient Data C

reat

inin

e (m

g/dL

)

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Time (years)-1 0 1 2 3 4

Stage 3: Comparison of Randomized Treated Patients to Control Groups

• At the end of the 2nd stage, there will be complete data sets for the two control groups:

– A matched Historical control group: N~ 85

– A Placebo control group: N~25

• When the study is completed, the renal event rates between treatment (N~50) and control groups (N~110) will be compared, e.g., using time-to-event analyses within propensity scores subclasses

Conclusions

• The use of matching algorithms eliminates/minimizes potential sources of bias from historical controls

• The use of placebo controls retains benefits of randomized, controlled trial

• Multiple imputation allows both sources of controls to characterize disease progression in the absence of treatment

• Randomized trial supplemented with historical control data is a powerful method of verifying clinical benefit in a rare disease

Fabrazyme® (agalsidase beta)

Summary & Points for Consideration

1. Clinical Outcome Data

• Phase 3 double-blind clinical study conclusively demonstrated the agreed upon primary efficacy endpoint

– Statistically significant improvements in pain and renal function endpoints were not expected

• Objective clinical outcome measures such as renal function require long-term data

• Trends in patients receiving Fabrazyme® for up to 30 months indicate a slowing of progression of renal insufficiency compared to a matched historical database of untreated Fabry patients

2. Histological endpoint of essentially normal renal capillary endothelium

- female heterozygotes- cardiac variants

- female heterozygotes

GlomerularEpithelial cellinvolvement

VascularEndothelial cell

involvement

asymptomatic markedlysymptomatic

mildlysymptomatic

Clinical Status

- classical hemizygotes

Fabrazyme treatment

• Highly statistically significant (p<0.001) and robust

• Clearance or reduction of GL-3 also seen in other critical cell types

3. Impact of anti-GAL A antibodies on long-term efficacy of Fabrazyme

• Sustained efficacy demonstrated independent of IgG

seroconversion

– Sustained clearance of tissue and plasma GL-3

– Stable renal function

• Reduced titers in most IgG positive patients, some tolerized

• Continued monitoring proposed in labeling

4. Phase 4 clinical study for verification of clinical benefit

• Normalization of underlying pathology of disease (GL-3 in capillary endothelium) could be considered a clinical endpoint

– Verification studies would not be required

• FDA Guidance: Fast Track Drug Development, and Application Review, Sept. 1998

“Approval based on clinical endpoints other than survival or irreversible morbidity would be considered under the accelerated approval regulations only when it is essential to determine effects on survival or irreversible morbidity in order to confirm the favorable risk/benefit judgment that led to approval.”

4. If Phase 4 clinical study is needed for verification of clinical benefit

• Design consideration should take into account the very small patient population

• Renal outcome requires large numbers and long term study

• Phase 4 study fully enrolled and ongoing

– Meets accelerated approval requirements

• Proposed modifications for Phase 4 study allow for maximum flexibility, adequate rigor, and optimal feasibility

– Details can be finalized post approval

5. Use of Natural History Database in Modifying the Phase 4 Study

• Blinded, randomized trial supplemented with matched historical control data is a reasonable method of verifying clinical benefit in a rare disease

• The proposed statistical methods eliminate bias and use all available data (historical & placebo)

• Addresses FDA concerns regarding historical data set for comparative control

• Main advantage - all patients can receive a promising drug for a disease that is serious or life threatening

Relevance of accelerated approval regulations

Serious or life-threatening illnesses

Meaningful therapeutic benefit over existing treatments

Approval on the basis of adequate and well-controlled clinical trials

Fabry disease is progressive and fatal

Current therapies are palliative only

Evidence from randomized, multi-center, placebo-controlled Phase 3 Study

Confirmed by Phase 3 Extension (cross-over) & Japan Bridging Study

Surrogate endpoint that is reasonably likely based on pathophysiologic or other evidence to predict clinical benefit

Post-marketing studies would usually be studies already underway

Relevance of accelerated approval regulations

Pathophysiology of Fabry disease supports normalization of GL-3 in capillary endothelium is predictive of clinical benefit

Phase 4 Study is fully enrolled, underway, and can be modified to a randomized, blinded, matched-control study

Conclusions

• Currently no treatment for preventing/slowing progressive vascular damage and resultant end organ destruction of Fabry disease

• Fabrazyme meets the requirements for accelerated approval

• US Fabry patients should be allowed Fabrazyme treatment