# Presentation: 179856

## Endocrinologic and Metabolic Drugs Advisory Committee Meeting

- January 15, 2003
- Sponsor Presentation

- Aldurazyme® (laronidase)

## Introduction

- Meeting subject
- Aldurazyme (laronidase) for the treatment of Mucopolysaccharidosis I (MPS I)
- Recombinant human –L-iduronidase (rhIDU)
- Sponsor
- BioMarin Pharmaceutical Inc.
- Genzyme Corporation

## Sponsor Presentation

- Introduction
- Matt Patterson
- VP, Regulatory and Government Affairs, BioMarin
- Description of MPS I
- Joseph Muenzer, M.D., Ph.D.
- Associate Professor of Pediatrics, UNC at Chapel Hill
- Principal Investigator, Phase 1/2 and Phase 3 clinical studies
- Aldurazyme Clinical Program
- Gerald Cox, M.D., Ph.D.
- Medical Director, Genzyme
- Clinical Geneticist, Children’s Hospital, Harvard Medical School
- Clinical Perspective
- Joseph Muenzer, M.D., Ph.D.
- Concluding Remarks
- Matt Patterson

## Additional Participants

- Kenneth Berger, M.D.		FVC Methodology
- Assistant Professor of Medicine, Director PFT Laboratory
- New York University School of Medicine
- Lorne Clarke, M.D., Ph.D.		Principal Investigator
- Associate Professor, Medical Genetics
- University of British Columbia Vancouver, BC
- William Kramer, Ph.D.		Pharmacokinetics
- Consultant
- Reed Pyeritz, M.D., Ph.D. 		Pulmonary, Sleep Apnea
- Chief, Division of Medical Genetics
- University of Penn. School of Medicine
- David Rapoport, M.D. 		Sleep Study Methodology
- Associate Professor of Medicine, Director Sleep Study Laboratory
- New York University School of Medicine, New York, NY
- Gillian Shepherd, M.D. 		Immunology
- Clinical Associate Professor of Medicine
- Cornell University Medical College
- Patrick Trown, Ph.D. 		Preclinical
- Consultant
- Patrick Trown, Ph.D.

## Regulatory History

- Orphan Drug designation: September, 1997
- Prevalence of approximately 1000 patients in U.S.
- IND filed: October, 1997
- Fast Track designation: September, 1998
- BLA filed: July, 2002
- BLA granted priority review
- Frequent, detailed collaboration between Sponsor and FDA:
- Pre-IND
- End of Phase 1/2
- Phase 3 protocol development
- Phase 3 statistical analysis plan
- Pre-BLA

## Development History

- Preclinical pharmacology studies
- MPS I canine model
- Phase 1/2 Open-Label Study
- 10 patients
- 152 week efficacy data, 235 week safety data
- Phase 3 Double-Blind/Extension study
- 45 patients
- 26 weeks: Randomized, placebo-controlled, multi-national
- Extension: Open-label, 36 week data
- Compassionate Use Program: 16 patients globally

## Aldurazyme Administration

- Dose
- 100 units/kg (approximately 0.58 mg/kg)
- Route
- IV infusion once per week

## Proposed Indication

- Aldurazyme® (laronidase) is indicated as long term enzyme replacement therapy in patients with Mucopolysaccharidosis I (MPS I; -L–iduronidase deficiency) to treat the non-central nervous system manifestations of the disease.

## Description of MPS I

- Joseph Muenzer, M.D., Ph.D.
- Associate Professor of Pediatrics
- University of North Carolina at Chapel Hill
- Principal Investigator, Phase 1/2 and
- Phase 3 clinical studies

## Mucopolysaccharidosis I (MPS I)A lysosomal storage disorder

- Deficiency of lysosomal enzyme -L-iduronidase
- Progressive accumulation of glycosaminoglycans (GAG)
- Multi-systemic, heterogeneous
- Severe morbidity and early mortality
- Rare (est. incidence 1:100,000)
- Significant unmet medical need

- Age 5

- Age 5

## Spectrum of Disease

- <date/time>

-   Normal intelligence
-   Less progressive
-     physical problems
-   Corneal clouding
-   Joint stiffness
-   Valvular heart disease
-   Death in later decades

-   Severe mental retardation
-   More progressive
-   Severe respiratory disease
-   Obstructive airway disease
-   Death before age 10 years

-  Little or no intellectual defect
-  Respiratory disease
-  Obstructive airway disease
-  Cardiovascular disease
-  Joint stiffness/contractures
-  Skeletal abnormalities
-  Decreased visual acuity
-  Death in teens and 20’s

- Severe
- Hurler
- MPS I H

- Intermediate
- Hurler-Scheie
- MPS I H/S

- Mild
- Scheie
- MPS I S

## Heterogeneity in Hurler-Scheie

- Severe joint disease
- Tracheostomy for Airway Dz
- Modest Liver enlargement

- Severe joint disease
- No sleep apnea
- Moderate liver enlargement

- Milder joint disease
- Severe sleep apnea, on CPAP
- Massive liver enlargement

- Age 17

- Age 12

- Age 22

- Age 17

- Age 12

- Age 22

## MPS IBiochemistry

- MPS IBiochemistry

- -L iduronidase cleaves a terminal iduronic acid residue from dermatan sulfate and heparan sulfate (GAG)

## MPS Disorders Biochemistry

- Iduronidase deficiency causes a block in the sequential breakdown steps of glycosaminoglycans

- e.g. Dermatan Sulfate Degradation

- MPS I

## Lysosomal Storage in MPS I

- Virtually all tissues have some degree of storage and disease

- Methylene blue stained thick section from MPS I dog liver

## Multi-systemic Involvement

**Lysosomal Storage of GAG**

**Respiratory **
**Connective tissue**
**Cardiovascular **
**Gastrointestinal**
**Ocular **
**Neurologic**
**Skeletal **

******-L-iduronidase**
**deficiency**

- MPS I leads to disease in multiple tissues/organ systems

## Pulmonary Disease

- Caused by storage in lung, airway epithelium and bone
- Outcomes
- Decreased pulmonary function
- Restrictive lung disease due to small ribcage and stiff joints
- Decreased diaphragmatic excursion due to hepatomegaly
- Frequent infections with thick secretions
- Respiratory insufficiency

## Upper Airway Obstruction

- Caused by storage at many levels
- Tongue
- Lymphoid tissues
- Airway epithelium
- Pharyngeal soft tissues

- 17 year old Hurler-Scheie patient

## Upper Airway Obstruction

- Outcomes
- Respiratory insufficiency
- Severe sleep apnea with cor pulmonale
- CPAP/Tracheostomy
- High rate of anesthesia complications/deaths

- Example of Sleep Apnea

## Joint and Skeletal Disease

-   Caused by progressive storage in synovium, 	periarticular tissues, and bone
-   Outcomes
-  Joint stiffness and joint contractures
-  Joint pain
-  Severe skeletal deformity
-  Significant loss of mobility and functional 	independence

## Joint Restriction and Stiffness

- Hip and Knee restriction and contractures

- Shoulder restriction and contractures

- Age 17

- Age 12

## Enlarged Liver and Spleen

- Caused by excessive storage in liver and spleen cells
- Outcomes
- Restricted movement
- Impaired breathing
- Difficulty eating
- Discomfort
- Hernias

- 22 year old Hurler-
- Scheie patient

## Cardiac Disease in MPS I

- Caused by storage in heart valves, coronary arteries and aorta
- Outcomes
- Valve disease
- Pulmonary hypertension with right heart failure
- Cardiomyopathy
- Coronary artery/vascular disease
- Congestive heart failure

## Eye Disease in MPS I

- Corneal clouding
- Retinal disease
- Glaucoma
- Outcomes
- Decreased visual acuity
- Blindness

## CNS Disease in MPS I

- Caused by storage in neurons, macrophages, and meninges
- Outcomes
- Mental retardation in
- 	severe patients
- Communicating hydrocephalus
- Headaches
- Spinal cord compression

## Current Treatment for MPS I Patients

- Symptomatic management
- Palliates condition - does not prevent progression
- Limited utility
- High risk of anesthesia/surgical complications
- Examples
- Oxygen for respiratory insufficiency
- CPAP/BIPAP
- Tracheostomy for severe airway obstruction
- Physical therapy for joint stiffness
- Cardiac valve replacement surgery

## MPS I Bone Marrow Transplantation

- First reported in 1981 by Hobbs et al
- Can improve some physical features and can stabilize the CNS in some patients
- Significant morbidity and mortality*
- Due to risks, primarily used to treat severeMPS I patients under 2 years of age

- * Peters et al, 1996, 1998; Vellodi et al, 1997

## MPS IA lysosomal storage disorder

- Severe, multi-system, heterogeneous disease
- Progressive decline with high morbidity and mortality
- Significant unmet medical need

- 9 year old Hurler-
- Scheie patient

## Aldurazyme Clinical Program

- Gerald F. Cox, M.D., Ph.D.
- Medical Director
- Genzyme Corporation

## Outline

- Clinical Program
- Phase 1/2 Study - Efficacy
- Phase 3 Study - Efficacy
- Safety
- Conclusions

## Clinical Program

- Phase 1/2 Open-Label Study (N=10)
- Phase 3 Double-Blind/Extension Study (N=45)
- Compassionate Use Program (N=16)
- 71 patients treated with Aldurazyme

## Phase 1/2 Study

- Objectives
- Demonstrate efficacy by reducing lysosomal GAG storage
- Demonstrate safety
- Design
- Open-label, 10 patients (5-22 yrs old, 8 Hurler-Scheie)
- Aldurazyme 100 U (0.58 mg)/kg IV q wk
- Study ongoing (approx. 5 yrs)
- Primary Efficacy Endpoints
- Urinary GAG level
- Hepatosplenomegaly

## Phase 1/2:Reduction in Urinary GAG Level

- By Week 152, urinary GAG level approached normal

- p<0.001

- % Baseline GAG Value

- Weeks

- 100
-   80
-   60
-   40
-   20
-    0

- 0

- 52

- 104

- 152

## Phase 1/2 Study:

- Reduction in Hepatosplenomegaly

- Weeks

- 0

- 26

- 52

- 104

- % of Baseline Volumes

- 70

- 75

- 80

- 85

- 90

- 95

- 100

- 105

- Liver

- Spleen

- After Week 52, liver volumes
- normalized in 90% (9/10) of patients

- p<0.001

- p=0.025

## Phase 1/2 Study:Long-Term Efficacy Results

- Efficacy Variables

-      Baseline

-  Year 1

- Year 2

- Urinary GAG Excretion

- >5 fold

- elevated

- 63%

- Reduction

- 74%

- Reduction

- Liver Size

- All enlarged

- 9 normal

- 9 normal

- Shoulder Flexion (degrees)

- 101

-  128

- 129

- Sleep Study AHI (events/hr)

- 2.08

- 0.97*

- NYHA Score

- None at Class I

- 5 at Class I

- 6 at Class I

- Visual Acuity

-     3 patients
- severely impaired

- All 3 patients
-   improved

*Kakkis et al. (2001) NEJM 344:182-88*

- *Week 26

## Phase 3 Study

## Phase 3 Study:Endpoint Considerations

- MPS I
- Rare, multi-system, progressive disorder
- Patient-to-patient heterogeneity
- Reversible and irreversible components
- Study Duration
- Efficacy Assessments
- Reversal of underlying pathophysiology
- Clinical improvement in functional measures
- Broad treatment effect
- Non-CNS only

## Phase 3 Study:Design

- Design
- Randomized, double-blind, placebo-controlled
- 45 patients, 5 sites in 4 countries
- Aldurazyme 100 U/kg or Placebo IV q wk for 26 wks
- Open-label extension study on-going (approx. 2 yrs)
- Entry Criteria
- MPS I disease, iduronidase deficiency, 5 yrs old
- FVC 80% predicted, stand 6 minutes, walk 5 meters
- No tracheostomy or prior BMT

## Phase 3 Study:Efficacy Variables

- Lysosomal Storage of GAG
- Urinary GAG level
- Liver volume
- Respiratory Function
- % Predicted Forced Vital Capacity (FVC): Co-Primary
- Sleep Study Apnea/Hypopnea Index (AHI)
- Functional Capacity
- 6 Minute Walk Test (6MWT): Co-Primary
- Shoulder Flexion
- Additional
- Visual acuity, CHAQ/HAQ, SF-36/CHQ, others

## Phase 3 Study:Baseline Patient Characteristics

- 				   	Placebo	   Aldurazyme
- 				   	 (n=23)		(n=22)
- Age Mean (Range)	15.4 (6,39)	      15.6 (7,43)
- Male/Female		  11/12		 11/11
- Height Mean (cm)	  137.2		 133.5
- Weight Mean (kg)	   40.3		  35.3
- Hurler-Scheie	   	19 (83%)	       18 (82%)

## Phase 3 Study:Baseline Patient Characteristics

- 				   	Placebo	   Aldurazyme
- 				   	 (n=23)		(n=22)
- % Predicted FVC
- Median		 	   53.6		  51.1
- Range			18 - 77		16 - 70
- 6MWT (meters)
- Median			  360.0		  348.5
- Range			60 - 571		14 - 591

## Phase 3 Study:Baseline Frequency of Respiratory Disease

- Respiratory Complications
- Respiratory infections				51%
- Sleep apnea					47%
- Reactive airway/asthma			24%
- Interventions
- Tonsillectomy/ Adenoidectomy	 	67%
- CPAP					  	 9%
- Nebulizer				  	 7%

## Phase 3 Study: Baseline Frequency of Musculoskeletal Disease

- Musculoskeletal Disease
- Joint stiffness				76%
- Joint contractures			51%
- Joint pain				29%
- Spinal deformity			27%
- Outcomes
- Physical therapy			31%
- Wheelchair				30%
- Walker					  7%

## Phase 3 Study:Efficacy Results

- Lysosomal Storage of GAG
- Urinary GAG level
- Liver volume
- Respiratory Function
- Functional Capacity
- Additional Efficacy Variables

## Phase 3 Study:Aldurazyme Reduces Urinary GAG Levels

- Phase 3 Study:Aldurazyme Reduces Urinary GAG Levels

**Baseline                                                            Week 26                                                       Week 50**

- p<0.001

**Mean Urinary GAG Levels (********g/mg Creatinine)**

- 0

- 300

- 150

-       Double-Blind                Open-Label Extension

- -54%

- +47%

## Phase 3 Studies:Aldurazyme Reduces Hepatomegaly

- Phase 3 Studies:Aldurazyme Reduces Hepatomegaly

- % of Baseline Liver Volume

- 	       Double-Blind     	     Open-Label Extension

- Shift from abnormal to normal liver volume in Aldurazyme patients: 	  72% after 6 months, 80% after 12 months

**60**

**65**

**70**

**75**

**80**

**85**

**90**

**95**

**100**

**105**

**110**

- Baseline

- Week 26

- Week 50

- p=0.001

## Phase 3 Efficacy Variables

- Lysosomal Storage of GAG
- Respiratory Function
- % Predicted Forced Vital Capacity (FVC)
- Co-Primary Endpoint
- Sleep Study Apnea/Hypopnea Index (AHI)
- Secondary Endpoint
- Functional Capacity
- Additional Supporting Measures

## Phase 3 Study: Aldurazyme Improves FVC

- Phase 3 Study: Aldurazyme Improves FVC

**Baseline                                                            Week 26                                                                                  Week 62**

- p= 0.009*

**Mean Change in % Predicted FVC**

-       Double-Blind                Open-Label Extension

- 0

- 2

- 4

- 6

- -2

- -4

-   * Change from Baseline

-  ANCOVA
- p= 0.007*

## Phase 3 Study: Clinically Significant Improvement in FVC

- p=0.017

*American Thoracic Society (1991)  Am Rev Resp Dis 144: 1202-18** *

## Phase 3 Study: Aldurazyme Reduces Sleep Apnea

- Phase 3 Study: Aldurazyme Reduces Sleep Apnea

- Baseline AHI  10 in children and AHI  15 in adults

- Double-Blind       	    Open-Label Extension

- -12

- -10

- -8

- -6

- -4

- -2

- 0

- 2

**          **

**Change in AHI (Events/Hr)**

- 0.3 (n=9)

- -6.0 (n=10)

- Baseline

- Week 26

- Week 50

- p = 0.014

## Phase 3 Efficacy Variables

- Lysosomal Storage of GAG
- Respiratory Function
- Functional Capacity
- 6 Minute Walk Test (6MWT)
- Co-Primary Endpoint
- Shoulder Flexion
- Secondary Endpoint
- Additional Supporting Measures

## Phase 3 Study: Aldurazyme Increases 6MWT Distance

- Phase 3 Study: Aldurazyme Increases 6MWT Distance

**Baseline                                                        Week 26                                                                                        Week 62**

-  p= 0.066*

**Mean Change, Meters**

- -10

- 10

- 30

- 50

- -30

- -50

- -40

- -20

- 0

- 20

- 40

-   * Change from Baseline

-  ANCOVA
- p= 0.039*

**Placebo**

**Aldurazyme**

-       Double-Blind                Open-Label Extension

## Phase 3 Study: Clinically Significant Improvement in 6MWT

**% Patients, 54 Meter Increase**

- p=0.047

*Redelmeier et al (1997) Am J Resp Crit Care Med 155: 1278-82*

## Phase 3 Studies:Aldurazyme Increases Shoulder Flexion

- Phase 3 Studies:Aldurazyme Increases Shoulder Flexion

- -10

- -5

- 0

- 5

- 10

- 15

- 20

- Degrees

- -4.8 (n=12)

- 9.6 (n=7)

- Shoulder Flexion  Median (90.5 **o**) at Baseline

- Double-Blind  		     Open-Label Extension

- Baseline

- Week 26

- Week 50

## Phase 3 Efficacy Variables

- Lysosomal Storage of GAG
- Respiratory Function
- Functional Capacity
- Additional Efficacy Variables
- Visual Acuity
- CHAQ/HAQ
- SF-36/CHQ

## Phase 3 Study: Aldurazyme Improves Visual Acuity

- Phase 3 Double-Blind Study
- Most patients had normal to near-normal corrected visual acuity
- In patients with the worst corrected vision (20/60), 5/6 Aldurazyme vs. 0/4 placebo patients showed a 2-line improvement in both eyes

## Phase 3 Study: Disability and Quality of Life

- After 24-26 Weeks, no significant changes
- After 50 Weeks, clinically meaningful improvements in both instruments:
- CHAQ/HAQ Disability Index Score
- SF-36/CHQ Summary and Subscale Scores
- Physical and Mental Component Scales
- General Health
- Physical Functioning
- Bodily Pain
- Social Functioning
- Need for disease-specific instruments

## Post-Hoc Analysis: Composite Endpoint Approach

## Post-Hoc Analysis: Composite Endpoint Approach

- Change in individual patients
- Accommodates patient heterogeneity
- Several domains with thresholds of clinically significant change (+1, 0, -1)
- Endpoints
- Responders
- Proportion of patients with net improvement
- Net Change
- Improvements minus declines per patient

## Phase 3 Study: Composite Endpoint

- FVC 			  	 11%
- 6MWT			 54m
- AHI			  	 10 events/hour
- Shoulder Flexion	 20 degrees
- Visual Acuity		 2 lines on eye chart

- Domains		       Clinically Significant
-                           	      Thresholds

## Phase 3 Study: Post-Hoc Analysis Composite Endpoint 

- Improvement              Decline

-    Placebo                                Aldurazyme

- No Change    NA   Not Available

- Clinically Significant Changes

## Phase 3 Study: Post-Hoc AnalysisAldurazyme Leads to Net Improvement

- Responders
-      59% Aldurazyme
-      22% Placebo
-         (p=0.016)
- Mean Net Change
-      1.0 Aldurazyme
-     -0.4 Placebo

## Aldurazyme Efficacy Summary

## Aldurazyme Efficacy Summary:Improved Respiratory Function

- FVC: Co-Primary Endpoint
- Statistically significant difference (p=0.009)
- Clinically meaningful difference between groups
- Clinically meaningful improvement in more Aldurazyme patients (41% vs. 9%, p=0.017)
- Supportive Results: AHI
- Sleep apnea in 47% of patients at baseline
- Statistically significant improvement in patients with sleep apnea (p=0.014)
- Results confirmed and maintained in extension study

## Aldurazyme Efficacy Summary: Improved Functional Capacity 

- 6MWT: Co-Primary Endpoint
- Clinically meaningful 38 m difference (p=0.066)
- Statistically significant by prospectively defined ANCOVA (p=0.039) controls for baseline variables
- Clinically meaningful increase in more Aldurazyme patients (41% vs. 13%, p=0.047)
- Supportive Results
- Shoulder flexion improvement in most restricted patients
- NYHA Scores in Phase 1/2 Study
- Results confirmed and maintained in extension study

## Aldurazyme Efficacy Summary:Additional Measures

- Visual Acuity
- Improvements in most severe patients
- Disability and Quality of Life
- Clinically meaningful improvements after 50 weeks
- Lysosomal Storage
- Urinary GAG Excretion
- Statistically significant reduction (p<0.001)
- Hepatomegaly
- Statistically significant reduction (p=0.001)
- Results confirmed and maintained in extension study

## Aldurazyme Efficacy Summary: Post-Hoc Composite Endpoint

- Broad treatment effect across individual patients
- Majority of Aldurazyme patients are responders
- 59% vs. 22% placebo (p=0.016)
- Net improvement in Aldurazyme patients
- +1.0 domain per patient vs. – 0.4 domain per placebo

## Safety and Immunogenicity

## Safety and Immunogenicity: Summary

- Overall adverse event profile similar to placebo
- Most mild or moderate and not related
- Infusion-associated reactions similar to placebo
- Most mild and no intervention required
- Majority of SAEs unrelated (29/31) in 14 patients
- Single patient had 2 related serious adverse events
- No treatment related deaths
- Most patients developed low IgG antibody titers without apparent effect on safety or efficacy

## Phase 3 Double-Blind: Overall Adverse Events 

- (30% of patients in any treatment group)

## Phase 3 Study: Infusion Associated Reactions 

- (5% of patients in any treatment group)

|  | Phase 3
Double-Blind  |  | Phase 3 
Open-Label Extension  |  |
| --- | --- | --- | --- | --- |
| WHO-ART
Preferred Term  | Placebo

N=23, n(%) | Aldurazyme

N=22, n(%) | Placebo/
Aldurazyme
N=23, n(%) | Aldurazyme/Aldurazyme
N=22, n(%) |
| Any IAR | 11 (48) | 7 (32) | 7 (30) | 8 (36) |
| Flushing | 4 (17) | 5 (23) | 1 (4) | 3 (14) |
| Fever | 3 (13) | 1 (5) | 1 (4) | 0 |
| Headache | 2 (9) | 2 (9) | 0 | 1 (5) |
| Rash | 2 (9)  | 1 (5) | 0 | 1 (5) |

## Phase 3 Study: Immunogenicity

- Phase 3 Double-Blind
- 91% (20/22) Aldurazyme patients developed                IgG antibody, generally low titers
- Median time to seroconversion: 50 days
- IgE: 3 patients tested, all negative
- 1 additional patient met criteria but not tested per investigator
- Phase 3 Open-Label Extension
- 89% (40/45) patients seroconverted at Week 24
- 2 Aldurazyme/Aldurazyme patients tolerized
- IgE: 2 patients tested, results inconsistent with          skin test and serum tryptase results

## Phase 3 Study: Immunogenicity

- Safety
- Nearly all Aldurazyme patients seroconverted, yet incidence of IARs similar to placebo
- Pharmacokinetics/Pharmacodynamics
- Decreased volume of distribution with no impact on clearance of Aldurazyme from plasma
- Sustained reductions in liver volume and GAG levels
- Efficacy
- Aldurazyme patients maintained improvements in FVC and 6MWT after seroconversion

## Conclusions

- MPS I is a rare, progressive, life-threatening disorder that represents an unmet medical need
- Aldurazyme has been demonstrated to:
- Rapidly decrease lysosomal storage of GAG
- Produce meaningful clinical improvements in respiratory function and functional capacity
- Aldurazyme is well-tolerated
- Aldurazyme has a favorable risk-benefit profile

## Clinical Perspective

- Joseph Muenzer, M.D., Ph.D.
- Associate Professor of Pediatrics
- University of North Carolina at Chapel Hill
- Principal Investigator, Phase 1/2 and
- Phase 3 clinical studies

## Clinical Perspective(points to consider) 

-  Rare Disorder
-  Progressive with some 	irreversible changes
-  Multiple organ    	involvement compounds 	symptoms
-  No treatment

- Age 5

## Clinical Perspective

-  6 Minute Walk
- Improved endurance
- Improved self-care
-  Forced Vital Capacity
- Decreased shortness of breath

## Concluding Remarks

- Matt Patterson
- Vice President
- Regulatory and Government Affairs
- BioMarin Pharmaceutical Inc.

## Statistically significant improvement 
Primary endpoint/Primary analysis: p=0.009 
Statistically significant treatment effect after controlling for baseline variables (analysis of covariance, p=0.007)
Clinically significant improvement 
41% of Aldurazyme patients had a clinically meaningful 11% increase versus 9% of placebo patients (p=0.017) 
Additional support for results 
Extension study data
Improvement in sleep apnea
Context of patient heterogeneity

- Primary endpoint/Primary analysis: p=0.009
- Statistically significant treatment effect after controlling for baseline variables (analysis of covariance, p=0.007)
- Clinically significant improvement
- 41% of Aldurazyme patients had a clinically meaningful 11% increase versus 9% of placebo patients (p=0.017)
- Additional support for results
- Extension study data
- Improvement in sleep apnea
- Context of patient heterogeneity

- Pulmonary Function as Measured by FVC

## Functional Capacity as Measured by 6MWT

- Statistical support
- Primary endpoint/Primary analysis: p=0.066
- Statistically significant treatment effect after controlling for baseline variables (analysis of covariance, p=0.039)
- Changes consistent over a range of baseline values
- Clinically significant improvement
- 41% of Aldurazyme patients had a clinically meaningful 54 meter increase versus 13% of placebo patients (p=0.047)
- Additional support for results
- Extension study data
- Improvement in shoulder flexion, NYHA
- Context of patient heterogeneity

## Demographic Subset Analyses

- Patient heterogeneity limits usefulness of subset analyses unless based on clinical manifestations
- p-values for treatment effect maintained for nearly all analyses after covariate adjustment
- FDA conclusions of no effect in demographic subsets are based on small numbers and are not supported by individual patient improvements

## Effect of Antibodies on                 Long-Term Efficacy

- No effect of antibodies on efficacy outcomes
- 1 year: FVC and 6MWT
- 3 years: urinary GAG and liver volume
- Sponsor open to working with FDA to determine appropriate means of continued data collection post-approval

## Use in Patients with Profound Respiratory Impairment

- Question highlights one single case
- Patients with a similar degree of respiratory impairment have been treated and have not experienced related serious adverse events
- Patients with profound respiratory impairment can be treated with Aldurazyme with careful management

## Effect of Antibodies on Clinical Course of Patients with Residual Enzyme Activity

- Endogenous enzyme is intracellular in lysosomes and not accessible to circulating antibodies
- Gaucher Disease experience indicates no impact of antibodies on endogenous enzyme
- All patients in Aldurazyme clinical trials have residual enzyme and improvements have been demonstrated for up to three years of treatment

## Conclusions

- MPS I is a heterogeneous, progressive disorder
- Rationale for enzyme replacement therapy well-established
- Preclinical studies predictive of successful outcome in patients
- Clinical studies demonstrated benefit
-  ERT performed as expected: lysosomal storage cleared
-  Clinical benefit: meaningful and consistent with nature of disease
-  Good safety profile
-  Infusion reactions manageable
- Favorable risk-benefit ratio