1 Endocrinologic and Metabolic Drugs Advisory Committee Meeting January 15, 2003 Sponsor Presentation Aldurazyme ® (laronidase)

1

Endocrinologic and Metabolic Drugs Advisory Committee

Meeting

Endocrinologic and Metabolic Drugs Advisory Committee

Meeting

January 15, 2003

Sponsor Presentation

Aldurazyme® (laronidase)

2

IntroductionIntroduction

• Meeting subject– Aldurazyme (laronidase) for the treatment of

Mucopolysaccharidosis I (MPS I)• Recombinant human –L-iduronidase (rhIDU)

• Sponsor– BioMarin Pharmaceutical Inc.– Genzyme Corporation

3

Sponsor PresentationSponsor 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

4

Additional ParticipantsAdditional 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.

5

Regulatory HistoryRegulatory 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

6

Development HistoryDevelopment 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

7

Aldurazyme AdministrationAldurazyme Administration

• Dose– 100 units/kg (approximately 0.58 mg/kg)

• Route– IV infusion once per week

8

Proposed IndicationProposed 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.

9

Description of MPS IDescription 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

10

Mucopolysaccharidosis I (MPS I)A lysosomal storage disorder

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 5Age 5

11

Spectrum of DiseaseSpectrum of Disease

• 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

ScheieMPS I S

12

Heterogeneity in Hurler-ScheieHeterogeneity in Hurler-Scheie

Severe joint diseaseTracheostomy for Airway DzModest Liver enlargement

Severe joint diseaseNo sleep apneaModerate liver enlargement

Milder joint diseaseSevere sleep apnea, on CPAPMassive liver enlargement

Age 17 Age 12 Age 22Age 17 Age 12 Age 22

13

MPS IBiochemistry

MPS IBiochemistry

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

14

MPS Disorders BiochemistryMPS Disorders Biochemistry

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

e.g. Dermatan Sulfate Degradation

MPS I

15

Lysosomal Storage in MPS ILysosomal Storage in MPS I

Virtually all tissues have some degree of storage and disease

Methylene blue stained thick section from MPS I dog liver

16

Lysosomal Storage of

GAG

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

-L-iduronidasedeficiency

Multi-systemic InvolvementMulti-systemic Involvement

MPS I leads to disease in multiple tissues/organ systems

17

Pulmonary DiseasePulmonary 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

Trach

Abnormal oar-shaped ribs, curved clavicles and scoliosis

18

Upper Airway ObstructionUpper Airway Obstruction

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

tissues

17 year old Hurler-Scheie patient

19

Upper Airway ObstructionUpper Airway Obstruction

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

Oxygen desaturation below 90% for 13% of sleep time

REM

Example of Sleep Apnea

20

Joint and Skeletal DiseaseJoint 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

21

Joint Restriction and StiffnessJoint Restriction and Stiffness

Hip and Knee restriction and contractures

Shoulder restriction and contractures

Age 17 Age 12

22

Enlarged Liver and SpleenEnlarged 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

23

Cardiac Disease in MPS ICardiac 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

24

Eye Disease in MPS IEye Disease in MPS I

• Corneal clouding• Retinal disease• Glaucoma

• Outcomes– Decreased visual acuity– Blindness

25

CNS Disease in MPS ICNS Disease in MPS I

• Caused by storage in neurons, macrophages, and meninges

• Outcomes– Mental retardation in

severe patients– Communicating hydrocephalus– Headaches– Spinal cord compression

26

Current Treatment for MPS I Patients

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

27

MPS I Bone Marrow Transplantation

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

28

MPS IA lysosomal storage disorder

MPS IA 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

29

Aldurazyme Clinical ProgramAldurazyme Clinical Program

Gerald F. Cox, M.D., Ph.D.Medical Director

Genzyme Corporation

30

OutlineOutline

• Clinical Program

• Phase 1/2 Study - Efficacy

• Phase 3 Study - Efficacy

• Safety

• Conclusions

31

Clinical ProgramClinical 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

32

Phase 1/2 StudyPhase 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

33

Phase 1/2:Reduction in Urinary GAG Level

Phase 1/2:Reduction in Urinary GAG Level

By Week 152, urinary GAG level approached normal

p<0.001

% B

ase

line G

AG

Valu

e

Weeks

100

80

60

40

20

00 52 104 152

34

Phase 1/2 Study:Reduction in Hepatosplenomegaly

Weeks0 26 52 104

% o

f B

ase

line V

olu

mes

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

35

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 patientsseverely impaired

All 3 patients improved

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

*Week 26

36

Phase 3 StudyPhase 3 Study

37

Phase 3 Study:Endpoint Considerations

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

38

Phase 3 Study:Design

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

39

Phase 3 Study:Efficacy Variables

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

40

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 11/11Height Mean (cm) 137.2 133.5Weight Mean (kg) 40.3 35.3Hurler-Scheie 19 (83%) 18 (82%)

41



Placebo Aldurazyme (n=23) (n=22)

% Predicted FVC Median 53.6 51.1Range 18 - 77 16 - 70

6MWT (meters)Median 360.0 348.5Range 60 - 571 14 - 591

42

Phase 3 Study:Baseline Frequency of Respiratory

Disease

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%

43

Phase 3 Study: Baseline Frequency

of Musculoskeletal Disease

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%

44

Phase 3 Study:Efficacy ResultsPhase 3 Study:Efficacy Results

• Lysosomal Storage of GAG– Urinary GAG level– Liver volume

• Respiratory Function

• Functional Capacity

• Additional Efficacy Variables

45

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

Uri

nary

GA

G L

evels

(g

/mg

Cre

ati

nin

e)

0

300

150

Double-Blind Open-Label Extension

-54%

+47%

Placebo

Aldurazyme

-69%

-65%

Placebo/Aldurazyme

Aldurazyme/Aldurazyme

46

Phase 3 Studies:Aldurazyme Reduces

Hepatomegaly

Phase 3 Studies:Aldurazyme Reduces

Hepatomegaly%

of

Base

line L

iver

Volu

me


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

6065707580859095

100105110

Placebo

Aldurazyme


p=0.001

Placebo/Aldurazyme


47

Phase 3 Efficacy VariablesPhase 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

48

Phase 3 Study: Aldurazyme Improves FVC

Phase 3 Study: Aldurazyme Improves FVC


p= 0.009*

Mean

Ch

an

ge in

% P

red

icte

d F

VC


0

2

4

6

-2

-4

* Change from Baseline

PlaceboAldurazyme

ANCOVAp= 0.007*

p= 0.001*

p= 0.065**

Placebo /AldurazymeAldurazyme /Aldurazyme

** Change from Week 26

49

Phase 3 Study: Clinically Significant Improvement

in FVC

Phase 3 Study: Clinically Significant Improvement

in FVC

0

10

20

30

40

50

Placebo Aldurazyme

% P

atie

nts,

11%

Inc

reas

e

p=0.017

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

50

Phase 3 Study: Aldurazyme Reduces Sleep Apnea

Phase 3 Study: Aldurazyme Reduces Sleep ApneaBaseline AHI 10 in children and AHI 15 in adults


-12

-10

-8

-6

-4

-2

0

2

Ch

an

ge

in A

HI (

Eve

nts

/Hr) 0.3 (n=9)

-6.0 (n=10)Placebo

Aldurazyme

Placebo

Aldurazyme


p = 0.014

-9.2 (n=8)

-5.5 (n=10)

Placebo/Aldurazyme


51


• Lysosomal Storage of GAG

• Respiratory Function

• Functional Capacity – 6 Minute Walk Test (6MWT)

• Co-Primary Endpoint– Shoulder Flexion

• Secondary Endpoint

• Additional Supporting Measures

52

Phase 3 Study: Aldurazyme Increases 6MWT

Distance

Phase 3 Study: Aldurazyme Increases 6MWT

Distance


p= 0.066*

Mean

Ch

an

ge,

Mete

rs

-10

10

30

50

-30

-50

-40

-20

0

20

40

* Change from Baseline

ANCOVAp= 0.039*

Placebo

Aldurazyme


p= 0.023**

p= 0.005*

** Change from Week 26

Placebo/Aldurazyme


53

Phase 3 Study: Clinically Significant Improvement in

6MWT

Phase 3 Study: Clinically Significant Improvement in

6MWT

0

10

20

30

40

50

Placebo Aldurazyme

% P

ati

en

ts,

54 M

ete

r In

cre

ase

p=0.047

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

54

Phase 3 Studies:Aldurazyme Increases Shoulder

Flexion

Phase 3 Studies:Aldurazyme Increases Shoulder

Flexion

-10

-5

0

5

10

15

20

Deg

rees

-4.8 (n=12)

9.6 (n=7)

Shoulder Flexion Median (90.5 o) at Baseline


Placebo

Aldurazyme

Placebo

Aldurazyme


15.2 (n=12)

8.7 (n=9)

Placebo/Aldurazyme


55


• Lysosomal Storage of GAG• Respiratory Function• Functional Capacity• Additional Efficacy Variables

– Visual Acuity– CHAQ/HAQ– SF-36/CHQ

56

Phase 3 Study: Aldurazyme Improves Visual

Acuity

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

57

Phase 3 Study: Disability and Quality of Life

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

58

Post-Hoc Analysis: Composite Endpoint Approach


59



• 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

60

Phase 3 Study: Composite Endpoint

Phase 3 Study: Composite Endpoint

FVC 11%6MWT 54mAHI 10 events/hourShoulder Flexion 20 degreesVisual Acuity 2 lines on eye

chart

Domains Clinically Significant Thresholds

61

Phase 3 Study: Post-Hoc Analysis Composite Endpoint

Phase 3 Study: Post-Hoc Analysis Composite Endpoint

Patient FVC 6MWT SHFLEX AHI ACUITY Patient FVC 6MWT SHFLEX AHI ACUITY11% 54m 20 deg 10 ev/ hr 2-lines 11% 54m 20 deg 10 ev/ hr 2-lines

1 242 253 264 275 286 297 308 319 3210 3311 3412 3513 3614 3715 3816 3917 4018 4119 4220 4321 4422 4523

Improvement Decline

Placebo Aldurazyme

No Change NA Not Available

Clinically Significant Changes

62

Phase 3 Study: Post-Hoc AnalysisAldurazyme Leads to Net

Improvement

Phase 3 Study: Post-Hoc AnalysisAldurazyme Leads to Net

Improvement

0

2

4

6

8

10

12

-5 -4 -3 -2 -1 0 1 2 3 4 5

Net Change Per Patient

Num

ber

of P

atie

nts Placebo

AldurazymeResponders 59% Aldurazyme 22% Placebo (p=0.016)

Mean Net Change 1.0 Aldurazyme -0.4 Placebo

63

Aldurazyme Efficacy SummaryAldurazyme Efficacy Summary

64

Aldurazyme Efficacy Summary:Improved Respiratory FunctionAldurazyme 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

65

Aldurazyme Efficacy Summary: Improved Functional Capacity 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

66

Aldurazyme Efficacy Summary:Additional Measures

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

67

Aldurazyme Efficacy Summary: Post-Hoc Composite EndpointAldurazyme 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

68

Safety and ImmunogenicitySafety and Immunogenicity

69

Safety and Immunogenicity: Summary

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

70

Phase 3 Double-Blind: Overall Adverse Events Phase 3 Double-Blind:

Overall Adverse Events

1 (5)8 (35)Earache

7 (32)4 (17)Upper respiratory tract infection

7 (32)6 (26)Coughing

8 (36)5 (22)Rash

5 (23)7 (30)Pain

5 (23)9 (39)Vomiting

7 (32)8 (35)Diarrhea

8 (36)10 (43)Rhinitis

10 (45) 14 (61)Fever

11 (50) 16 (70)Headache

21 (95)23 (100)Any Adverse Event

Aldurazyme

N = 22, n (%)Placebo

N=23, n (%)WHO-ART

Preferred Term

(30% of patients in any treatment group)

71

Phase 3 Study: Infusion Associated Reactions

Phase 3 Study: Infusion Associated Reactions

(5% of patients in any treatment group)

Phase 3Double-Blind

Phase 3 Open-Label Extension

WHO-ARTPreferred

Term

Placebo

N=23, n(%)

Aldurazyme

N=22, n(%)

Placebo/Aldurazym

eN=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)

72

Phase 3 Study: ImmunogenicityPhase 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

73

Phase 3 Study: ImmunogenicityPhase 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

74

ConclusionsConclusions

• 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

75

Clinical PerspectiveClinical 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

76

Clinical Perspective(points to consider)

Clinical Perspective(points to consider)

• Rare Disorder

• Progressive with some irreversible changes

• Multiple organ involvement compounds

symptoms

• No treatment Age 5

77

Clinical PerspectiveClinical Perspective

• 6 Minute Walk– Improved endurance

– Improved self-care

• Forced Vital Capacity

– Decreased shortness of breath

78

Concluding RemarksConcluding Remarks

Matt PattersonVice President

Regulatory and Government AffairsBioMarin Pharmaceutical Inc.

79

• 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

Pulmonary Function as Measured by FVC

Pulmonary Function as Measured by FVC

80

Functional Capacity as Measured by 6MWT

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

81

Demographic Subset AnalysesDemographic 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

82

Effect of Antibodies on Long-Term Efficacy

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

83

Use in Patients with Profound Respiratory Impairment

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

84

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

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

85

ConclusionsConclusions

• 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

Documents

1 Endocrinologic and Metabolic Drugs Advisory Committee Meeting January 15, 2003 Sponsor Presentation Aldurazyme ® (laronidase)