Transcript Endocrinologic and Metabolic Drugs Advisory Committee Meeting Aldurazyme (laronidase)

Endocrinologic and Metabolic Drugs
Advisory Committee Meeting
Aldurazyme® (laronidase)
January 15, 2003
Sponsor Presentation
1
Introduction
• Meeting subject
– Aldurazyme (laronidase) for the treatment of
Mucopolysaccharidosis I (MPS I)
• Recombinant human –L-iduronidase (rhIDU)
• Sponsor
– BioMarin Pharmaceutical Inc.
– Genzyme Corporation
2
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
3
Additional Participants
Kenneth Berger, M.D.
•
•
Assistant Professor of Medicine, Director PFT Laboratory
New York University School of Medicine
Lorne Clarke, M.D., Ph.D.
•
•
Immunology
Clinical Associate Professor of Medicine
Cornell University Medical College
Patrick Trown, Ph.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.
•
•
Pulmonary, Sleep Apnea
Chief, Division of Medical Genetics
University of Penn. School of Medicine
David Rapoport, M.D.
•
•
Pharmacokinetics
Consultant
Reed Pyeritz, M.D., Ph.D.
•
•
Principal Investigator
Associate Professor, Medical Genetics
University of British Columbia Vancouver, BC
William Kramer, Ph.D.
•
FVC Methodology
Preclinical
Consultant
4
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
5
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
6
Aldurazyme Administration
• Dose
– 100 units/kg (approximately 0.58 mg/kg)
• Route
– IV infusion once per week
7
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.
8
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
9
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
Age55
Age
10
Spectrum of Disease
•
•
•
•
•
Severe
Intermediate
Mild
Hurler
MPS I H
Hurler-Scheie
MPS I H/S
Scheie
MPS I S
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
• Normal intelligence
• Less progressive
physical problems
• Corneal clouding
• Joint stiffness
• Valvular heart disease
• Death in later decades
11
Heterogeneity in Hurler-Scheie
Severe joint disease
Tracheostomy for Airway Dz
Modest Liver enlargement
Severe joint disease
No sleep apnea
Moderate liver enlargement
Age 17
17
Age
Age
Age 12
12
Milder joint disease
Severe sleep apnea, on CPAP
Massive liver enlargement
Age
Age2222
12
MPS I
Biochemistry
-L iduronidase cleaves a terminal iduronic acid residue
from dermatan sulfate and heparan sulfate (GAG)
13
MPS Disorders
Biochemistry
MPS I
e.g. Dermatan Sulfate Degradation
Iduronidase deficiency
causes a block in the
sequential breakdown steps
of glycosaminoglycans
14
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
15
Multi-systemic Involvement
MPS I leads to disease in multiple
tissues/organ systems
-L-iduronidase
deficiency
Lysosomal
Storage of
GAG
• Respiratory
• Connective tissue
• Cardiovascular
• Gastrointestinal
• Ocular
• Neurologic
• Skeletal
16
Pulmonary Disease
• Caused by storage in lung,
airway epithelium and bone
Trach
• 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
Abnormal oar-shaped ribs,
curved clavicles and scoliosis
17
Upper Airway Obstruction
• Caused by storage at
many levels
–
–
–
–
Tongue
Lymphoid tissues
Airway epithelium
Pharyngeal soft tissues
17 year old Hurler-Scheie patient
18
Upper Airway Obstruction
• Outcomes
–
–
–
–
Respiratory insufficiency
Severe sleep apnea with cor pulmonale
CPAP/Tracheostomy
High rate of anesthesia complications/deaths
Example of Sleep Apnea
REM
Oxygen desaturation below 90% for 13% of sleep time
19
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
20
Joint Restriction and Stiffness
Hip and Knee
restriction and
contractures
Shoulder
restriction and
contractures
Age 17
Age 12
21
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 HurlerScheie patient
22
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
23
Eye Disease in MPS I
• Corneal clouding
• Retinal disease
• Glaucoma
• Outcomes
– Decreased visual acuity
– Blindness
24
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
25
Current Treatment for MPS I Patients
• Symptomatic management
– Palliates condition - does not prevent progression
– Limited utility
– High risk of anesthesia/surgical complications
• Examples
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–
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–
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Oxygen for respiratory insufficiency
CPAP/BIPAP
Tracheostomy for severe airway obstruction
Physical therapy for joint stiffness
Cardiac valve replacement surgery
26
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 severe
MPS I patients under 2 years of age
* Peters et al, 1996, 1998; Vellodi et al, 1997
27
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 HurlerScheie patient
28
Aldurazyme Clinical Program
Gerald F. Cox, M.D., Ph.D.
Medical Director
Genzyme Corporation
29
Outline
• Clinical Program
• Phase 1/2 Study - Efficacy
• Phase 3 Study - Efficacy
• Safety
• Conclusions
30
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
31
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
32
Phase 1/2:
Reduction in Urinary GAG Level
% Baseline GAG Value
100
80
60
40
p<0.001
20
0
0
52
104
152
Weeks
By Week 152, urinary GAG level approached normal
33
Phase 1/2 Study:
Reduction in Hepatosplenomegaly
% of Baseline Volumes
105
After Week 52, liver volumes
normalized in 90% (9/10) of patients
100
95
90
85
p=0.025
80
75
70
p<0.001
0
26
52
Weeks
Spleen
Liver
104
34
Phase 1/2 Study:
Long-Term Efficacy Results
Efficacy Variables
Urinary GAG Excretion
Liver Size
Baseline
Year 1
Year 2
>5 fold
elevated
63%
Reduction
74%
Reduction
All enlarged
9 normal
9 normal
None at Class I
NYHA Score
Shoulder Flexion
(degrees)
101
5 at Class I
128
Sleep Study AHI
(events/hr)
2.08
0.97*
Visual Acuity
6 at Class I
129
3 patients
All 3 patients
severely impaired improved
*Week 26
Kakkis et al. (2001) NEJM 344:182-88
35
Phase 3 Study
36
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
37
Phase 3 Study:
Design
• Design
–
–
–
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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
38
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
39
Phase 3 Study:
Baseline Patient Characteristics
Age Mean (Range)
Male/Female
Height Mean (cm)
Weight Mean (kg)
Hurler-Scheie
Placebo
Aldurazyme
(n=23)
(n=22)
15.4 (6,39)
11/12
137.2
40.3
19 (83%)
15.6 (7,43)
11/11
133.5
35.3
18 (82%)
40
Phase 3 Study:
Baseline Patient Characteristics
% Predicted FVC
Median
Range
6MWT (meters)
Median
Range
Placebo
Aldurazyme
(n=23)
(n=22)
53.6
18 - 77
51.1
16 - 70
360.0
60 - 571
348.5
14 - 591
41
Phase 3 Study:
Baseline Frequency of Respiratory Disease
• Respiratory Complications
– Respiratory infections
– Sleep apnea
– Reactive airway/asthma
51%
47%
24%
• Interventions
– Tonsillectomy/ Adenoidectomy
– CPAP
– Nebulizer
67%
9%
7%
42
Phase 3 Study: Baseline Frequency
of Musculoskeletal Disease
• Musculoskeletal Disease
–
–
–
–
Joint stiffness
Joint contractures
Joint pain
Spinal deformity
76%
51%
29%
27%
• Outcomes
– Physical therapy
– Wheelchair
– Walker
31%
30%
7%
43
Phase 3 Study:
Efficacy Results
• Lysosomal Storage of GAG
– Urinary GAG level
– Liver volume
• Respiratory Function
• Functional Capacity
• Additional Efficacy Variables
44
Phase 3 Study:
Aldurazyme Reduces Urinary GAG Levels
Mean Urinary GAG Levels (mg/mg Creatinine)
Double-Blind
Open-Label Extension
300
Placebo
Placebo/Aldurazyme
Aldurazyme
Aldurazyme/Aldurazyme
+47%
150
p<0.001
-69%
-54%
-65%
0
Baseline
Week 26
Week 50
45
Phase 3 Studies:
Aldurazyme Reduces Hepatomegaly
% of Baseline Liver Volume
Double-Blind
Open-Label Extension
110
105
100
95
p=0.001
90
85
80
75
Placebo
Placebo/Aldurazyme
70
Aldurazyme
Aldurazyme/Aldurazyme
65
60
Baseline
Week 26
Week 50
Shift from abnormal to normal liver volume in Aldurazyme patients:
72% after 6 months, 80% after 12 months
46
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
47
Phase 3 Study:
Aldurazyme Improves FVC
Double-Blind
Placebo /Aldurazyme
Aldurazyme /Aldurazyme
6
Mean Change in % Predicted FVC
Open-Label Extension
p= 0.001*
4
p= 0.009*
2
ANCOVA
p= 0.007*
0
p= 0.065**
-2
-4
Baseline
Week 26
* Change from Baseline
** Change from Week 26
Week 62
48
% Patients, 11% Increase
Phase 3 Study:
Clinically Significant Improvement in FVC
50
p=0.017
40
30
20
10
0
Placebo
Aldurazyme
American Thoracic Society (1991) Am Rev Resp Dis 144: 1202-18
49
Phase 3 Study:
Aldurazyme Reduces Sleep Apnea
Baseline AHI  10 in children and AHI  15 in adults
Double-Blind
Change in AHI (Events/Hr)
2
Open-Label Extension
0.3 (n=9)
0
-2
p = 0.014
-4
-5.5
(n=10)
-6
-8
-10
-12
-6.0 (n=10)
Placebo
Placebo/Aldurazyme
-9.2
(n=8)
Aldurazyme
Aldurazyme/Aldurazyme
Baseline
Week 26
Week 50
50
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
51
Phase 3 Study:
Aldurazyme Increases 6MWT Distance
Double-Blind
Open-Label Extension
50
40
Mean Change, Meters
30
Placebo
Placebo/Aldurazyme
Aldurazyme
Aldurazyme/Aldurazyme
p= 0.005*
20
10
p= 0.066*
0
ANCOVA
p= 0.039*
-10
p= 0.023**
-20
-30
-40
-50
Baseline
Week 26
* Change from Baseline
Week 62
** Change from Week 26
52
% Patients, 54 Meter Increase
Phase 3 Study:
Clinically Significant Improvement in 6MWT
50
p=0.047
40
30
20
10
0
Placebo
Aldurazyme
Redelmeier et al (1997) Am J Resp Crit Care Med 155: 1278-82
53
Phase 3 Studies:
Aldurazyme Increases Shoulder Flexion
Shoulder Flexion  Median (90.5 o) at Baseline
Double-Blind
20
Degrees
15
Open-Label Extension
Placebo
Placebo/Aldurazyme
15.2 (n=12)
Aldurazyme
Aldurazyme/Aldurazyme
9.6 (n=7)
10
8.7 (n=9)
5
0
-5
-4.8 (n=12)
-10
Baseline
Week 26
Week 50
54
Phase 3 Efficacy Variables
•
•
•
•
Lysosomal Storage of GAG
Respiratory Function
Functional Capacity
Additional Efficacy Variables
– Visual Acuity
– CHAQ/HAQ
– SF-36/CHQ
55
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
56
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
57
Post-Hoc Analysis:
Composite Endpoint Approach
58
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
59
Phase 3 Study: Composite Endpoint
Domains
Clinically Significant
Thresholds
FVC
6MWT
AHI
Shoulder Flexion
Visual Acuity





11%
54m
10 events/hour
20 degrees
2 lines on eye chart
60
Phase 3 Study: Post-Hoc Analysis
Composite Endpoint
Placebo
Patient
FVC
11%
6MWT SHFLEX
AHI
ACUITY
54m
20 deg 10 ev/hr 2-lines
Aldurazyme
Patient
FVC
11%
6MWT
54m
SHFLEX
AHI
ACUITY
20 deg 10 ev/hr 2-lines
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Improvement
Clinically Significant Changes
Decline
No Change
NA Not Available 61
Phase 3 Study: Post-Hoc Analysis
Aldurazyme Leads to Net Improvement
Number of Patients
12
Placebo
Aldurazyme
10
8
6
Responders
59% Aldurazyme
22% Placebo
(p=0.016)
4
Mean Net Change
2
1.0 Aldurazyme
-0.4 Placebo
0
-5 -4 -3 -2 -1 0
1 2
3
4
5
Net Change Per Patient
62
Aldurazyme Efficacy Summary
63
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
64
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
65
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
66
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
67
Safety and Immunogenicity
68
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
69
Phase 3 Double-Blind:
Overall Adverse Events
(30% of patients in any treatment group)
WHO-ART
Preferred Term
Placebo
N=23, n (%)
Aldurazyme
N = 22, n (%)
Any Adverse Event
Headache
Fever
Rhinitis
Diarrhea
Vomiting
Pain
Rash
Coughing
Upper respiratory tract infection
Earache
23 (100)
16 (70)
14 (61)
10 (43)
8 (35)
9 (39)
7 (30)
5 (22)
6 (26)
4 (17)
8 (35)
21 (95)
11 (50)
10 (45)
8 (36)
7 (32)
5 (23)
5 (23)
8 (36)
7 (32)
7 (32)
1 (5)
70
Phase 3 Study:
Infusion Associated Reactions
(5% of patients in any treatment group)
Phase 3
Double-Blind
WHO-ART
Preferred
Term
Phase 3
Open-Label Extension
Placebo
Aldurazyme
Placebo/
Aldurazyme/
Aldurazyme Aldurazyme
N=23, n(%) N=22, n(%) N=23, n(%) 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)
71
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
72
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
73
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
74
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
75
Clinical Perspective
(points to consider)
• Rare Disorder
• Progressive with some
irreversible changes
• Multiple organ
involvement compounds
symptoms
• No treatment
Age 5
76
Clinical Perspective
• 6 Minute Walk
– Improved endurance
– Improved self-care
• Forced Vital Capacity
– Decreased shortness of
breath
77
Concluding Remarks
Matt Patterson
Vice President
Regulatory and Government Affairs
BioMarin Pharmaceutical Inc.
78
Pulmonary Function as Measured by FVC
• 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
79
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
80
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
81
Effect of Antibodies on
Term Efficacy
Long-
• 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
82
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
83
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
84
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
85