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
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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
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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.
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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
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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
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Aldurazyme AdministrationAldurazyme Administration
• Dose– 100 units/kg (approximately 0.58 mg/kg)
• Route– IV infusion once per week
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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.
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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
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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
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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
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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
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MPS IBiochemistry
MPS IBiochemistry
-L iduronidase cleaves a terminal iduronic acid residue from dermatan sulfate and heparan sulfate (GAG)
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MPS Disorders BiochemistryMPS Disorders Biochemistry
Iduronidase deficiency causes a block in the sequential breakdown steps of glycosaminoglycans
e.g. Dermatan Sulfate Degradation
MPS I
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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
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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
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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
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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
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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
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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
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Joint Restriction and StiffnessJoint Restriction and Stiffness
Hip and Knee restriction and contractures
Shoulder restriction and contractures
Age 17 Age 12
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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
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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
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Eye Disease in MPS IEye Disease in MPS I
• Corneal clouding• Retinal disease• Glaucoma
• Outcomes– Decreased visual acuity– Blindness
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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
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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
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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
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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
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Aldurazyme Clinical ProgramAldurazyme Clinical Program
Gerald F. Cox, M.D., Ph.D.Medical Director
Genzyme Corporation
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OutlineOutline
• Clinical Program
• Phase 1/2 Study - Efficacy
• Phase 3 Study - Efficacy
• Safety
• Conclusions
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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
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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
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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
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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
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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
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Phase 3 StudyPhase 3 Study
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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
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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
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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
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Phase 3 Study:Baseline Patient Characteristics
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%)
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Phase 3 Study:Baseline Patient Characteristics
Phase 3 Study:Baseline Patient Characteristics
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
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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%
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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%
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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
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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
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Phase 3 Studies:Aldurazyme Reduces
Hepatomegaly
Phase 3 Studies:Aldurazyme Reduces
Hepatomegaly%
of
Base
line L
iver
Volu
me
Double-Blind Open-Label Extension
Shift from abnormal to normal liver volume in Aldurazyme patients: 72% after 6 months, 80% after 12 months
6065707580859095
100105110
Placebo
Aldurazyme
Baseline Week 26 Week 50
p=0.001
Placebo/Aldurazyme
Aldurazyme/Aldurazyme
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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
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Phase 3 Study: Aldurazyme Improves FVC
Phase 3 Study: Aldurazyme Improves FVC
Baseline Week 26 Week 62
p= 0.009*
Mean
Ch
an
ge in
% P
red
icte
d F
VC
Double-Blind Open-Label Extension
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
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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
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Phase 3 Study: Aldurazyme Reduces Sleep Apnea
Phase 3 Study: Aldurazyme Reduces Sleep ApneaBaseline AHI 10 in children and AHI 15 in adults
Double-Blind Open-Label Extension
-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
Baseline Week 26 Week 50
p = 0.014
-9.2 (n=8)
-5.5 (n=10)
Placebo/Aldurazyme
Aldurazyme/Aldurazyme
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Phase 3 Efficacy VariablesPhase 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
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Phase 3 Study: Aldurazyme Increases 6MWT
Distance
Phase 3 Study: Aldurazyme Increases 6MWT
Distance
Baseline Week 26 Week 62
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
Double-Blind Open-Label Extension
p= 0.023**
p= 0.005*
** Change from Week 26
Placebo/Aldurazyme
Aldurazyme/Aldurazyme
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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
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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
Double-Blind Open-Label Extension
Placebo
Aldurazyme
Placebo
Aldurazyme
Baseline Week 26 Week 50
15.2 (n=12)
8.7 (n=9)
Placebo/Aldurazyme
Aldurazyme/Aldurazyme
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Phase 3 Efficacy VariablesPhase 3 Efficacy Variables
• Lysosomal Storage of GAG• Respiratory Function• Functional Capacity• Additional Efficacy Variables
– Visual Acuity– CHAQ/HAQ– SF-36/CHQ
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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
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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
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Post-Hoc Analysis: Composite Endpoint Approach
Post-Hoc Analysis: Composite Endpoint Approach
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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
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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
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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
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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
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Aldurazyme Efficacy SummaryAldurazyme Efficacy Summary
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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
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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
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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
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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
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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)
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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