Post on 02-Jan-2016
FDA Review of Clinical Data
Agalsidase alfa for treatment of Fabry Disease
Transkaryotic Therapies, Inc.
FDA/Center for Biologics Evaluation and Research
Agalsidase alfaAgalsidase alfaIntroductionIntroduction
Proposed indication: “Replagal is indicated for long-term enzyme replacement therapy for patients with Fabry Disease (-galactosidase A deficiency)”
Proposed dose: 0.2 mg/kg IV every 2 weeks
Agalsidase alfaAgalsidase alfa Overview of Overview of StudiesStudies
Studies submitted to BLA:
Study
Country Design n
001 USA Single dose/dose escalation
10
003 USA Placebo-controlled 26
006 USA Noncontrolled, post 003 25
011 USA Noncontrolled, post 006 24
005 UK Placebo-controlled 15
014 Germany
Noncontrolled 15
Agalsidase alfaAgalsidase alfa OverviewOverview
Notable observations: Pain outcomes Renal function Renal histopathology Cardiac outcomes Weight changes Antibody formation Safety findings
Agalsidase alfaAgalsidase alfa Study 003 Study 003 DesignDesign
Study 003 design:
Single center, randomized, double-blind, placebo-controlled, six
months
26 Men with neuropathic pain
EvaluationsPain scores, renal biopsy, cardiac data
Primary EP: “Worst Pain” score while “off pain medication”
Many 2⁰ and 3⁰ EP
Agalsidase alfa Agalsidase alfa Study 003 Study 003 DesignDesign
Analytic Plan Primary endpoint:
T-test comparison of area under the curve of pain score change from baseline for the four “off pain medication” assessments
Numerous exploratory analyses: Repeated measures analysis Analyses of all pain assessments (on and off pain medication; RM & AUC)
Missing value imputations
Agalsidase alfa Agalsidase alfa Study 003 Study 003 ResultsResults
Primary endpoint result:
Agalsidase
n = 14m ± se
Placebon = 12m ± se
AUC - 22 ± 9 - 1 ± 14P-value 0.20
Agalsidase alfa Agalsidase alfa Study 003 Study 003 ResultsResults
Limitations to “off medication” analyses:
Inability to verify medication use status at the time of pain score assessment
Definition of “pain medication” highly problematic
Distinguished between types of analgesics
Common analgesics (e.g. NSAID, opiates) treated as ineffective on Fabry pain
Agalsidase alfa Agalsidase alfa Study 003 Study 003 ResultsResults
Additional pain outcomes and exploratory analyses
Other prospective planned analytic methods (repeated measures) and analyses of all pain assessments (mixed on and “off” medication; AUC or RM analyses) generally provide no support for a finding of efficacy in the reduction of pain.
Agalsidase alfa Agalsidase alfa Study 003 Study 003 ResultsResults
Study 003 Pain endpoint findings:
Primary endpoint data cannot be interpreted due to inability to verify pain medication usage and a problematic definition of “pain medication.”
Exploratory and additional pain data analyses also provide no evidence for a treatment effect.
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Agalsidase
Placebo
P-value
Ch to Wk 24
0 - 20 0.05
Ch to Wk 23
4 - 2 0.54
Study 003 Average Cr Cl Change (mL/min)
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Study 003 Serum Cr (mg/dL) & Cr Cl
(mL/min)Agalsidase Placebo
Cr Cr Cl Cr Cr Cl
Baseline
1.0 103 1.3 103
Week 23
1.1 107 1.9 101
Week 24
1.1 103 1.9 85
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Creatinine clearance
0 10 20 30 40 50 60 70 8060
80
100
120
NoncontrolledControlledCre
ati
nin
e C
leara
nce
Week
Placebo/Agal Agal/Agal
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Study Agalsidase
Placebo
P-value
003 - 9 - 20 0.65005 25 14 0.34
Average GFR Change (mL/min)
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
GFR
0 10 20 30 40 50 60 70 8060
80
100
120
NoncontrolledControlled
GF
R
Week
Placebo/Agal Agal/Agal
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Renal function in noncontrolled studies show no change in:
Cr Cl
GFR
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunction
Historical Assessment of Renal Deterioration
Data nRate of decline
(mL/min/yr)
Literature review 11 21
Branton et al. 14 12.2
003 Placebo subjects
11 25
Summary 36 18.7
• Average age of 38 years for onset of ESRD from literature review of 363 subjects
• Average age of 34.5 at enrollment in Study 003
Agalsidase alfa Agalsidase alfa Renal Renal FunctionFunctionLimitations of Historical
Assessment of Renal Deterioration:
Small sample size
Published data are from subjects with marked renal
insufficiency at baseline
Agalsidase alfa Agalsidase alfa HistopathologyHistopathology
Renal histopathology: Data:
Paired samples for 21 subjects Missing samples for 5 subjects:
Agalsidase n = 2, Placebo n = 3
Analyses: Acute Lipid Damage Score (ALDS) Chronic Damage Score (CDS) Standard Histopathology
Agalsidase alfa Agalsidase alfa HistopathologyHistopathology
Average ALDS score
Agalsidase
n = 11
Placebo
n = 9
P-value
Baseline 9 8 n/a
Wk 24 Change
- 2 1 0.11
Agalsidase alfa Agalsidase alfa HistopathologyHistopathology
ALDS Components
Change in:Agalsida
sen = 11m ± se
Placebo
n = 9m ± se
P-value
Endocapillary cells- 0.7 ±
0.20.0 ± 0.3
0.04
Vascular endothelium
- 1.2 ± 0.3
0.2 ± 0.3
< 0.01
Glomerular epithelial cells
0.0 ± 0.30.0 ± 0.3
0.83
Proximal tubules- 0.1 ±
0.10.1 ± 0.1
0.31
Distal tubules 0.2 ± 0.40.0 ± 0.2
0.72
Vascular media 0.0 ± 0.20.2 ± 0.4
0.80
Agalsidase alfa Agalsidase alfa HistopathologyHistopathology
Standard Histopathology
Change in fraction of glomeruli with:
Agalsidase
n = 12m ± se
Placebon = 9
m ± se
P-value
Normal appearance
0.08 ± 0.04
- 0.16 ± 0.08
0.01
Mesangial widening
- 0.13 ± 0.05
0.17 ± 0.08
0.01
Segmental sclerosis
0.04 ± 0.02
- 0.03 ± 0.02
0.05
Obsolescence
0.00 ± 0.05
0.02 ± 0.03
0.87
Agalsidase alfa Agalsidase alfa HistopathologyHistopathology
Renal histopathology limitations: Unclear clinical correlation
Limited rigor:
Criteria for “severity” of deposition
Criteria for glomerular category
Training of pathologists
Number of slides/stains/glomeruli reviewed
Source documents unavailable
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomesStudy 005 design:
Single center, randomized, double-blind, placebo-controlled, six months
15 men with left ventricular enlargement on
echo
Cardiac biopsy, MRI, echo, EKG
Primary endpoint: Cardiac Gb3
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomesStudy 005 primary endpoint:
Change to:
Agalsidase
n = 6m ± se
Placebon = 8
m ± seP-value
Week 13
- 0.0 ± 0.1
0.1 ± 0.1
0.73
Week 24
- 0.1 ± 0.2
0.1 ± 0.1
0.42
Change from baseline in cardiac Gb3 content(nmol/mcg protein)
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomes
Other cardiac outcomes:
LV mass by MRI and Echo
Electrocardiographic changes
Study 005
Study 003
Noncontrolled studies
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomesMRI LV Mass, Study 005,
Change:Agalsidas
em ± se
Placebom ± se
P-value
LV M ITT (gm)
- 12 ± 11n = 7
11 ± 12n = 8
0.10
LV M Subset (gm)
- 12 ± 11n = 7
22 ± 6n = 7
0.04
LV P Wall (mm)
0.7 ± 0.4n = 7
0.6 ± 0.6n = 7
0.95
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomes
Echo LV Mass, Study 005, Change :
Agalsidase
n = 7m ± se
Placebon = 8
m ± se
P-value
Mass(g)
- 20 ± 27 22 ± 20 0.26
Mass Index (g/m2)
4 ± 26 40 ± 28 0.66
LV P Wall (mm)
- 0.7 ± 1.0
1.0 ± 0.5
0.15
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomesLV mass findings, Study 003,
Change :Measur
eAgalsida
sen = 14
Placebon = 11
P-value
MRI (g)
4 ± 3 4 ± 6 0.93
Echo (g/m2)
14 ± 4 - 8 ± 13 0.06• Similar findings in subset of subjects
with LV enlargement, Agalsidase n = 7, Placebo n =
6
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomes
Study 006 LV massPrior
AgalsidasePrior
Placebo
MRI (g) - 22 ± 5n = 14
- 28 ± 10n = 10
Echo (g/m2)
7 ± 11n = 12
28 ± 43n = 7
Study 014 LV massSubjects completing 6
months
Echo (g/m2)
- 23 ± 6n = 11
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomesQRS duration in Study 005:
QRS duration in Study 003:
Agalsidase
n = 7m ± se
Placebo
n = 8m ± se
P-value
Change (msec)
- 12.9 ± 11.7
4.6 ± 1.9
0.81
Agalsidase
n = 14*m ± se
Placebo
n = 12m ± se
P-value
Change (msec)
- 2.4 ± 3.9
3.6 ± 1.2
0.05*one subject with intermittent BBB, baseline = 150 or 103 msec
Agalsidase alfa Agalsidase alfa Cardiac Cardiac OutcomesOutcomes
Study006 No change from
baseline 014 Duration at week 27
only
QRS Changes in Noncontrolled Studies
Agalsidase alfa Agalsidase alfa WeightWeight
Weight changes in controlled studies:
Study
Change (kg)P-
valueAgalsidase Placebo
0031.6 ± 0.6
n = 13- 1.4 ± 1.3
n = 10 0.03
0050.7 ± 0.7
n = 71.3 ± 0.5
n = 8 0.33
Agalsidase alfa Agalsidase alfa WeightWeight
Weight changes in noncontrolled studies:
Two years of follow-up, Study 006 & 011:
Prior Agalsidase group ~ 2.1 kg (n = 12)
Prior Placebo group ~ 2.7 kg (n = 9)
Six months follow-up in Study 014:
Weight gain of ~ 0.9 kg (n = 11)
Agalsidase alfa Agalsidase alfa WeightWeightLimitations of weight data:
Concomitant medication
steroids
diuretics
Unclear nutritional status
Average baseline weights in controlled studies ~ 70 kg
Agalsidase alfa Agalsidase alfa AntibodyAntibody
Antibody formation in Study 003: 50% to 64%, depending on assay (ELISA, immunoprecipitation, neutralization)
Antibody formation (ELISA) during 003, 006, 011 time periods:
13/25 (52%) positive at some point
3/13 had reversion to baseline levels
10 had persistently positive levels
-- 7 had increasing magnitude
Agalsidase alfa Agalsidase alfa Antibody ImpactAntibody Impact
Plasma Gb3 Concentration Among Subjects Completing Study 011 Interim
0 5 10 15 20 25 304
6
8
10
12
14
Persistent Ab
No Ab
Transient Ab
Pla
sm
a C
TH
(G
b3);
n
mo
l/m
L
Months
Agalsidase alfa Agalsidase alfa Antibody ImpactAntibody Impact
Urine Gb3 Content Among Subjects Completing Study 011 Interim
0 5 10 15 20 25 30
0
1000
2000
3000
4000
No Ab
Transient Ab
Persistent Ab
Uri
ne G
b 3, n
mo
l/g
Month
Agalsidase alfa Agalsidase alfa SafetySafety
Safety findings
No anaphylaxis
Infusion reactions ~ 60 % in 003
~ 40 % in 006
~ 25 % in 011
Two infusion reaction SAE
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Multi-dose studies:
47 Adult Fabry Disease subjects infused with Agalsidase at 0.2 mg/kg on alternate weeks
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Controlled studies: Study 003 (pain)
1 endpoint uninterpretable Renal, cardiac, safety data
Study 005 (cardiac) 1 endpoint: no statistical difference between treatment groups in cardiac Gb3 content
Renal, safety data
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Major observations from studies:
Renal function
Renal histopathology
Cardiac outcomes
Weight changes
Antibody formation
Infusion reactions
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Renal Function in controlled studies:
Cr Cl: Study 003—Wk 23/24 inconsistent
Study 005—uninterpretable
GFR: Study 003—no difference Study 005—no difference
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Renal function in noncontrolled studies:
GFR and CC generally unchanged over 0.5 – 2.5 years
Limitations in historical review of renal function changes over time preclude meaningful comparisons to noncontrolled clinical findings
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Renal histopathology: Vascular Gb3 deposition
Standard histopathology: Agalsidase :
fraction normal glomeruli
fraction glomeruli with mesangial widening
Placebo :
fraction glomeruli with segmental sclerosis
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Cardiac outcomes:
Study MRI Echo
005 in AgalNo difference
003No difference
No difference
LV Mass in Controlled Studies
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Cardiac outcomes:
QRS Changes in Controlled StudiesStudy
003 Duration with Agalsidase
005 No difference
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Weight changes: Study 003:
Agalsidase group gain, p = 0.03
Study 005:
No statistical difference
Study 006 & 011:
Gain of 2.1 – 2.7 kg over 2 yrs
Agalsidase alfa Agalsidase alfa Overall SummaryOverall Summary
Infusion reactions:
~ 60% in Study 003, lower in subsequent studies
Most mild – moderate severity
Antibody formation:
~ 30% have persistent antibody formation
Antibodies impact biomarkers