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