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Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977

Transkaryotic Therapies, Inc. January 14, 2003

4000.01

REPLAGAL: agalsidase alfa


Human -galactosidase A Homodimer comprised of two ~50kDa subunits Produced in continuous human cell line

Identical amino acid sequence to endogenous protein

4002.03

Clinical Summary: Replagal


Improves standard glomerular pathology Correlates with renal function
Stabilizes renal function over 30 months

Reduces LV mass
Improves cardiac conduction system function

Safe and well-tolerated after 2 years of therapy

4001.06

TKT Presentations
Introduction Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston

Fabry Disease

Renal Pathology of Fabry Disease


Replagal Clinical Data

Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT


Thomas J. Schuetz, M.D., Ph.D.

4778.05

Experts
Dr. Wilson Colucci
Chief of Cardiovascular Medicine, Boston Medical Center. Director, Myocardial Biology Unit, Boston University School of Medicine.

Dr. Christoph Kampmann


Professor of Pediatrics, Pediatric Cardiology and Neonatology, Director of the Dept. of Pediatric Cardiology, Childrens Heart Center, University Childrens Hospital, Johannes Gutenberg University, Mainz, Germany.

Dr. Edwin Kolodny


Chairman, Department of Neurology, New York University School of Medicine, New York.

Dr. Kathleen Lamborn


Professor of Neurological Surgery (Biostatistics), University of California, San Francisco.
4780.06

Experts (cont)
Dr. Atul Mehta
Consultant Hematologist, Royal Free Hospital, London, UK.

Dr. Ronald Perrone


Professor of Medicine, Tufts University School of Medicine. Associate Chief of New England Medical Center Division of Nephrology. Medical Director of Renal Transplantation, Tufts New England Medical Center, Boston.

Dr. Melvin Schwartz


Professor, Department of Pathology at Rush-Presbyterian-St Lukes Medical Center, Chicago.

4784.04

TKT Presentations
Introduction Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston

Fabry Disease

Renal Pathology of Fabry Disease


Replagal Clinical Data

Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT


Thomas J. Schuetz, M.D., Ph.D.

4546.05

Fabry Disease
X-linked glycosphingolipid lysosomal storage disorder Deficiency of -galactosidase A leading to accumulation of Gb3 Rare: Approximately 1500-2000 patients in USA Progressive, multisystem disease
Renal Cardiac Cerebrovascular Neurologic Gastrointestinal Metabolic

Death in 4th or 5th decade of life


4003.04

Disease Management

No specific treatment Patient care generally restricted to palliation:


Renal failure: dialysis/transplantation Heart disease/stroke: standard treatment GI disease: antidiarrheals Neuropathic pain: generally refractory to analgesics and opioids empiric use of anticonvulsants has been useful for pain control in some patients

4004.01

Pathophysiology
Parenchymal cell deposition of Gb3 leads to multisystem pathology
Kidney: Glomerular epithelial cells (podocytes) Glomerular mesangial cells

Renal failure Concentrating defects

Tubular epithelial cells

Heart: Myocytes Cardiomyopathy and cardiac hypertrophy Conduction system QRS complex widening Nerves: Autonomic ganglia
4005.06

Pain
10

Fabry Disease: Renal Natural History


Progression of Renal Disease Early manifestations
Proteinuria Renal concentrating defects

Late manifestations
Nephrotic syndrome Diabetes insipidus

Progressive decline in renal function

ESRD

4006.04

11

Fabry Disease: Renal Natural History


Summary
120 110 Normal

Renal Function (mL/min)

100 90
80 70 60 50 40 30 20 10 0

Impaired Renal Function

Chronic Renal Insufficiency

ESRD

Time (years)
4782.05

12

Fabry Disease: Renal Natural History


Age and Renal Function All patients (n=116)
Age: 33.6 10.4 years Renal function: 48.9 44.9 mL/min

Patients not in ESRD (n=54)


Age: 30.7 9.8 years Renal function: 85.1 33.8 mL/min

Patients in ESRD (n=62)


Age of onset: 36.7 10.1 years

4007.03

13

Fabry Disease: Renal Natural History


Decline of Renal Function Over Time
Rate of Decline of Renal Function (mL/min/yr)
21

Patient Population Individual literature patients

Patients (Number) 11

Age* 28.8 32.1

Branton, et al
TKT003, TKT005, and TKT010 placebo patients Mean

14
59 84

39.8 43.1
35.7 36.2 35.5 36.8

12.2
8.3 10.6

* Mean patient age range over the period of the decline of renal function

4008.08

14

Fabry Disease: Renal Natural History


Predicted Rate of Decline
120

Creatinine Clearance (mL/min)

100

80

8.3 mL/min/yr

10.6mL/min/yr

60
21.0mL/min/yr Predicted Rate of Decline

40
0 4741.04 6 12 18 24 30

Month

15

Fabry Disease: Renal Natural History


Age at End Stage Renal Disease
References Barnes (1975) Maizel (1981) Nissenson (1989) Tsakiris (1996) Ojo (2000) MacDermot (2001) Thadhani (2002) Branton (2002) Individual case reports in the literature Summary
* age at kidney transplant

Patients (n) 9 7 17 83 93 26 42 24 62 363 patients

Age of ESRD (yrs) 41* 43.3 Median ~40 38 388 36.7 39-42 3910 36.710.1 ~38

among the 116 patients identified in the literature search there are 62 individual case reports of patients who progressed to ESRD, and the mean age of these patients is 36.7 10.1 years.

4679.06

16

Fabry Disease: Renal Natural History


Progression to ESRD
100 Percent of Patients w/o ESRD 80

60
40 20 0

10

20

30

40

50

60

70

Age (years)

Fabry ESRD Patients


4742.02

All USRDS Patients

17

Fabry Disease: Renal Natural History


Summary
120 110 Early to mid 30s Normal ~10.6 mL/min/yr Impaired Renal Function

Renal Function (mL/min)

100 90
80 70 60 50 40 30 20 10 0

Chronic Renal Insufficiency mean age of ESRD ~38 yrs ESRD ~ 4.3 yrs

Time (years)
4009.07

18

Fabry Disease: Renal Natural History


Two Major Conclusions Beginning at approximately age 30-35 years the rate of decline of renal function is ~10.6 mL/min/year

The mean age at which patients with Fabry disease progress to ESRD is ~38 years

4011.04

19

Fabry Disease: Heart Disease


Accumulation of Gb3 in myocytes and conduction system

Cardiomyopathy with LV hypertrophy


Progressive increase in LV mass Significant age-related progression in males and females

Conduction system dysfunction


Widening of QRS complex leading to bundle branch blocks

20% incidence of cardiac death

4012.07

20

Other Manifestations
Cerebrovascular system
Stroke Altered cerebrovascular blood flow

Neuropathic pain
Chronic pain Refractory to pain medications

Gastrointestinal system
Abdominal pain; diarrhea Chronic weight loss

Progressive hearing loss


Angiokeratoma; hypohydrosis
4015.02

21

Fabry Disease: Conclusions


Complex, multisystem disorder Progressive deterioration of renal function Progressive increase in LV mass Major causes of mortality
Progressive renal failure Progressive cardiac failure

4520.04

22

TKT Presentations
Introduction Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT Thomas J. Schuetz, M.D., Ph.D.
23

Fabry Disease

Renal Pathology of Fabry Disease Replagal Clinical Data


4547.05

Kidney Pathology: Introduction


Intracellular Deposition Disease of the Nephron: Glomerular epithelial cell Gb3 deposition Glomerular mesangial widening Segmental glomerular sclerosis

Obsolescent glomeruli
Tubular epithelial cell deposition Capillary endothelial cells relatively spared

4016.03

24

Kidney: Normal Glomeruli

PAS Stain

Toluidine Blue Stain

4540.04

25

Kidney: Early Glomerular Disease

PAS Stain

Toluidine Blue Stain

4017.06

26

Kidney: Mesangial Widening

PAS Stain

Toluidine Blue Stain

4018.04

27

Kidney: Segmental Sclerosis

PAS Stain

Toluidine Blue Stain

4019.07

28

Kidney: Obsolescence

PAS Stain

Toluidine Blue Stain

4020.03

29

Histopathological Spectrum of Disease


Histopathological Progression
Early Deposition

Mesangial Widening

Segmental Sclerosis

Obsolescence
4021.03

30

Replagal Clinical Data

4867.02

31

Replagal Clinical Studies


Study NIH Clinical Study TKT001 TKT003 TKT006 TKT011 Open label, dose escalation safety study Randomized, double blind, placebo controlled Open label maintenance study for patients completing TKT003 Open label maintenance study for patients completing TKT006 10 26 25 24 single dose 6 months 1 yr 1 yr interim analysis Design # Pts Duration

RFH Clinical Study TKT005 Randomized, double blind, placebo controlled 15 6 months

University of Mainz Clinical Study TKT014 TOTAL


4026.02

Open label safety and efficacy trial in females Multidose Studies

15 56

3 12 months > 2 yrs

32

Replagal: NIH Clinical Studies

40
Patients Enrolled

TKT003

TKT006

TKT011 (1 year analysis)

30 20 10 0 0
Replagal 6 months (n=14) placebo 6 months (n=12)

Replagal (n=25)

Replagal (n=24)

Total Time of Studies (years)


4027.05

33

TKT003: Creatinine Clearance


Creatinine Clearance (mL/min)
130 120 110 100 p=0.051 (Replagal vs placebo)

90
80 70 60 0 6 TKT003 Replagal (n=14 : mean age = 34.0) TKT003 placebo (n=11 : mean age = 34.4)

Treatment Period (months)


4028.03

34

TKT003: Creatinine Clearance


Creatinine Clearance (mL/min)
130 120 110 100 90 80 70 60 0
9 5 10 15 17 20 23/24 25 Treatment Period (weeks)
Replagal Placebo

p=0.045 (Replagal vs placebo)

4683b.04

35

TKT003: Glomerular Filtration Rate (GFR)


130

GFR (mL/min/1.73m )

120 110 100 90 80 70 60


0 23/24 Treatment Period (weeks)
p=0.25 (Replagal vs placebo)

Replagal (n=14) Placebo (n=11)

4683c.05

36

TKT010: Glomerular Filtration Rate (GFR)


130

GFR (mL/min/1.73m )

120 110 100 90 80 70 60 Baseline 6 Months Treatment Period


TKT010 Replagal (n=40) TKT010 Placebo (n=40)
p=0.74 (Replagal vs placebo)

4869.01

37

NIH Clinical Trials: Creatinine Clearance


Creatinine Clearance (mL/min)
130 120 110 100 90 80 Study TKT003 Replagal Study TKT006/TKT011 Replagal (n=13) Study TKT003 placebo Study TKT006/TKT011 Replagal (n=12)

70
TKT003 60 0 6 12 18 24 30 TKT006 TKT011

Treatment Period (months)


4029.05

38

NIH Clinical Trials: GFR


130 Study TKT003 Replagal Study TKT006/TKT011 Replagal Study TKT003 placebo Study TKT006/TKT011 Replagal TKT003 TKT006 TKT011

GFR (mL/min/ 1.73m2)

120 110 100 90 80

70
60 0 6 12 18 24 30

Treatment Period (months)


4744.02

39

Renal Function: 2 years of Replagal


Creatinine Clearance (mL/min)
130 120 110 100 90 80 70 60 0 6 12 18 24
GFR TKT006 TKT011

GFR (mL/min/1.73m )

Creatinine clearance

Month
4031.02

40

Progression of Renal Disease: NIH Replagal Patients vs. Historical Controls


120

Creatinine Clearance (mL/min)

100

80

8.3 mL/min/yr 10.6 mL/min/yr

60
TKT003, TKT006, TKT011 Patients 21.0 mL/min/yr

Predicted Rate of Decline

40 0 6 12 18 24 30

Month
4034.03

41

Individual Patient Data: Creatinine Clearance


Change in Creatinine Clearance (mL/min)
72.5

70
59

50 30 10 -10 -30 -50 -70

47 38.5 32.5 28.5 21.5 16 10.5 9.5 8 6 6

-7

-8

-11

-14 -16

-20 -20

-22.5-22.5 -31

Patients
4777.04

42

Progression to ESRD: Age Range of Replagal-Treated Patients vs. Literature


Percent of Patients not in ESRD
100

80

60

40

20

10

20

30

40

50

60

70

Age (years)
Source: 4032.06 Literature Patients TKT003/006/011 Replagal Patients

43

Histopathological Spectrum of Disease


Histopathological Progression
Early Deposition

Mesangial Widening

Segmental Sclerosis

Obsolescence
4868.01

44

TKT003: Kidney Pathology


Patients underwent Baseline and Month 6 renal biopsies

Outcomes
Lipid deposition (ALDS) Chronic damage (CDS) Standard histopathology Normal glomeruli Mesangial widening Segmental sclerosis Obsolescence

Mean of 24.3 glomeruli examined per biopsy


4035.02

45

TKT003: Kidney Pathology Procedures


Biopsies performed at baseline and week 24 Biopsy cores fixed and embedded All blocks assigned random numbers Blocks sectioned and stained Investigators amended planned analysis to include assessment of standard glomerular histopathology Slides read in one batch by 2 AFIP pathologists consensus reached
4922.01

46

TKT003: Kidney Pathology


80 70 60
Normal glomeruli p=0.012 Mesangial widening p=0.010 Segmental sclerosis p=0.048 Obsolescence p=0.870

Percent

50
40 30 20

10
0

0 6m 0 6m Replagal placebo
4036.03

0 6m 0 6m 0 6m 0 6m 0 6m 0 6m Replagal placebo Replagal placebo Replagal placebo

47

Mean Baseline Creatinine Clearance vs Normal Glomeruli (%) F IGURE 2 . 1


Tr a n s k a r y o t i c Th e r a p i e s , I n c . Pr o t o c o l No . TKT0 0 3 Pa g e 1 o f 1

Me a n B a s e l i n e C rC l v s No rma l (%) P e a r s o n Co r r e l a t i o n Co e f f i c i e n t r =0 . 7 6 3 8 6 , p <0 . 0 0 0 1


200 200 180 180 160 160

r = 0.76

Creatinine Clearance

140 140 120 120


cc

100 100 80 80 60 60 40 40 20 20 0

0 00
20 20 40 40 60 60 80 80 100 100

No rma l (%) Normal Glomeruli (%)

4748.01

Re g r e s s i o n Eq u a t i o n : CC = 5 2 . 3 4 3 0 3 + 1 . 1 5 3 9 5 4 * NL

48

Mean Baseline Creatinine Clearance vs Segmental F IGURE 2 .Glomeruli 3 Sclerosis and Obsolescent (%)
Tr a n s k a r y o t i c Th e r a p i e s , I n c . Pr o t o c o l No . TKT0 0 3 Pa g e 1 o f 1

Me a n B a s e l i n e C rC l v s S e gme n t a l S c l e r o s i s a n d Ob s c e l e s c e n t G l ome r u l i (% ) P e a r s o n Co r r e l a t i o n Co e f f i c i e n t r = - 0 . 6 8 1 4 4 , p =0 . 0 0 0 2
200 200 180 180 160 160 140 140 120 120

r = -0.68

Creatinine Clearance

cc

100 100 80

80

60

60
40 20 0
0 0 20 20 40 40 60 60 80 80 100 100

40

20

gme n t a l S c l e and r o s i s Obsolescent a n d Ob s c e l e s c e n t Glomeruli G l ome r u l i (%) (%) SegmentalS e Sclerosis

4749.01

Pr o g r a m: p : \ t k t 0 0 3 \ p o s t b l a \ f d a _ 2 0 0 2 _ 0 9 \ 2 0 0 2 _ 0 9 _ 0 9 \ f _ g f r _ p a t h 3 . s a s

Re g r e s s i o n Eq u a t i o n : CC = 1 3 0 . 8 4 6 5 - 1 . 0 2 6 1 9 7 * SEG_ OB

Ou t p u t : f _ g f r _ p a t h 3 . d o c

No v e mb e r 1 5 , 2 0 0 2

07: 0

49

Renal Efficacy of Replagal: Conclusions


Replagal stabilizes renal function
Replagal may delay progression to ESRD compared with historical controls

Replagal therapy significantly improves the renal pathology of Fabry Disease


Standard renal glomerular histopathology is reasonably likely to predict clinical benefit

4039.08

50

Effect of Replagal on Cardiomyopathy: Study TKT005


Randomized, double-blind, placebo controlled study of 15 patients over six months
Males with LVH by Echo (mean LV mass = 262 g)

Reduction in cardiac Gb3 favoring Replagal, but not statistically significant

Statistically significant reduction in LV mass (MRI)


Placebo: 8.8% LV mass increase Replagal: 4.2% LV mass decrease p-value = 0.041

4040.03

51

TKT005: LV Mass by MRI


300 290

p=0.041

LV Mass (g)

280 270 260 250 240

Baseline Week 24 Placebo

Baseline Week 24 Replagal

4750.02

52

Effect of Replagal on Cardiomyopathy: NIH Studies (TKT003/TKT006)


No selection criteria for cardiomyopathy (mean cardiac mass = 219 g)

Statistically significant decline in LV mass compared to baseline


LV mass declined in 13 of the 16 patients with elevated LV mass LV mass declined to the normal range after 12 to 18 months in 8 of the 16 patients

Significant decline in QRS complex duration in Replagal treated patients compared with placebo (p = 0.047)
Replagal: 94.1 91.7 msec Placebo: 94.0 97.6 msec
4041.08

53

LV Mass: TKT003/TKT006
260
260

240
LV Mass (g)

240

p=0.006

220

220

200

p=0.023

200

180 6 12 18 (month) TKT003 Placebo/TKT006 Replagal


4751.03

180

6 12 18 (month) TKT003 Replagal/TKT006 Replagal

54

Replagal Reduces LV Mass in Female Patients (Study TKT014)


Mean LV mass at Baseline: 254 g
38.5 g decline from baseline at Week 27 (p = 0.003) 42.7 g decline from baseline at Week 41 (p = 0.039)

Statistically significant declines in cardiac mass index and wall thicknesses


LV mass declined in all 12 patients with elevated LV mass, and normalized in 4 of the 12 patients

Statistically significant improvement in QRS complex duration (p = 0.007)

4042.05

55

TKT014: LV Mass Response to Replagal


280 270 260
p=0.29 p=0.04 p=0.003

LV Mass (g)

250 240 230 220 210 200 0 (n=15) 13 (n=15) Week 27 (n=11)

41 (n=7)

4752.03

56

TKT014: LV Mass Index Long Term Therapy with Replagal


200 180
LVMI (g/m )
2

160 140

(n=13)

p=0.025
(n=13) (n=13)
Upper limit of Normal

120 100

6 Month

12

4753.05

57

Cardiac Efficacy of Replagal: Conclusions

Initiation of the reversal of cardiomyopathy


Regression of LVH Normalization of LV mass in many patients

Improved cardiac conduction system function with significantly decreased QRS duration

4043.03

58

Replagal: Metabolic Effects


Statistically significant change in body weight in Study TKT003
Placebo patients: 1.85 kg weight loss Replagal patients: 1.55 kg weight gain
p = 0.025

Long term effects confirmed in study TKT006

Gb3 declines
Plasma: ~ 50% statistically significant decline in Studies TKT003 and TKT005 Urine Sediment: 40-60% statistically significant decline in Studies TKT003 and TKT005 Tissue: Trends favoring Replagal in kidney and heart tissue
4047.05

59

Safety Experience: Adverse Events


Over 300 patients treated with Replagal

The most common adverse events were consistent with the natural history of Fabry Disease
No withdrawals due to adverse events Most events mild to moderate in severity Most assessed as not related to study drug

4049.03

60

Safety Experience: Infusion Reactions


Routine use of premedications not required
Mild infusion reactions (~10% patients) with recommended infusion over 40 minutes
Chills Facial flushing No apparent association with antibodies

Infusion reactions easily managed Infusion reactions generally disappear over time

4050.03

61

TKT003/TKT006: Infusion Reactions and IgG Antibodies

Infusion Reaction + + Antibody 6 4 10

4
10

11
15

15
25

4754.01

62

Antibody Response to Replagal Therapy


Patients originally enrolled in Studies TKT003 and TKT005
40 male patients followed for up to 2.5 years Persistent IgG antibodies observed in 12/40 patients (30%) No patients were positive for IgE, IgA, or IgM antibodies Most patients positive at 1:50 or 1:100 dilution; 1 positive at 1:2,500

Patients enrolled in Study TKT014


15 female patients followed for 3 to 12 months No patients positive for IgG, IgE, IgA or IgM antibodies

4791.03

63

Study TKT011: Plasma Gb3 Results


14
No Ab Persistent Ab Transient Ab

Plasma Gb3 nmol/mL

13 12 11 10 9 8 7 6 5 4 0 6 12 18 24 30

Months
4793.04

64

Study TKT011: Creatinine Clearance Results


150
No Ab, Transient Ab Persistent Ab

Creatinine Clearance (mL/min)

140 130 120 110 100 90 80 70 0 6 12 18 24 30

Months
4796.03

65

Study TKT011: LV Mass Results


No Ab, Transient Ab 280 260 Persistent Ab

LV Mass (g)

240 220 200 180 160 0 6

Months

12

18

4800.03

66

Antibody Response to Replagal Therapy: Conclusions


Persistent IgG antibodies may occur in approximately 30% of treated patients

No IgE antibodies or hypersensitivity


Fully human glycosylation pattern

No clear correlation of IgG antibody with infusion reactions Mean reductions in plasma and urine Gb3 are lower for subset of patients with persistent antibodies
Gb3 levels remain below baseline after 2-2.5 years of therapy

No effect of IgG antibody formation on renal function or cardiac mass No evidence of immune complex deposition
4051.03

67

Conclusions: Replagal
Improves glomerular pathology Stabilizes renal function over 30 months Delay in time to ESRD

Reduces LV mass
Improves cardiac conduction system function Concomitant metabolic improvements Safe and well-tolerated
4052.04

68

TKT Q&A Slides

69

Figure 12A: GFR vs the Fraction of Glomeruli F I GURE 1 .(%): 2 with Mesangial Widening Scatter Plot
Tr a n s k a r y o t i c Th e r a p i e s , I n c . Pr o t o c o l No . TKT0 0 3 Pa g e 1 o f 1

B a s e l i n e GFR v s Me s a n g i a l Wi d e n i n g (% ) P e a r s o n Co r r e l a t i o n Co e f f i c i e n t r = - 0 . 1 4 5 6 , p =0 . 4 8 7 4
200 200 180 180 160 160 140 140 120 120

GFR

G FR

100 100

80

80 60 40 20 0
0 0 20 20 40 40 60 60 80 80 100 100

60

40

20

Me s a n g i a l Wi d e n i n g (%) Mesangial Widening (%)


P r o g r a m: p : \ t k t 0 0 3 \ p o s t b l a \ f d a _ 2 0 0 2 _ 0 9 \ 2 0 0 2 _ 0 9 _ 0 9 \ f _ g f r _ p a t h 3 . s a s Ou t p u t : f _ g f r _ p a t h 3 . d o c No v e mb e r 1 5 , 2 0 0 2 07: 0

4532.02

70

Reversal of Proteinuria

400

Albuminuria (mg/d) Proteinuria (mg/d)

300

mg/24 Hours

200

100

Upper Limit Normal

0 0 6 12 18 24

Treatment Period (months)


4280.03

71

Effect of Replagal on Glomerular Endocapillary Gb3 Deposition

Replagal Baseline Change to Week 24 p-value 1.2 0.1 -0.7 0.2 0.04

Placebo 1.1 0.2 0.0 0.3

4787.02

72

Change of Creatinine Clearance vs Change of Normal (%) and Mesangial Widening


Tr a n s k a r y o t i c Th e r a p i e s , P r o t o c o l No . TKT0 0 3 I nc . F I GURE 4 .
a n d Me s a n g i a l W i d e n i n g ( %)
R e p l a g a l P a t i e n t s On l y No r ma l r = 0 . 2 4 8 8 p = 0 . 4 3 5 5 Me s a n g i a l W i d e n i n g r =- 0 . 5 4 9 1 8 p =0 . 0 6 4 4

Replagal Patients Only


Co r r e l a t i o n Co e f f i c i e n t : Co r r e l a t i o n Co e f f i c i e n t : Ch a n g e o f Ch a n g e o f Cr Cl Cr Cl

Ch a n g e o f C r C l v s Ch a n g e o f No r m a l ( %)
v s Ch a n g e o f v s Ch a n g e o f

Change of Creatinine Clearance

30 30

20 20

101 0 00
Change of CrCl
-1 0 -10

-2 0 -20

-3 0 -30

-4 0 -40

-5 0 -50 -40 -40

Baseline Normal (%) and Mesangial Widening (%)


C h a n g e o f No r ma l ( %) a n d Me s a n g i a l Wi d e n i n g ( %) No r ma l Normal M e s a ngi al W i den i ng Mesangial Widening

-30 -30

-20 -20

-10 -10

0 0

10 10

20 20

30 30

40 40

50 50

P r o g r a m:

p: \ t kt 003\ pos t bl a \ f da _2002_09\ 2002_09_17\ f _c c_pa t h. s as

Ou t p u t :

f _c c _pa t h. doc

S e p t e mb e r

17,

2002

10: 58

4815.01

73

TKT003 Creatinine Clearance Over/Under Collections


Mean Urine Urine Creatinine Creatinine (g) Body Weight (n=5) (mg/kg) 1.32 1.50 1.67 1.67 22.2 17.6 25.0 19.4 Visit Urine Creatinine (g) 0.85 0.94 0.86 3.19 Urine Creatinine Body Weight (mg/kg) 14.1 11.0 12.9 36.5

Visit Placebo Placebo Placebo Replagal W23 W24 W24 W9

TKT003 creatinine clearance (6 collections)


Over/under collections defined by 35% difference 2.7% of creatinine clearance measurements were over/under collections
4808.03

74

GFR in Study TKT003


GFR (MDRD Estimate) Baseline Week 24 Change to Week 24 p-value
Mean SE

Replagal (n = 14) 96.6 8.5 93.7 8.3 -2.9 5.3 0.098

Placebo (n = 11) 98.0 11.3 89.6 11.7 -8.5 2.9

4939.01

75

Replagal Liver Biodistribution vs. Dose in Humans (75 Kg patient, 2 hours after infusion)
3

2
mg/liver

0 0 0.05 0.1 0.15 0.2 0.25 Dose (mg/kg)

4823.01

76

Choice of Recommended Human Dose (0.2 mg/kg)

Phase I single (escalating) dose study Rodent biodistribution data Gb3 clearance in a knockout mouse model for Fabry disease Comparative pharmacokinetics

4816.01

77

TKT003: Two Interpretations of Placebo Arm


Creatinine Clearance (mL/min)

130 120 110 100 90 80 70 60 0 5 10 15 20 25 Treatment Period (weeks)

4783.02

78

Figure 23A: GFR vs Plasma Gb3


F I GURE 1 . 1
200 200

Tr a n s k a r y o t i c Th e r a p i e s , P r o t o c o l No . TKT0 0 3

I nc.

Pa g e 1 o f 1

B a s e l i n e GFR v s P l a s ma CTH P e a r s o n Co r r e l a t i o n Co e f i c i e n t r = - 0 . 1 6 6 7 7 p = 0 . 4 1 5

r = -0.17

180
180 160 160 140 140 120 120

GFR

GFR

100 100

80

80 60 40 20 0
4 . 00 5 . 00

60

40

20

6 . 00

7 . 00

8 . 00

9 . 00

10

10 . 00

11 . 00

12 . 00

13 . 00

14 . 00

P l a s ma CTH

15

15 . 00

16 . 00

17 . 00

18 . 00

19 . 00

20

20 . 0

P r o g r a m:

p: \ t kt 003\ pos t bl a\ f da _2002_09\ 2002_12_09\ f _gf r _c t h_bas e . s as

Plasma Gb Ou t3 put :

f _gf r _c t h_bas e . doc

De c e mb e r

9,

2002

4854.02

79

Table 20: Effect of Replagal on Interstitial Vascular Endothelial Gb3 Deposition

Vascular Endothelium Baseline Change to Week 24 p-value

Replagal (n=12) 2.0 0.23 -1.2 0.26 0.003

Placebo (n=9) 1.6 0.29 0.2 0.28

4570.01

80

Figure 9: TKT003 Kidney Pathology Results


80 70 60
Normal glomeruli p=0.012 Mesangial widening p=0.010 Segmental sclerosis p=0.048 Obsolescence p=0.870

Percent

50
40 30 20

10
0

0 6m 0 6m Replagal placebo
4712.01

0 6m 0 6m 0 6m 0 6m 0 6m 0 6m Replagal placebo Replagal placebo Replagal placebo

81

Branton, et al Decline in Renal Function


Branton et al, Medicine 2002

4916.01

82

Table 21: Reduction of Interstitial Capillary Endothelial Cell Gb3 by Agalsidase Beta (Fabrazyme, Genzyme Corporation)

Interstitial Capillary Endothelial Gb3 Content Baseline Change to Week 20 p-value

Agalsidase Beta (n=29) 1.9 0.8 -1.6 1.2 <0.001

Placebo (n=29) 2.2 0.7 0.1 1.1

4571.01

83

Effect of Replagal on Gb3 Storage in the Kidney: Peritubular Capillaries


TC4000

Baseline
330x 4914.02

Week 24

84

Figure 6: Fabry Disease: Heart Biopsy (Toluidine Blue Stain: 40x)

4581.01

85

FOS - Fabry Outcome Survey


A database on medical outcomes of patients with Fabry disease
Dr. Atul Mehta
Consultant Hematologist, Royal Free Hospital, London, UK

5001.02

86

Number of Patients on Agalsidase Alfa

Untreated
34.2% n=119

65.8 % n=217

Treated

5005.02

87

Number of Involved Organ Systems


10 9 8 7 6 5 4 3 2 1 0

Number of organ systems

Females Males

<10

10-20

20-30

30-40

40-50

50-60

60+

Age at FOS entry

5008.01

88

Clinical Manifestations in Obligate Carrier Females: MacDermot, 2001


Most frequent symptoms included:
Neuropathic pain (70%); fatigue (66%) GI symptoms (58%); chest pain/palpitations (53%) Heart valve abnormalities (48%) Angiokeratoma and abnormal renal function (35%) Arrhythmia and hypohidrosis (33%); Tinnitus (25%); hearing loss (23%); TIA or CVA (22%) LVH (19%)

4669.02

89

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