Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
4000.01
4002.03
Reduces LV mass
Improves cardiac conduction system function
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
4778.05
Experts
Dr. Wilson Colucci
Chief of Cardiovascular Medicine, Boston Medical Center. Director, Myocardial Biology Unit, Boston University School of Medicine.
Experts (cont)
Dr. Atul Mehta
Consultant Hematologist, Royal Free Hospital, London, UK.
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
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
Disease Management
4004.01
Pathophysiology
Parenchymal cell deposition of Gb3 leads to multisystem pathology
Kidney: Glomerular epithelial cells (podocytes) Glomerular mesangial cells
Heart: Myocytes Cardiomyopathy and cardiac hypertrophy Conduction system QRS complex widening Nerves: Autonomic ganglia
4005.06
Pain
10
Late manifestations
Nephrotic syndrome Diabetes insipidus
ESRD
4006.04
11
100 90
80 70 60 50 40 30 20 10 0
ESRD
Time (years)
4782.05
12
4007.03
13
Patients (Number) 11
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
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
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
60
40 20 0
10
20
30
40
50
60
70
Age (years)
17
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
The mean age at which patients with Fabry disease progress to ESRD is ~38 years
4011.04
19
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
21
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
Obsolescent glomeruli
Tubular epithelial cell deposition Capillary endothelial cells relatively spared
4016.03
24
PAS Stain
4540.04
25
PAS Stain
4017.06
26
PAS Stain
4018.04
27
PAS Stain
4019.07
28
Kidney: Obsolescence
PAS Stain
4020.03
29
Mesangial Widening
Segmental Sclerosis
Obsolescence
4021.03
30
4867.02
31
RFH Clinical Study TKT005 Randomized, double blind, placebo controlled 15 6 months
15 56
32
40
Patients Enrolled
TKT003
TKT006
30 20 10 0 0
Replagal 6 months (n=14) placebo 6 months (n=12)
Replagal (n=25)
Replagal (n=24)
33
90
80 70 60 0 6 TKT003 Replagal (n=14 : mean age = 34.0) TKT003 placebo (n=11 : mean age = 34.4)
34
4683b.04
35
GFR (mL/min/1.73m )
4683c.05
36
GFR (mL/min/1.73m )
4869.01
37
70
TKT003 60 0 6 12 18 24 30 TKT006 TKT011
38
70
60 0 6 12 18 24 30
39
GFR (mL/min/1.73m )
Creatinine clearance
Month
4031.02
40
100
80
60
TKT003, TKT006, TKT011 Patients 21.0 mL/min/yr
40 0 6 12 18 24 30
Month
4034.03
41
70
59
-7
-8
-11
-14 -16
-20 -20
-22.5-22.5 -31
Patients
4777.04
42
80
60
40
20
10
20
30
40
50
60
70
Age (years)
Source: 4032.06 Literature Patients TKT003/006/011 Replagal Patients
43
Mesangial Widening
Segmental Sclerosis
Obsolescence
4868.01
44
Outcomes
Lipid deposition (ALDS) Chronic damage (CDS) Standard histopathology Normal glomeruli Mesangial widening Segmental sclerosis Obsolescence
45
46
Percent
50
40 30 20
10
0
0 6m 0 6m Replagal placebo
4036.03
47
r = 0.76
Creatinine Clearance
100 100 80 80 60 60 40 40 20 20 0
0 00
20 20 40 40 60 60 80 80 100 100
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
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
4039.08
50
4040.03
51
p=0.041
LV Mass (g)
4750.02
52
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
54
4042.05
55
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
160 140
(n=13)
p=0.025
(n=13) (n=13)
Upper limit of Normal
120 100
6 Month
12
4753.05
57
Improved cardiac conduction system function with significantly decreased QRS duration
4043.03
58
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
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
Infusion reactions easily managed Infusion reactions generally disappear over time
4050.03
61
4
10
11
15
15
25
4754.01
62
4791.03
63
13 12 11 10 9 8 7 6 5 4 0 6 12 18 24 30
Months
4793.04
64
Months
4796.03
65
LV Mass (g)
Months
12
18
4800.03
66
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
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
4532.02
70
Reversal of Proteinuria
400
300
mg/24 Hours
200
100
0 0 6 12 18 24
71
Replagal Baseline Change to Week 24 p-value 1.2 0.1 -0.7 0.2 0.04
4787.02
72
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
30 30
20 20
101 0 00
Change of CrCl
-1 0 -10
-2 0 -20
-3 0 -30
-4 0 -40
-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:
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
74
4939.01
75
Replagal Liver Biodistribution vs. Dose in Humans (75 Kg patient, 2 hours after infusion)
3
2
mg/liver
4823.01
76
Phase I single (escalating) dose study Rodent biodistribution data Gb3 clearance in a knockout mouse model for Fabry disease Comparative pharmacokinetics
4816.01
77
4783.02
78
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:
Plasma Gb Ou t3 put :
De c e mb e r
9,
2002
4854.02
79
4570.01
80
Percent
50
40 30 20
10
0
0 6m 0 6m Replagal placebo
4712.01
81
4916.01
82
Table 21: Reduction of Interstitial Capillary Endothelial Cell Gb3 by Agalsidase Beta (Fabrazyme, Genzyme Corporation)
4571.01
83
Baseline
330x 4914.02
Week 24
84
4581.01
85
5001.02
86
Untreated
34.2% n=119
65.8 % n=217
Treated
5005.02
87
Females Males
<10
10-20
20-30
30-40
40-50
50-60
60+
5008.01
88
4669.02
89