Transcript GAUCHER DISEASE THE ICCG REGISTRY

Expected Response to Enzyme Replacement Therapy
For Gaucher Disease, Type 1
Neal J. Weinreb, M.D.
Patient Demographics - Type 1 Patients
Mean
Ages
On
ERT
Not
On ERT
Age
Mean (SD)
Range
(n=1601)
37.1 (19.5)
1, 92
(n=518)
39.3 (20.6)
0, 93
Diagnosis
Mean (SD)
Range
(n=1406)
17.9 (17.4)
0, 82
(n=488)
25.7 (19.4)
0, 91
First Infusion
Mean (SD)
Range
(n=1600)
30.6 (19.2)
0, 84
N/A
2000 Gaucher Registry Aggregate Data Report
Patient Genotypes - Type 1 Patients
Genotype
On ERT
Not On ERT
N370S/?
190 (19%)
48 (16%)
N370S/N370S
275 (28%)
169 (56%)
N370S/L444P
164 (17%)
31 (10%)
N370S/84GG
144 (15%)
12 (4%)
L444P/L444P
26 (3%)
1 (<1%)
L444P/?
28 (3%)
3 (1%)
N370S/IVS2+1
28 (3%)
4 (1%)
?/?
13 (1%)
4 (1%)
All Others
118 (12%)
29 (10%)
Sixty percent (1287/2129) of all Type 1 patients enrolled reported genotype.
2000 Gaucher Registry Aggregate Data Report
HEMOGLOBIN RESPONSE TO ERT: 6 PATIENT COHORTS
HEMOGLOBIN RESPONSE TO ERT IN A SINGLE PATIENT COHORT
N=57
N=30
N=135
N=49
N=19
N=78
PLATELET RESPONSE TO ERT: 6 PATIENT COHORTS
PLATELET RESPONSE TO ERT IN A SINGLE PATIENT COHORT
N=140
N=222
N=16
N=82
LIVER RESPONSE TO ERT: 6 PATIENT COHORTS
REDUCTION IN HEPATOMEGALY WITH ERT IN A SINGLE PATIENT COHORT
N=17
N=11
N=35
N=94
N=83
N=18
SPLEEN RESPONSE TO ERT: 6 PATIENT COHORTS
REDUCTION IN SPLENOMEGALY WITH ERT IN A SINGLE PATIENT COHORT
N=53
N=96
N=43
Impact of Skeletal Manifestations
• Discomfort, pain, and disability occur in a
majority of patients.
• Impact QOL more than hematological and
organ abnormalities.
• Bone disease is common even with normal
hematology.
History of Bone Symptoms at
Baseline Type 1 Patients
Symptom
On ERT
Not on
ERT
Bone Pain
66%
(811/1232)
49%
(147/299)
Bone Crisis
29%
(336/1162)
5%
(15/280)
2000 Gaucher Registry Aggregate Data Report
History of Bone Disease at Baseline –
Type 1 Patients
On ERT
Not on ERT
Radiological
Bone Disease
94% (1201/1278)
76% (275/360)
Avascular
Necrosis
34% (406/1201)
12% (32/275)
Erlenmeyer Flask
Deformity
61% (733/1201)
56% (153/275)
Infarction
35% (424/1201)
16% (45/275)
Joint Replacement
14% (171/1201)
6% (16/275)
Lytic Lesions
18% (214/1201)
10% (28/275)
Marrow
Infiltration
59% (708/1201)
53% (147/275)
New Fractures
26% (310/1201)
10% (28/275)
Osteopenia
50% (595/1201)
34% (94/275)
2000 Gaucher Registry Aggregate Data Report
Percent of
Patients
Gaucher Registry: Baseline Severe Bone
Disease Inpatients on ERT
60
50
40
30
20
10
0
55
49
45
34
N = 449
N = 196
1992-94
1995-96
N = 159
1997-98
Year of 1st Infusion
N = 61
1999-00
Gaucher Registry: Mean Age at 1st Infusion
35
Mean Age (Years)
30
29.3
29.4
28.3
25
23.4
20
15
10
5
0
1992-94
N = 810
1995-96
N = 311
1997-98
N = 237
Year of 1st Infusion
1999-00
N = 73
History of Bone Pain at Baseline - Type 1 Patients
By Age Category
90
Percent of Patients
80
Yes No
76.5
69.1
70
62.3
60
50
60.3
58.9
51.9
48.1
58.3
50.8
49.2
41.1
40
39.7
38.8
41.7
30.9
30
23.5
20
10
0
0-18 Y 19-40 Y 41-60 Y 61+ Y
N=335
N=362 N=247
Patients on ERT
N=90
0-18 Y 19-40 Y 41-60 Y 61+ Y
N=80
Gaucher Registry: April 2001
N=122
N=73
N=36
Patients Not on ERT
History of Bone Crises at Baseline
Type 1 Patients By Age Category
100.0
92.6
Yes
90.0
Percent of Patients
80.0
94.5
97.1
97.0
No
80.0
78.3
70.4
70.0
61.9
60.0
50.0
38.1
40.0
31.6
29.6
30.0
20.0
20.0
7.4
10.0
5.5
3.0
2.9
0.0
0-18 Y 19-40 Y 41-60 Y 61+ Y
N=304 N=312
N=21
Patients on ERT
N=81
0-18 Y 19-40 Y 41-60 Y 61+ Y
N=81
N=110
N=67
N=34
Patients Not on ERT
History of Bone Disease at Baseline
Type 1 Patients By Age Category
100.0
96.7
98.1
97.5
93.2
Yes
90.0
No
87.2
82.5
Percent of Patients
80.0
73.7
76.4
70.0
60.0
50.0
40.0
30.0
26.3
23.6
17.5
20.0
12.8
10.0
6.8
3.3
1.9
2.5
0.0
0-18 Y 19-40 Y 41-60 Y 61+ Y
0-18 Y 19-40 Y 41-60 Y 61+ Y
N=339 N=360 N=266
N=80
Patients on ERT
N=81
Gaucher Registry: April 2001
N=118
N=72
N=39
Patients Not on ERT
History of Bone Pain at Baseline
Type 1 Patients By Genotype
70
63.6
63.2
Yes
No
60
Percent of Patients
52.3
50
40
52.2
47.7
36.8
47.8
36.4
30
20
10
0
N370S/N370S
N=209
All Others
N=472
Patients on ERT
N370S/N370S
N=130
All Others
N=92
Patients Not on ERT
History of Bone Crises at Baseline
Type 1 Patients By Genotype
99.2
100.0
90.0
80.0
Percent of Patients
89.7
Yes No
77.0
70.0
66.5
60.0
50.0
40.0
33.5
30.0
23.0
20.0
10.3
10.0
0.8
0.0
N370S/N370S
N=196
All Others
N=454
Patients on ERT
N370S/N370S
N=129
All Others
N=87
Patients Not on ERT
History of Bone Disease at Baseline
Type 1 Patients By Genotype
100.0
Percent of Patients
90.0
95.2
98.5
Yes
No
79.8
80.0
73.6
70.0
60.0
50.0
40.0
30.0
26.4
20.2
20.0
10.0
4.8
1.5
0.0
N370S/N370S
N=194
All Others
N=501
Patients on ERT
N370S/N370S
N=125
All Others
N=99
Patients Not on ERT
Mobility History at Baseline –
Type 1 Patients on ERT
Walks with
Difficulty : 12.0%
Orthopedic
Aid: 7.1%
Wheelchair: 1.2%
Bedridden: 0.5%
N=602
Unrestricted: 79.2%
Gaucher Registry: March 2001
Skeletal Response to ERT
Neal J. Weinreb, M.D.
Problems in Assessing Skeletal
Symptoms and Response to ERT
• Multiple etiologies
– Degenerative vertebral disk disease
– Concurrent “senile” osteoporosis
– Degenerative and other arthritis
– Increased incidence of myeloma
• Uncertain correlation between clinical and
MRI status
Concurrent Illnesses in Patients > 65 Years Old
50.0%
N = 159
45.0%
40.0%
38.4%
Percent of Patients
35.0%
30.0%
25.0%
24.5%
20.0%
20.1%
18.2%
15.0%
17.6%
10.0%
5.0%
0.0%
Cardiovascular
Musculoskeletal
Gastrointestinal
Renal/Urological
Disease Category
Gaucher Registry: March 2001
Metabolic/Endocrine
Response to ERT (Literature)
• Decreases in bone pain during first year
– Both frequency and intensity
• Radiological improvement rare
• Painful crises may persist more than 3
years
• New AVN and fractures may occur
History of Bone Pain
12 Months*
24 Months**
Overall at 24 Months
N-64/76(84.2%)
N-129/292(44.2%)
Y-12/76(15.8%)
N-89/172(51.7%)
Y (n=620)
N-25/96(26.0%)
Y-83/172(48.3%)
Y-163/292(55.8%)
Y-71/96(74.0%)
N-106/111(95.5%)
N-166/177(93.8%)
Y-5/111(4.5%)
N-108/116(93.1%)
N (n=349)
N-2/5(40.0%)
Y-8/116(6.9%)
Y-11/177(6.2%)
Y-3/5(60.0%)
Y = yes or present
N = no or absent
* Last report of Bone Pain through 12 months.
** Last report of Bone Pain between 12 and 24 months among those
with data at 12 months.
History of Bone Crisis
12 Months*
24 Months**
Overall at 24 Months
N-50/52(96.2%)
N-87/107(81.3%)
Y-2/52(3.8%)
N-57/61(93.4%)
Y (n=283)
N-7/9(77.8%)
Y-4/61(6.6%)
Y-20/107(18.7%)
Y-2/9(22.2%)
N-186/187(99.5%)
N-297/300(99.0%)
Y-1/187(0.5%)
N-187/188(99.5%)
N (n=597)
N-1/1(100.0%)
Y-1/188(0.5%)
Y-3/300(1.0%)
Y-0/1(0.0%)
Y = yes or present
N = no or absent
* Last report of Bone Crisis through 12 months.
** Last report of Bone Crisis between 12 and 24 months
among those with data at 12 months.
Overall Bone Assessment: Response to ERT
Type 1 Patients <18 Years Old
80.0
73.7
Stable
64.7
70.0
Percent of Patients
Improved
Worse
55.0
60.0
50.0
41.3
40.0
40.0
32.3
26.3
30.0
17.4
20.0
10.0
2.9
0.0
5.0
0.0
12 Months
N=46
24 Months
36 Months
N=34
N=19
Time (Months) Post 1st Infusion
48 Months
N=20
Natural History of Gaucher Disease in
Untreated Patients: Growth in Childhood
• Zevin et al, 1993 (Shaare Zedek) N=34
– Growth retardation (height and weight) prominent (30%)
– Most marked ages 2-5
• Kaplan et al, 1996 (Gaucher Registry) N=99
– Abnormal growth pattern relative to general population
and family in 50% at all ages to 15 years
– Associated with degree of hepatomegaly
• Kauli et al, 2000 (Petah Tiqva) N=52
– Growth retardation and delay in puberty are common
– More frequent with severe disease
– Spontaneous catch-up even in untreated patients
Overall Bone Assessment: Response to ERT
Type 1 Patients > 18 Years Old
80.0
68.5
76.0
71.7
Percent of Patients
70.0
56.8
60.0
50.0
40.0
30.0
20.0
32.4
23.9
22.5
20.0
9.0
10.8
4.0
4.4
10.0
0.0
12 Months
N=111
24 Months
N=46
36 Months
N=37
Time (Months) Post 1st Infusion
48 Months
N=25
Mobility: Response to ERT - Type 1 Patients
12 Months Post 1st Infusion (N=188/602) (31.2%)
90
Unrestricted
Walks with Difficulty
Orthopedic Aid
Wheelchair
Bedridden
99.3
70
60
50
50
50
47.6
46.1
47.6
40
20
Baseline
Status
23.0
30
30.7
Percent of Patients
80
10
0
4.8
Unrestricted Walks with
Wheelchair
Difficulty Orthopedic
Aid
12 Months
Bedridden
Bedridden
Wheelchair
Orthopedic Aid
Walks with Difficulty
Unrestricted
(N=152)
(N=0)
(N=2)
(N=13)
(N=21)
Gaucher Registry Results
• Bone pain resolves in 50% of
symptomatic patients within 1-2 years of
starting ERT.
• New onset of bone pain in asymptomatic
patients occurred in 4% on ERT for 2
years.
• 80-90% with prior bone crises had no
recurrences during first 2 years of ERT.
• Incidence of de novo crises during first 2
years of ERT is less than 1%.
Gaucher Registry Results
• After 2-4 years of ERT, physician
assessment of overall bone involvement
(clinical and radiological) suggests:
–
–
–
–
Improvement in 30-40% in pediatric patients
Progression in <5% in pediatric patients
Improvement in 20-30% of adult patients
Progression in 5-10% of adult patients
Gaucher Registry Results
• After 12 months of ERT, mobility status is
often improved:
– 54% of patients requiring orthopedic aid at
baseline able to ambulate without assistance.
– 48% of patients who walked only with
difficulty at baseline have unrestricted mobility.
– Only 5% of patients who walked with difficulty
at baseline progressed to use an orthopedic aid.
– Worsening mobility occurred in <5% of
patients who were unrestricted at baseline.
Gaucher Registry Results
• After 2 years of ERT, patients with
residual bone pain are significantly
older than those whose pain resolved
– Long-standing skeletal damage may
be irreversible.
– ERT usually prevents symptomatic
progression and may forestall
irreversible complications
– Early treatment for symptomatic or
high risk patients is advisable.
Natural History of Gaucher Disease in
Untreated Patients: Gaucher Registry Goals
• Obtain missing data and retrieve
retrospective data on current patients
• Accrual of appropriate new patients
• Obtain data on untreated patients for
the existent sub-Registries:
– Quality of Life
Pregnancy
– Bone Density (DEXA) Pulmonary