Prevalence of Skeletal Disease Neal J. Weinreb, M.D.

Impact of Skeletal Manifestations Impact QOL more than hematological and organ abnormalities. Bone disease is common even with normal hematology. Discomfort, pain, and disability occur in a majority of 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 Patient Demographics - Type 1 Patients 2000 Gaucher Registry Aggregate Data Report

History of Bone Symptoms at Baseline Type 1 Patients 2000 Gaucher Registry Aggregate Data Report SymptomOn ERTNot on ERT Bone Pain66% (811/1232) 49% (147/299) Bone Crisis29% (336/1162) 5% (15/280)

History of Bone Disease at Baseline – Type 1 Patients 2000 Gaucher Registry Aggregate Data Report On ERTNot 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) Infarction35% (424/1201)16% (45/275) Joint Replacement14% (171/1201)6% (16/275) Lytic Lesions18% (214/1201)10% (28/275) Marrow Infiltration 59% (708/1201)53% (147/275) New Fractures26% (310/1201)10% (28/275) Osteopenia50% (595/1201)34% (94/275)

N = 449N = 196N = 159N = 61

Gaucher Registry: Mean Age at 1st Infusion Year of 1st Infusion Mean Age (Years) N = 810N = 311N = 237N = 73

History of Bone Pain at Baseline - Type 1 Patients By Age Category Gaucher Registry: April 2001 Percent of Patients Patients on ERTPatients Not on ERT Y19-40 Y Y61+ Y 0-18 Y19-40 Y Y61+ Y YesNo N=335N=247N=80N=122N=362N=90N=73N=36

History of Bone Crises at Baseline Type 1 Patients By Age Category Percent of Patients Patients on ERTPatients Not on ERT N=304N=216N=81N=110N=312N=81N=67N= Y Y41-60 Y61+ Y 0-18 Y Y41-60 Y61+ Y YesNo

History of Bone Disease at Baseline Type 1 Patients By Age Category Gaucher Registry: April 2001 Percent of Patients Patients on ERTPatients Not on ERT N=339N=266N=80N=118N=360N=81N=72N= Y19-40 Y41-60 Y61+ Y0-18 Y19-40 Y41-60 Y61+ Y YesNo

Patient Genotypes - Type 1 Patients 2000 Gaucher Registry Aggregate Data Report Sixty percent (1287/2129) of all Type 1 patients enrolled reported genotype. 29 (10%)118 (12%)All Others 4 (1%)13 (1%)?/? 4 (1%)28 (3%)N370S/IVS2+1 3 (1%)28 (3%)L444P/? 1 (<1%)26 (3%)L444P/L444P 12 (4%)144 (15%)N370S/84GG 31 (10%)164 (17%)N370S/L444P 169 (56%)275 (28%)N370S/N370S 48 (16%)190 (19%)N370S/? Not On ERTOn ERTGenotype

History of Bone Pain at Baseline Type 1 Patients By Genotype N370S/N370SAll OthersN370S/N370SAll Others YesNo Percent of Patients Patients on ERTPatients Not on ERT N=209N=472N=130N=92

History of Bone Crises at Baseline Type 1 Patients By Genotype Percent of Patients Patients on ERT Patients Not on ERT N370S/N370S All Others N370S/N370SAll Others YesNo N=196N=454N=129N=87

History of Bone Disease at Baseline Type 1 Patients By Genotype Percent of Patients Patients on ERTPatients Not on ERT N370S/N370S All Others N370S/N370S All Others YesNo N=194N=501N=125N=99

Mobility History at Baseline – Type 1 Patients on ERT Gaucher Registry: March 2001 Wheelchair: 1.2% Bedridden: 0.5% N=602 Unrestricted: 79.2% Orthopedic Aid: 7.1% Walks with Difficulty : 12.0%

Skeletal Manifestations in Elderly Gaucher Patients Dx Onset Pt Age Age Presenting Sx Subsequent Sx________ PL* AVN hipTHR (59) Fx distal femur (64) JW* Multiple Fx’s None on ERT; less pain MA AVN; THR Prosthesis failed (80) Wheelchair bound (82) RS R hip pain R hip Fx (79) L hip Fx (84) * Splenectomy

Age at Diagnosis and Severity Score Index (Weinreb)

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 Gaucher Registry: March 2001 Percent of Patients N = 159

Osteoarthritis: Association of Knee Pain With Bone Marrow Lesions

Clinical Course of Gaucher Disease (Zimran et al, Medicine 1992) Evaluation: 20 years after initial diagnosis Mean age at evaluation: 33 years Splenectomy: 43% Chronic symptoms mainly skeletal N370S homozygotes: milder clinical course Progression: childhood to early adulthood Stable in adulthood, especially N370S/ N370S

The Clinical Course of Treated and Untreated Gaucher Disease 45 patients examined at least 3 times Observation period greater than one year Little progression in adults (Beutler E et. al. Blood Cells Mol Dis 1995; 21(2):86-108) –Few changes in blood counts –No increase in liver and spleen sizes –Changes in bone lesions largely in preexistent site

Clinical Course of Gaucher Disease: Non-Jewish Patients Neiderau: 51 German patients, ages 5-74 –Observed average 16 years from diagnosis –Progressive complications until ERT started Bleeding and/or anemia  splenectomy Increasing bone disease including fracture Giraldo: 48 Spanish patients: progression 81% Goldblatt: 10 Afrikaner patients: rapid progression Hollak: 20 Dutch patients: progressive in most children and adults

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 Pain12 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) Y-83/172(48.3%) N-25/96(26.0%) 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) Y-8/116(6.9%) N-2/5(40.0%) Y-11/177(6.2%) Y-3/5(60.0%) Y = yes or present N = no or absent ** Last report of Bone Pain between 12 and 24 months among those with data at 12 months. * Last report of Bone Pain through 12 months.

History of Bone Crisis12 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) Y-4/61(6.6%) N-7/9(77.8%) 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) Y-1/188(0.5%) N-1/1(100.0%) Y-3/300(1.0%) Y-0/1(0.0%) * 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. Y = yes or present N = no or absent

Overall Bone Assessment: Response to ERT Type 1 Patients <18 Years Old

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

Time (Months) Post 1st Infusion Overall Bone Assessment: Response to ERT Type 1 Patients > 18 Years Old Months24 Months36 Months48 Months Percent of Patients N=111N=46N=37N=25

Unrestricted Walks with Difficulty Orthopedic Aid Wheelchair Bedridden Mobility: Response to ERT - Type 1 Patients 12 Months Post 1st Infusion (N=188/602) (31.2%) Unrestricted Walks with Difficulty Orthopedic Aid Wheelchair Bedridden 12 Months Percent of Patients Unrestricted Walks with Difficulty Orthopedic Aid Wheelchair Bedridden (N=152) (N=21) (N=13) (N=2) (N=0) Baseline Status

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 % 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.

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. Gaucher Registry Results

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 LifePregnancy –Bone Density (DEXA)Pulmonary