1. Impact of Velaglucerase Alfa Therapy on Bone Marrow Burden Score in Adults with Type 1 Gaucher Disease: 7-Year Experience
Deborah Elstein;1 Andrew H. Haims;2 David Zahrieh;3 Gabriel M. Cohn;3 Ari Zimran1
1Shaare Zedek Medical Center and Hebrew University-Hadassah Medical School, Jerusalem, Israel; 2Yale University School of Medicine, New Haven, CT, USA; 3Shire Human Genetic Therapies, Inc., Lexington, MA, USA
27-30 June 2012 1

2. Co-authors’ Disclosures
The authors declare the following potential competing interests:
Dr Elstein participated as an investigator in the clinical trials from which these data were taken and served as a consultant to Shire Human Genetic Therapies, Inc. (Shire HGT) during the course of the clinical trials.
Dr Haims has served as a consultant to Shire HGT.
Dr Cohn and Mr Zahrieh are employees of Shire HGT.
Dr Zimran participated as an investigator in the clinical trials from which these data were taken and served as a consultant to Shire HGT during the course of the clinical trials. Dr Zimran receives consulting fees from Protalix Biotherapeutics; has options in Protalix Biotherapeutics and sits on its Scientific Advisory Board; receives support from Genzyme for participation in the International Collaborative Gaucher Group Gaucher Registry and receives honoraria from Actelion and Pfizer.

3. Introduction
Type 1 Gaucher disease (GD1) is associated with significant bone pathology
Velaglucerase alfa has been studied in 3 Phase III trials and an extension study to these trials, which is ongoing
Since 2010 velaglucerase alfa has been approved for the long-term treatment of GD1 in 39 countries, including the USA, Israel, and the EU 3

4. Introduction: BMB scoring system
Semi-quantitative magnetic resonance imaging (MRI) is used to evaluate bone marrow involvement and response to enzyme replacement therapy (ERT) in GD1
Appearance of marrow in MR images of lumbar spine and femur is assessed using a bone marrow burden (BMB) scoring system (Maas M, et al. Radiology 2003;229:554-61)
0–1 point is considered normal at each site (LS and FN)
2-8 points for increasing abnormality at each anatomic site (8 = most abnormal)
Total possible score of LS +FN = points 4

5. 7 years of longitudinal data have been reported:
TKT025: A Brief History
TKT025 was a 9-month, open-label, Phase I/II trial of velaglucerase alfa in adult patients with GD1
TKT025EXT (ClinicalTrials.gov identifier NCT ) was an extension study to TKT025
7 years of longitudinal data have been reported:
Hematologic and visceral parameters (Zimran et al. Blood 2010;115: )
Achievement and maintenance of therapeutic goals (Elstein et al. Blood Cells Mol Dis 2011;46:119-23)
Bone mineral density (BMD) (Elstein et al. Blood Cells Mol Dis 2011;47:56-61.)

6. Eligibility Criteria for Patient Enrollment and Dosing
TKT025
9-month trial
TKT025EXT
Extension study
Enrollment
Diagnosis of type 1 GD
GD-related anemia (1O)
Thrombocytopenia
Age 18 years
Intact spleen
No GD treatment in past 12 months
60 U/kg EOW velaglucerase alfa, IV infusion
Complete TKT025
604530 U/kg EOW velaglucerase alfa, IV infusion
TKT025EXT was completed in December 2011.
Maximum duration of velaglucerase alfa therapy in TKT025EXT was 79.5 months.
bIn TKT025EXT, stepwise dose reduction was implemented after 3 months (1 year from start of TKT025) if patients met at least 2 of 4 therapeutic goals (the 1-year goals for hemoglobin concentration, platelet count, spleen volume, and liver volume).
EOW, every other week; IV, intravenous. 6

7. Analysis Population at Baseline: n=12
Demographics
Median age, years (range)
39.3 (18.8, 69.8)
Female gender, n (%)
7 (58)
Clinical parameters
Median (range)
Bone marrow burden score Lumbar spine
6 (3, 8)
Femura –
Bone mineral density z-score Lumbar spineb
−1.5 (−2.9, −0.4)
Femoral neckb
−1.6 (−2.9, 0.1)
Hemoglobin concentrationc, g/dL
11.1 (9.8, 13.3)
Platelet countc, ×109/L
60.3 (37.0, 98.5)
Spleen volume, % of body weight
3.6 (2.2, 6.5)
Liver volume, % of body weight
4.4 (2.6, 5.8)
Plasma chemokine (C-C motif) ligand 18 levelc, ng/mL
1978 (1563, 5247)
Normal spleen volume 0.2% of body weight. Normal liver volume 2.5% of body weight.
an=6 patients with Baseline femoral BMB score; descriptive statistics not calculated.
bn=11; 1 patient did not have a Baseline BMD assessment of the lumbar spine and 1 patient did not have a Baseline BMD assessment of the femoral neck.
cBaseline and Week 1 (prior to first dose) values averaged if both were available. 7

8. TKT 025 and TKT 025EXT Clinical Trial Results
-10
-20
-30
-40
-50
-60
-70
-80 20 40 60 80
100
120
160
140
180
Change from Baseline statistically significant at 9 months (P<0.003) and 48 months (P<0.004) for each parameter
Mean change per key clinical parameter (%)
025 (n=11)
025EXT (n=9 had data to 45 months)
Week 13 25 37 41 55 67 79 94
107
119
131
143
159
171
183
195 1 2 3
Year
Platelet count
Hemoglobin concentration
Liver volume
Spleen volume
Zimran A, et al. Blood 2010;115: 8

9. BONE DENSITY RESULTS: Z-Scores ; n = 10, ITT
Time
Z-Scores
Lumbar Spine
Mean [95% CI]
Femur
Baseline
[-2.17, -1.01]
[-2.11, -0.81]
Month 9
[-2.05, -0.95]
[-2.06, -0.72]
Month 24
[-1.80, -0.60]
[-2.04, -0.42]
Month 33
[-1.80, -0.52]
[-1.82, -0.32]
Month 45
[-1.72, -0.52]
[-1.86, -0.42]
Month 57
[-1.68, -0.46]
[-1.89, -0.31]
Month 69
[-1.55, -0.27]
[-1.83, -0.29] 9 9

10. Lumbar Spine BMD Z-scores: Individual Patients’ Data
13 patients were screened and all consented to participate in TKT025; patient 0004 was excluded before study start because of imiglucerase antibodies. Patients 0006 and 0012 did not enroll in the long-term extension study. Patients 0002, 0003, 0007, and 0010 received concomitant bisphosphonates.  
Elstein D, et al. Blood Cells Mol Dis 2011;47:56-61. 10 10

11. Femoral Neck BMD Z-scores: Individual Patients’ Data
13 patients were screened and all consented to participate in TKT025; patient 0004 was excluded before study start because of imiglucerase antibodies. Patients 0006 and 0012 did not enroll in the long-term extension study. Patients 0002, 0003, 0007, and 0010 received concomitant bisphosphonates.  
Elstein D, et al. Blood Cells Mol Dis 2011;47:56-61. 11 11

12. WHO Classification (T-scores) at Baseline and 69 Months Velaglucerase alfa without concomitant bisphosphonates (All 4 patients on bisphosphonates had no change in WHO Category)
Lumbar Spine (n=6)
Femoral Neck (n=6)
Normal = T-score ≥ –1
Osteopenia = T-score > –2.5 and < –1
Osteoporosis = T-score ≤ –2.5
Elstein D, et al. Blood Cells Mol Dis 2011;47:56-61. 12

13. Changes in WHO Category; n = 6 [No Bisphosphonates]
Patient
Lumbar
Spine
Femur
Baseline
69 Months
OPN
OPO *
NORMAL
Normal = T-score ≥ -1;
osteopenia (OPN) =T-score > -2.5 and < -1;
osteoporosis (OPO) = T-score ≤ -2.5
* Patient 23-years old at Baseline; one of two patients with osteonecrosis at Baseline 13 13

14. Conclusions: BMD improvement with velaglucerase alfa
In patients with type 1 Gaucher disease and baseline osteopenia/osteoporosis who were treated with velaglucerase alfa, BMD improved in both lumbar spine (Month 24) and femoral neck (Month 33).
Since the velaglucerase alfa dose was reduced from 60 to 30 unit/kg/infusion between months, the improvement in bone pathology was not dependent upon continuous high-dose therapy. 14 14

15. Bone Marrow Burden Score Analysis: Objectives
To evaluate the impact of up to 7 years of velaglucerase alfa therapy on BMB score at lumbar spine and femur
To explore possible correlations before treatment was initiated (at Baseline) between BMB score and other clinical parameters
DeMayo et al (Am J Roentgenol 2008;191:115-23) found positive correlation between spleen status (surgically absent or enlarged) and BMB scores at both sites, but not with duration of ERT with imiglucerase 15 15

16. Lumbar Spine BMB Scores at each assessment
Change from Baseline in BMB score
Patients with available data, n
Median BMB score (range)
Mean change (95% CI)
Decrease of 2 points or more,
n (%)
Decrease of 3 points or more,
Decrease of 4 points or more,
Baseline 12
6 (3, 8)
9 months 11
4 (1, 8)
–1.8 (–2.9, –0.7)
6 (55)
3 (27)
2 (18)
24 months 9
3 (1, 5)
–2.8 (–4.2, –1.4)
6 (67)
4 (44)
3 (33)
33 months
1 (1, 4)
–3.8 (–5.0, –2.5)
8 (89)
45 months 7
1 (1, 5)
–3.3 (–4.9, –1.7)
6 (86)
4 (57)
3 (43)
57 months 8
–4.3 (–5.7, –2.8)
8 (100)
6 (75)
5 (63)
69 months
–4.1 (–5.8, –2.5)
7 (88)
81 months
CI, confidence interval. 16

17. Individual Lumbar Spine BMB Scores over 81 months (7 Years) of velaglucerase alfa therapy
Patient number
Baseline
9 months
24 months
33 months
45 months
57 months
69 months
81 months 1 8 5 4 3 2 6 4a 7 – 6b 9 10
11c
12d
Dash indicates missing BMB score.
aDiscontinued from study before 24 months. bDiscontinued from study after 48 months.
cCompleted TKT025 but did not enroll in TKT025EXT. dDiscontinued from TKT025 after 3 infusions. 17

18. Mean temporal changes from Baseline in BMB Score at the Lumbar Spine
a Clinically meaningful improvement at each anatomic site defined as a decrease of 2 points or more.
CI, confidence interval. 18

19. all decreased by 2 points
Individual Femoral BMB Scores over 81 months (7 Years) of velaglucerase alfa therapy:
all decreased by 2 points
Patients with MR images available at both Baseline and during TKT025EXT
BMB score
Patient number
Baseline
9 months
24 months
33 months
45 months
57 months
69 months
81 months 2 5 – 4 3 9 1 10
Dash indicates missing BMB score. To score the femur, an image of the whole femur is needed. The imaging protocols for the studies did not specify that the whole femur needed to be imaged; consequently, many MR images only contained a part of it (eg, femoral neck) and could not be scored. 19

20. Clinical Correlations with Lumbar Spine BMB Score
Baseline values for the hematologic and visceral parameters, chemokine (C-C motif) ligand 18 level, and lumbar spine BMD z-score were assessed for correlation with lumbar spine BMB score at Baseline
The parameter with the strongest correlation with the lumbar spine BMB score at Baseline was with increased spleen volume, but this was not statistically significant (ρ=0.38; P=0.22) 20

21. Conclusions
Bone marrow involvement improved among adults with GD1 treated with velaglucerase alfa
At the lumbar spine, the mean change from Baseline in BMB score was statistically significant at 9 months and continued to improve through 5 years, despite dose reduction after the first year
At 5 years, all patients with available data had experienced a clinically meaningful decrease in BMB score and the 5-year scores were the same at 7 years 21

22. Thank you for your attention!22