Gregory M. Pastores1; Jeffrey Szer2; Milan Petakov3; Tim Cox4;
Pilar Giraldo5; Hanna Rosenbaum6; Dominick Amato7; Eugen Mengel8;
Raul Chertkoff9 ; Einat Almon-Brill9; Ari Zimran10
10th EWGGD Meeting
Paris June 2012
Disclosure
GM Pastores\NYU Neurogenetics is the recipient
of research grants\support from Actelion,
Amicus\GSK, Biomarin, Genzyme\Sanofi,
Protalix\Pfizer, Shire HGT, Synegeva and
Ultragenics; pharmaceutical\biotechnology
companies engaged in drug development
programs for the Lysosomal storage disorders
Taliglucerase alfa*
 Plant cell expressed human recombinant
Glucocerebrosidase
 Produced in disposable bioreactors
 Expression process is free of any
mammalian components
 As of May 1,2012, approved by the US
Food and Drug Administration as an ERT
for Gaucher disease
* Y. Shaaltiel el al;,Plant Biotechnology J., September 2007, volume 5, Issue5
* D. Aviezer et al; ,1 March 2009 Volume 4, Issue 3
A Phase 3 Multicenter, Open-label,
Switchover Trial to Assess the Safety and
Efficacy of taliglucerase alfa in Patients with
Gaucher Disease Treated with Imiglucerase
(Cerezyme®) Enzyme Replacement Therapy
PB-06-002
Objective
 Assess the safety and efficacy of taliglucerase alfa in
patients with Gaucher disease who are currently
being treated with imiglucerase enzyme replacement
therapy (ERT).
Sites
Investigator
Institution
Ari Zimran
Shaare Zedek Medical Center, Jerusalem, Israel
Dominick Amato
Mount Sinai Hospital, Toronto, Canada
Eugen Mengel
University Mainz, Mainz, Germany
Gregory Pastores
NYU School of Medicine, New York USA
Hanna Rosenbaum
Rambam Medical center, Haifa, Israel
Jeffrey Szer
Royal Melbourne Hospital, Australia
Milan Petakov
Clinical Center of Serbia, Belgrade, Serbia
Paul Fernhoff
Emory University School of Medicine, GA USA
Pilar Giraldo
Hospital Universitario Miguel Servet, Zaragoza, Spain
Tim Cox
Addenbrooke’s Hospital, Cambridge, UK
Design and Patient Population
PB-06-002 Switch Over
Screening
Clinical stable disease:
≥ 2 years on imiglucerase
≥ 6 months same regimen
Stability Evaluation
Period
Based on 6 evaluations of
platelets & hemoglobin
Dec. 2008 First patient enrolled
Jul. 2009, due to imiglucerase shortage
protocol was amended;
-to recruit 30 patients
-allow the use of 6 historical
hematological parameters for stability
evaluation
Dec. 2009 protocol amended to include
children per EMA
9 Months
Treatment
Pediatric cohort (n=5) ongoing
2 completed
26 adult patients recruited
1 patient dropped out (AE)
May 1st 2011
Last adult patient last visit (n=25)
Extension Follow Up
PB-06-003
Disease Stability Evaluation
 Hematological Stability Evaluation
Parameters:
 12 weeks while on imiglucerase
or
 6 historical values for those patients
impacted by ERT shortage
“Clinically Relevant
Deterioration” Criteria
 Protocol Defined Criteria
 Sustained reduction of platelet
count:

 No major surgery in the last year
 No blood transfusion or major
bleeding episode in the last year
 No acute avascular necrosis event
in the last year
 No evidence of spleen or liver
increasing enlargement
A decrease of >20% from the mean value
of the Stability Evaluation Period values
of ≤120,000 or a decrease of >40% from
the mean value of the Stability Evaluation
Period values of >120,000
 Sustained reduction of
hemoglobin:

A decrease of >20% from the mean value
of the Stability Evaluation Period
 Increase in spleen volume:

A 20% increase in spleen volume by MRI
from Baseline to Month 9
 Increase in liver volume:

A10% increase in liver volume by MRI
from Baseline to Month 9
Platelet Count Stability
Hemoglobin Stability
14-210
A decrease of >20% from the mean value of the Stability
Evaluation Period
14-210
A decrease of >20% from the mean value of the Stability
Evaluation Period values of ≤120,000
or
A decrease of >40% from the mean value of the Stability
Evaluation Period values of >120,000
Demographic and Baseline Characteristics (n=26)
Patient
Characteristic
Mean ± SD
(range)
Disease
Parameter
Mean ± SD
(range)
Age
47.6 ± 12.9
(18 – 66)
Spleen volume*
(MN), (n=20)
6 ± 4.8
(0.1 – 20.5)
Male
Female
14 (53.2%)
12 (46.2%)
Liver volume* (MN)
(n=23)
1 ± 0.2
(0.7 – 1.6)
Ashkenazi Jewish
non-Jewish
14 (53.8%)
12 (46.2%)
Hemoglobin (g/dL)
13.4 ± 1.68
(10.0 – 16.0)
Splenectomized
3
Platelets (/mm3)
154,120 ± 86,550
(39,000 – 328,000)
N370S homozygous
other genotype†
8
11
Chitotriosidase
(nmol/mL.h)
7084.2 ± 9607.9
(103 - 41,528)
MN – Multiple of Normal
†DNA sequencing pending on 9 patients
*Organ volumes by MRI, except in 2 patients by US, patient choice, not included in analytic set
Dose Distribution
Taliglucerase dose = prior Imiglucerase dose
65
60
55
Dose Units/kg
50
45
≥ 30U/kg (n=9)
40
35
30
25
>15U/kg & < 30U/kg (n=8)
20
15
10
5
0
≤ 15U/kg (n=8)
Hematological Measurements (n=25):
Hemoglobin (mean)
200000
Hemoglobin g/dL (+/-SE)
Platelets/mm3 (+/-SE)
Platelet Count (mean)
150000
100000
50000
0
0
6 12
Weeks
18
24
30
36
150000
100000
≤15 U/kg
>15 & <30 U/kg
≥30 U/kg
6
12
18 24
Weeks
30
10
8
6
0
Hemoglobin g/dL (+/-SE)
Platelets/mm3 (+/-SE)
200000
0
12
6
12
18 24
Weeks
30
36
42
Hemoglobin (by dose)
250000
0
14
42
Platelet Count (by dose)
50000
16
36
42
16
14
12
10
≤15 U/kg
>15 & <30 U/kg
≥30 U/kg
8
6
0
6
12
18 24
Weeks
30
36
42
Organ Volumes
Liver Volume (n=23)
1.2
Liver volume MN
(+/-SE)
7
6
5
4
3
2
1
0
6
12
18
24
Weeks
30
36
0.8
0.6
0.4
0.2
42
Spleen Volume (by dose)
15
9
6
3
0
0
6
12
18 24
Weeks
30
6
12
18 24
Weeks
30
36
42
Liver Volume (by dose)
≤ 15 U/kg
< 15 & <30 U/kg
≥ 30 U/kg
12
0
36
42
(+/-
0
Spleen volume MN
(+/-SE)
1.0
0.0
Liver volume , MN
SE)
Spleen volume MN
(+/-SE)
Spleen Volume (n=20)
1.4
1.2
1.0
0.8
0.6
≤ 15 U/kg
< 15 & <30 U/kg
≥ 30 U/kg
0.4
0.2
0.0
0
6
12
18
24
Weeks
30
36
42
Chitotriosidase Activity (n=25)
Mean Value
Mean Value by Dose
≤ 15 U/kg
< 15 & <30 U/kg
≥ 30 U/kg
20000
activity nmol/mL.h (+/-SE)
Activity nmol/mL.h (+/-SE)
10000
8000
6000
4000
2000
15000
10000
5000
0
0
0
6
12 18 24 30 36 42
Weeks of treatment
0
6
12 18 24 30
Weeks of treatment
36
42
Disease Stability Outcome

Protocol defined stability and deterioration based on hematological,
organ volume measurements and clinical presentation

Overall, disease parameters remained stable following switch to
taliglucerase alfa

Three patients each had a change in only 1of 4 outcome measures per
protocol; all continue to receive taliglucerase alfa
Patient
ID
Dose
Spleen
volume
change (MN)
Liver
volume
change
(MN)
Platelets count
change
Hb change
Chitotrio
sidase
change
10-203
12U/kg
5.3 to 6.5
1.0 to 1.0
76,000 to 68,000
12.2 to 11.9
- 8.3%
10-205
13U/kg
4.5 to 5.1
0.9 to 1.1
126,000 to 107,000
15.9 to 14.7
-5.2%
18-219
9U/kg
splenectomized
0.8 to 0.7
146,000 , 113,800*
14.7 to 14.4
-8.2%
*Patient ‘s dose was doubled (week 24 visit onwards), platelet count 170,000 (week 38)
Safety: Adverse Events
Severity
# of AEs
(# of
patients)
AEs
% of
total
Adverse events
139 (25)
Mild or moderate
136 (25)
97.8%
Severe or very
severe*
3
(2)
2.2%
Relatedness
# of AEs
(# of
patients)
AEs
% of
total
Non-treatment related
115
(23)
82.4%
Treatment related
24
(10)
17.6 %
* All 3 severe AEs (hematuria and
renal stone; prolapsed rectum,
bladder and cervix) reported as
not treatment related
 Serious Adverse Events
 3 SAEs not related to treatment, resolved after intervention
(epistaxis; hematuria and renal stone; prolapsed rectum, bladder
and cervix - all of which required hospitalization)
Safety: Treatment Related Adverse Events
# Patients (%)
# events

17.6 % of the AEs were reported as
related (definitely or possibly)
Headache
2 (7.7%)
2

All AEs were mild or moderate in severity
Infusion-related
reaction
(headache, fatigue,
weakness after
infusion)
2 (7.7%)
3

* One patient withdraw after
experiencing hypersensitivity (urticaria,
rash) during the first infusion
Hypersensitivity*
1 (3.8%)
1

Negative for IgG and IgE antibodies
Flushing
1 (3.8%)
3

Weight increase
1 (3.8%)
1
Premedication with subsequent
infusions refused
Asthenia
1 (3.8%)
1
ALT increase
1 (3.8%)
1
GGT increase
1 (3.8%)
1
Pruritus
1 (3.8%)
9
Lethargy
1 (3.8%)
1
Diarrhea
1 (3.8%)
1
AEs

No emergent safety concerns from last
report at WORLD 2011
Neutralizing Antibodies & Clinical Outcome
 One patient (20-220) receiving 28 U/kg was positive for neutralizing
activity in an in vitro assay, but negative in a cell based assay
 At 9 months time point, hemoglobin, platelet, liver and spleen were
stable or improved except for the increase in chitotriosidase; the patient
continues to receive treatment
Patient
ID
20-220
Neutralizing activity
IgG antibodies
in vitro assay
Cell-based
assay
pos
neg
IgE
Spleen
volume
change
Liver
volume
change
Platelets
count
change
Hb
change
Chitotriosidase
change
neg
-21%
6.8-5.4MN
-1%
0.9-0.9MN
3%
117K-121K
0%
15.4-15.4
58%
4374*-6909
 3 unrelated AEs:


Facial discomfort and facial flushing
Upper respiratory infection
Summary – Switched Patients
Efficacy
 Overall, patients remained stable with regards to the main disease
parameters (hemoglobin, platelet count, spleen and liver volume and
chitotriosidase) after switching from imiglucerase to taliglucerase alfa
Safety
 All AEs were mild or moderate and transient in nature, none of the patients
are receiving premedication
 All patients continue to receive taliglucerase except the one patient with
hypersensitivity who declined to continue infusions with premedication
This study demonstrates that taliglucerase alfa has the potential to be an
alternative treatment for Gaucher disease