Phase 2 multicenter, open label, switch
over trial to evaluate the safety and
efficacy of Abcertin®(Imiglucerase) in
patients with type 1 Gaucher disease
previously treated with Cerezyme
Han Wook Yoo M.D., Ph.D.
Medical Genetics Center, Department of Pediatrics,
Asan Medical Center Children’s Hospital
University of Ulsan College of Medicine, Seoul, Korea
Disclosure statement
• Principal investigator of clinical studies using
recombinant enzyme products from ISU ABXIS in
Korean Gaucher and Fabry disease patients
Introduction
 Abcertin®
 CHO cell derived, human macrophage-targeted recombinant
human β-glucocerebrosidase (Imiglucerase)
 Structural, physicochemical, biological, and immunological
properties are well characterized in pre-clinical studies, and
comparable to the reference product.
 Reference product: Cerezyme® (Genzyme)
 Appearance: Lyophilized vial
 Developer: ISU ABXIS Co., Ltd. (S. Korea)
Introduction
Korean Gaucher Patient Registry
(April 1997∼ Dec 2011)
Phenotype
No. of
pts
(family
)
Treatment
Follow-up status
ERT
BMT
alive
dead
F/U
loss
Nonneuronopathic
35
(32)
31
0
30
2(*1)
3
Acute
neuronopathic
13 (12)
0
0
0
13
0
Chronic
neuronopathic
21 (18)
16
3
10
9
2
Total
69 (62)
* Discontinued ERT
47
3
40
24
5
Introduction
Spectrum of GBA mutations in
Korean Gaucher patients
R257Q
5%
R48W R496H Rec 8a V15L
3%
2%
3%
3%
Rec
3%
V191G
3%
R277C R409H
2%
2%
G46E
(36%)
c.630delC
2%
F213I
(13%)
L444P
(23%)
Non-neuronopathic
Neuronopathic
Phase 1 (Stand-alone in Korea)
Double-Blind, Placebo-controlled, Single Ascending Dose (SAD) phase 1 clinical trial
in Healthy Subjects
Day 0
Day 0
Day 0
Day 5
Abcertin: 15 Units/ kg
Day 5
Abcertin: 30 Units/ kg
Day 5
Abcertin: 60 Units/ kg
Abcertin: 6 subjects
Placebo: 2 subjects
Abcertin : 6 subjects
Placebo: 2 subjects
Abcertin: 6 subjects
Placebo: 2 subjects
• Primary objective: To determine the safety and tolerability of single ascending dose of Abcertin in healthy subjects
• Secondary objective: To evaluate pharmacokinetics of single ascending doses of Abcertin in healthy subjects
Phase 1 – Results (1/2)
Safety;
No clinically significant change was observed in vital signs, local tolerability test, laboratory
test and ECG monitoring following the administration of Abcertin in each dose level.
Dosing group
Total
Subjects
No.
Abcertin (Units/kg)
Placebo
15
30
60
Randomized No.
24
6
6
6
6
No. of ADR reported
1
1
0
0
0
No. of Subjects
1
1
0
0
0
Total No. of ADR
reported
1
1
0
0
0
Severity
Mild
Moderate
Severe
Total
Relationship
R*
NR*
R
NR
R
NR
R
NR
Headache
0
1
(100%)
0
0
0
0
0
1 (100%)
Phase 1 – Results (2/2)
Pharmacokinetics; Pharmacokinetic linearity was observed
15 units/kg
30 units/kg
60 units/kg
mean
SD
mean
SD
mean
SD
Half life (hr)
0.12
0.02
0.11
0.01
0.2
0
Tmax (hr)
0.96
0.1
1
0
1
0
Cmax (mIU/mL)
46.59
7.72
116.9
15.95
319.96
37.68
AUCall (hr*mIU/mL)
37.95
4.29
101.53
15.53
275.6
30.45
28,285.26
5,383.15
20,695
3,259.36
14,602.73
1,819.13
CL (mL/hr)
mean ( S.D) data
Semi-Log scale
1000
300
Imiglucerase (mU/mL)
Imiglucerase (mU/mL)
400
15 U/kg
30 U/kg
60 U/kg
200
100
0
0.0
0.5
cont. infusion
1.0
1.5
Time (hr)
2.0
2.5
100
15 U/kg
30 U/kg
60 U/kg
10
1
0.1
0.0
0.5
cont. infusion
1.0
1.5
Time (hr)
2.0
2.5
Phase 1 - Conclusion
 Phase I study showed favorable safety, tolerability and
pharmacokinetic linearity within the dose range with single dose
Abcertin infusion in healthy adults.
 No clinically significant change was observed in vital signs, local
tolerability test, laboratory test and ECG within the dose range.
 No serious adverse event was reported.
 No antibody formation was observed within the dose range .
Phase 2: Switch-over study
A multicenter, open label phase 2 study of Abcertin® in patients with Type 1 Gaucher
disease previously treated with Imiglucerase
0
Pts pretreated with Imiglucerase
Type I Gaucher patients stably treated with Cerezyme
during at least past 6 months
6 months
Abcertin*, every two weeks
The dose of Abcertin will be equal to
each patient’s previous Cerezyme dose.
Primary objective: To evaluate the safety of every other week dosing of Abcertin
in patients previously treated with Imiglucerase
Secondary objective: To evaluate the efficacy
Assessment criteria
Safety
√ Laboratory evaluation, Vital sign, ECG, Adverse event, Anti-drug antibody
Efficacy
Primary endpoint
√ Changes in hemoglobin concentration
√ Changes in platelet counts
Secondary endpoint
√ Changes in liver and spleen volume and liver function
√ Changes in biomarkers: acid phosphatase, angiotensin converting enzyme,
and chitotriosidase
√ Changes in skeletal status and bone mineral density
Inclusion criteria
•
Type 1 Gaucher disease
•
Patient who was stably treated with Cerezyme® and who was
maintaining the consistent dosage of Cerezyme® for at least 6 months
prior to study drug administration
•
Patient aged 2 years or older
•
Female patient with contraception during the study period (oral or
injectable contraceptive hormones, intrauterine device, physical
devices using condom, sponge form, jelly, and femidom)
•
Patient who signed the informed consent form
Exclusion criteria
•
Patient who participated in other clinical studies within 90 days
before study drug administration
•
Unstable hemoglobin concentration and platelet counts for at least 6
months before study drug administration
•
Hypersensitivity to Cerezyme
•
Positive to HIV antibody, hepatitis B antigen, and hepatitis C antibody
•
Fe, folic acid, or vitamin B12-deficient anemia
•
Patient who received Miglustat within 6 months before study drug
administration
•
Patient who received erythrocyte growth factor or chronic systemic
corticosteroids within 6 months before study drug administration
•
Patient who had clinically significant splenic infarction within 12
months before study drug administration or were splenectomized.
•
Pregnant or lactating patient
Study Flow Chart
Period
Screening
Treatment
End
Visit
0
1
2/3
4
5/6
7
8/9
10
11/12
13
14
Week
-2~0
0
2/4
6
8/10
12
14/16
18
20/22
24
26
Informed consent
√
Patient information
√
Physical examination
√
√
√
√
√
√
√
√
√
√
√
Vital signs
√
√
√
√
√
√
√
√
√
√
√
Inclusion/Exclusion
criteria
√
√
Hematology
√
Serum
chemistry,
Coagulation,
Urinalysis
√
√
√
Biomarker
√
√
√
Lab
test
√
√
√
√
ECG
√
√
Skeletal status (X-ray)
√
√
BMD (DEXA)
√
√
Liver, spleen volume(CT)
√
√
Anti-drug antibody
√
√
Adverse events
√
PK
√
√
√
√
√
√
√
√
√
√
√
Results - Study subjects
A total of six patients underwent screening, of whom one patient was withdrawn due to ineligibility of
inclusion/exclusion criteria, and the remaining five patients were enrolled in this study, and then
received the study drug.
Among enrolled five subjects, no subject was withdrawn due to adverse events, absence of efficacy, and
subject’s withdrawal from the study participation.
Status participation
Abcertin (N=5)
Abcertin (N)
Screening
6
Screening failure
1
Inappropriate for
inclusion/exclusion criteria
1
Enrolled
5
Administration of IP
5
Completed
5
Withdrawal
0
Age
Gender
Duration of previous
ERT (month)
Height
16.20 (±8.26)
Male
3
Female
2
104.00 (±48.16)
152.76 (±20.69) cm
Body weight
47.64 (±19.80) kg
History of surgical
treatment
No
Hemoglobin
13.76(±1.89)g/dL
Platelet
Previous Cerezyme
dosage
5
154.40(±34.62)x103/mm3
30~55 unit/kg
Results-Safety (1)
(1) Lab tests (Hematology, Serum chemistry, Urinalysis, Coagulation)
: There was no clinically significant change
(2) Vital signs (Systolic/Diastolic blood pressure, Heart rate, Body
temperature)
: There was no clinically significant change
(3) Adverse events:
• 10 cases, but no relevance to study drug
• No SAE
(4) Anti-drug antibody: No antibody formation
Results- Safety (2) “Adverse events”
One or more adverse events occurred in all of five subjects. Thus, a total of 10
adverse events were reported.
No serious adverse event occurred, and no relevance to the study drug was found.
In addition, neither withdrawal nor death caused by adverse events was found.
[Adverse Events]
[Summary of AE]
Abcertin (N=5)
Abcertin (N=5)
After IP administration
AE related to IP
N(%)
[cases]
5(100.00)
[10]
0(0.00)
[0]
SAE
0(0.00)
[0]
AE that caused withdrawal
during the study period
0(0.00)
[0]
Death
0(0.00)
[0]
System organ class*
Preferred term
All AEs
Related AEs
N(%), [cases]
N(%), [cases]
Nasopharyngitis
3(60.00),
[3]
-
Acute tonsillitis
1(20.00),
[1]
-
Arthralgia
1(20.00),
[2]
-
Diarrhea
1(20.00),
[1]
-
Abdominal pain
1(20.00),
[1]
-
Respiratory, thoracic and
mediastinal disorders
Cough
1(20.00),
[1]
-
Reproductive system and
breast disorders
Vaginal discharge
1(20.00),
[1]
-
Infections and
infestations
Musculoskeletal and
connective tissue
disorders
Gastrointestinal disorders
Results - Efficacy (1)
Primary endpoint
“the mean percentage changes in
hemoglobin concentration and platelet
count between at the baseline and 24
weeks ”
Abcertin (N=5)
Parameter
Hemoglobin
(g/dL)
Platelet
(x103/µL)
→The mean percent change in hemoglobin
concentration and platelet count were increased to
be 0.30% and 6.86%, respectively, but no
statistically significant change was found (pvalue=0.9332, p-value=0.6217).
N
Mean±SD
Median
Min-Max
Baseline
5
13.76±1.89
12.60
12.30-16.20
Week 24
5
13.86±2.61
12.40
11.20-17.00
% Change
-
0.30±7.63
0.81
-11.11-10.39
p-value
-
0.9332
0.6250
-
Change
-
0.10±1.06
0.10
-1.40-1.60
90% CI
-
(-0.91,1.11)
-
-
Baseline
5
154.40±34.62
151.00
113.00-209.00
Week 24
5
162.60±47.04
149.00
108.00-215.00
% Change
-
6.86±28.73
-0.48
-29.87-48.28
p-value
-
0.6217
1.0000
-
90% CI
-
(-20.53,34.26)
-
-
Results - Efficacy (2)
Hemoglobin concentration and Platelet count were ranged within ±1g/dL and ±20%,
respectively, at all measurement points.
▶ Abcertin® maintained the efficacy of Cerezyme® throughout the administration period.
Results - Efficacy (3)
Secondary endpoint
1. Changes in liver and spleen volume: No significant changes
2. Changes in liver function (ALT, AST): No significant changes
3. Changes in skeletal status: No significant changes
4. Changes in bone mineral density: No significant changes
4. Changes in biomarkers (ACE, Acid phosphatase, and Chitotriosidase): No significant changes
Liver & spleen volume
Liver function
Skeletal status
Bone mineral density
Biomarkers
Liver
(cc)
Spleen
(cc)
ALT
(IU/L)
Osteosclerosis
L-SPINE
ACE
(U/L)
Baseline
1,187.00
±399.06
332.00±1
84.54
16.80±
12.15
23.40±
4.67
0.00±
0.00
0.20±
0.45
-1.27±
0.40
-0.43±1.37
79.42±
31.77
18.68±
8.71
1,279.82±
1,041.47
Week 24
1,100.80
±380.11
330.00±1
42.26
38.80±
42.48
41.60±
44.14
0.00±
0.00
0.00±
0.00
-0.80±
0.53
-0.20±1.35
81.50±
45.84
17.10±
4.77
1,103.76±
884.36
Changes
(%)
5.86±
16.90
14.67±
69.07
212.16±4
46.38
68.95±
163.63
No
change
-
24.56±
50.60
-147.33±
441.79
-2.59±
20.61
-0.92±
22.97
-9.11±
15.53
p-value
0.4818
-
-
-
-
-
0.3389
-
0.7927
0.933
0.2598
AST
(IU/L)
Osteonecrosis
Femur
Neck
ACP
(IU/L)
Chitotriosidase
Conclusion
Safety
No clinically significant
adverse events
Efficacy
No changes in hemoglobin
concentration, platelet count,
liver and spleen size, skeletal
status and bone mineral density
 Abcertin® maintained the efficacy of Cerezyme® and showed no clinically
significant AE
 Abcertin® could be used as an alternative therapeutic agent in patients who
are treated with Cerezyme®
 Further study is needed in treatment-naïve Gaucher patients from a larger
cohort to further verify its clinical efficacy.
Acknowledgement
Son YB, Department of Clinical Genetics, Ajou University School of Medicine
Koh JM, Department of Pediatrics, Seoul National University College of Medicine
Lee JS, Department of Clinical Genetics, Severance Children’s Hospital
Lee BH, Medical Genetics Center, University of Ulsan College of Medicine