Adacolumn Device for Granulocyte and Monocyte Apheresis Otsuka / JIMRO .
Post on 27-Mar-2015
242 Views
Preview:
Transcript
Adacolumn
Device for Granulocyte and Monocyte Apheresis
Otsuka / JIMROwww.otsuka.de
www.adacolumn.com
Legal Status
• Adacolumn is indicated – for induction of remission in patients suffering from
active Ulcerative Colitis– for the treatment of objective and subjective symptoms
in patients suffering from active Rheumatoid Arthritis not responding to standard therapy
• Adacolumn is approved and reimbursable in Japan• Adacolumn is CE-certified by the „TÜV“
Adamonitor
Adacolumn +Adacircuit
Adastand
www.adacolumn.com
dacolumn
Carrier Cellulose acetate beads
Carrier weight 220g
Main Body Polycarbonate
Size 60mm Ø ×206mm
Filling solution Physiological saline
Column void volume 130mL
Sterilization method Autoclave at high vapor pressure
Granulocyte and Monocyte Apheresis Therapy
Adacolumn Apheresis System
Adacolumn
Vein
Vein
Flow rate: 30mL/minuteApheresis time: 60 minutesTotal apheresis volume: 1800mL
P
Anticoagulant port
Blood return
Blood draw
Basics
Patients with autoimmune diseases have a significant higher level of immune complexes and inflammatory factors as well as an increased number of granulocytes:
Normal: 3,4 0,4 x 103 granulocytes/µL
Ulcerative Colitis: 6,4 0,4 x 103 granulocytes/µL
Rheumatoide Arthritis: 5,5 0,3 x 103 granulocytes/µL
Carcinoma (progressed stadium): 5,2 0,7 x 103 granulocytes/µL
Rationale for using granulocyte and monocyte apheresis in autoimmune diseases (e.g. Crohn‘s disease, Ulcerative Colitis, etc.)
Granulocytes: A Double-Edged Cellular Species
Stem cell
Differentiation in different immuno-competent cells
Microorganisms
Neutrophil
Phagocytosis and degradation of infectious microorganisms
Defense of body against infection
Neutrophil Proteases, inflammatory cytokines
Active superoxide
Pro-inflammatory function
Tissue Damage Loss of Function
Tissuedamage
• Adsorption of complement fragments by cellulose acetate surfaces, for instance C5a
Neutrophils and macrophages can adhere (direct adsorption)
• Patients with autoimmune diseases have a high number of circulating immune complexes which adhere to cellulose acetate and produce C5a locally
IgG plus C5a can bind neutrophils and monocytes via Fc receptor (indirect adsorption)
• L-selectin down regulation (LECAM)• PBL produce less proinflammatory cytokines• Granulocyte apoptosis is enhanced• young granulocytes appear in the blood (not active)
Basics
Granulocyte/Monocyte adsorbed on the beads
In vitro Determination of Human Granulocyte and Lymphocyte Adsorption Efficiency
Heparinized blood was incubated with each type of beads (3mm in diameter) at 37 °C for 60 minutes
Lymphocytes
0
5
10
15
20
25
30
35
40
Co
ntr
ol
Po
lyst
yren
e
PE
TF
Gla
ss
Cel
lulo
se A
ceta
te
6-N
ylo
n
Granulocytes
% A
dso
rpti
on
Co
ntr
ol
Po
lyst
yren
e
PE
TF
Gla
ss
Cel
lulo
se A
ceta
te
6-N
ylo
n
0
5
10
15
20
25
30
35
40
Adsorption Selectivity of Adacolumn Carriers
The results show that the Adacolumn carriers
selectively adsorb granulocytes and monocytes
Data from 59 patients with active Ulcerative Colitis
Erythrocytes
Platelets
GranulocytesGranulocytes
MonocytesMonocytes
Lymphocytes
36.4±10.83
33.7±7.87
2.5±0.242.5±0.24
0.1±0.020.1±0.02
0.2±0.04
Number of cells adsorbed (×109)
0.5±0.15
5.7±1.35
24.9±1.9024.9±1.90
19.5±2.4719.5±2.47
6.6±1.27
Adsorption efficiency (%)
Preclinical
0
5
10
15
20
25
30
35
Adsorbed CD11b+
Healthy Arthritis
Ad
sorb
ed c
ells
(%
)
• Comparative trial of rabbits with induced arthritis and healthy controls
• In both groups identical apheresis was applied
• Results:
Adsorption of a significant higher number of granulocytes and monocytes during the apheresis in the rabbits with arthritis than in the controls
No significant differences in the adsorption of erythrocytes or lymphocytes
p < 0.05 Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997
• One group of arthritic rabbits was treated with apheresis while the other group was not
• Results:
After an apheresis with Adacolumn significantly less monocytes and T-cells migrate into the arthritic joint in comparison to the control group which received no apheresis (p < 0.001)
Preclinical
0
0.5
1
1.5
2
2.5
3
3.5
Monocytes T-cells
Without apheresis Post apheresis
Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997Infiltrated cells in the joint
Ad
sorb
ed c
ells
(%
)
• Changes in swelling of joint in 3 groups of arthritic rabbits
• 10 min. after induction of the arthritis one group received an apheresis with Adacolumn (n=6), another received a sham-column apheresis (n=6), the controls (n=7) received no apheresis
• Results:
The facts are statistically highly significant in favour of Adacolumn (p < 0.01 bzw. p< 0.001) Day 0: Induction of the arthritis
Day 0+10 min: Conduct of the apheresis
Preclinical
0
0,5
1
1,5
2
2,5
3
3,5
4
0 1 2 3 4 5 6 7
Arthritic rabbits without apheresis
Arthritic rabbits with placebo apheresis
Arthritic rabbits with Adacolumn apheresis
Sw
ellin
g o
f jo
int
(mm
)
Days after the induction of the arthritisSaniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997
Production of LECAM-1-marker on arthritic rabbits before and after an apheresis with Adacolumn (p < 0.05)
Preclinical
Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997
Decreased adhesion of granulocytes to inflammated tissue
Adacolumn Clinical Study Sites (14 Institutions)
Fukushima Medical University
Odate Municipal Hospital
Tohoku University
Hamamatsu University School of Medicine
Hirosaki University
Jichi Medical School
Gunma University
Chiba University
Niigata University
Hyogo College of Medicine
Oita Medical University
Tokyo University
Tokyo Women's Medical University
International Medical Center of Japan
Tokyo
Summary of Adacolumn Clinical Study Protocolin Patients with Active Ulcerative Colitis
Primary endpoint: To assess and evaluate the safety and efficacy of Adacolumn, patients with Ulcerative Colitis using Adacolumn were compared to patients treated with conventional drugs
Parallel controlled trial with 120 patients
Adacolumn apheresis: 60 patients
Conventional drugs: 60 patientsPrednisolon, 5-ASA, SASP
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
• Multicenter randomized comparative trial of standard therapy and of therapy with Adacolumn
• 14 centers in Japan
• 105 patients were enrolled and randomized whereas 53 patients received Adacolumn and 52 patients received standard therapy according to the guidelines of the national Japanese Ministry of Health
• Diagnoses were performed using clinical symptoms, endoscopy, histology and X-rays
Clinical Efficacy - Ulcerative Colitis
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
• Standard therapy consisted of prednisolone, salazosulphapyridine and 5-amino-salicylic acid
• Adacolumn apheresis 1x weekly for 5 weeks
• Patient age: 12-76 Years
• Exclusion criteria: Pregnancy/lactation, systolic blood pressure 80 mm Hg, anemia with < 8 g/dL Hb, increased tendency for coagulation
• Degree of the severity was classified using stool frequency, macroscopic visible blood in stool, fever, tachycardia (frequency 90), hemoglobin level and ESR (rate 30 mm)
Clinical Efficacy - Ulcerative Colitis
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
* Expert Committee on IBD, the Ministry of Health and Welfare of Japan
Adacolumn(1 apheresis/wk × 5 wks)
Time (week)
-2 1 2 3 4 5 6 7
Overall assessment
Adacolumn Clinical Study Protocol in Patients with Ulcerative Colitis (UC)
Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001
ConventionalDrugs*
• Assessment of overall improvement
More than 50% of improvement within three items which were considered as the main items for assessing response to Adacolumn apheresis therapy according to the following standards: Clinical symptoms, endoscopic findings and inflammation markers
Significantly improved: Complete remission
Improved: Conditions improved in at least more than 2 of the 3 categories
Unchanged: Conditions did not improve or worsen
Worsened: Conditions worsened in at least 2 of the 3 categories
• Assessment of overall usefulness
The overall usefulness of treatment was assessed based on the overall improvement and safety (assessment of adverse reactions)
Assessment of the Efficacy of Adacolumn
Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001
% Usefulness (safety + efficacy)
0 10 20 30 40 50 60
Refractory cases
Severe cases
All cases n=52
n=53
n=19
n=19
n=33
n=29
Drugs
AdacolumnP=0.045
P=0.030
P=0.016
Usefulness of Adacolumn vs. Conventional Drugs
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
Clinical Efficacy - Ulcerative Colitis
21,1%
30,3%
52,6%
51,7%
0 10 20 30 40 50 60
Severe cases
Refractory cases
Drug therapy
% Clinical usefulness(efficacy and safety of the therapy)
p = 0,016
p = 0,030
n = 29
n = 33
n = 19
n = 19
Shimoyama, T. J. Clin. Apheresis 18:117-131, 1999
Adacolumn
Usefulness (safety + efficacy) by disease background (1)
Adacolumn Clinical Study in Patients with UC
Classification based on severity
0
20
40
60
80
100
%
Drug(0)
Adacolumn(19)
Drug(19)
Adacolumn(34)
Drug(33)
Fulminant Severe Moderate
52.6
21.1
61.8 57.6
P < 0.05
Use
fuln
ess
(ver
y u
sefu
l an
d u
sefu
l)
ns ns
n
0 0
U-testAdacolumn
(0)
Classification based on disease location
Adacolumn(16)
Drug(15)
Adacolumn(37)
Drug(37)
Left-sided colitis Total colitis
75.0
33.3
51.4 48.6
Use
fuln
ess
(ver
y u
sefu
l an
d u
sefu
l)
0
20
40
60
80
100
%
ns ns
n
Adacolumn Clinical Study in Patients with UC
Usefulness (safety + efficacy) by disease background (2)
U-test
YA 22791-08
Adacolumn(10)
Drug(7)
Adacolumn(39)
Drug(35)
Adacolumn(4)
Drug(9)
First attack Relapsing-remitting Chronic continuous
70.0 71.4
53.8
42.9
75.0
22.2
Use
fuln
ess
(ver
y u
sefu
l an
d u
sefu
l)
0
20
40
60
80
100
(%)
n
ns ns ns
Classification based on clinical course
Adacolumn Clinical Study in Patients with UC
Usefulness (safety + efficacy) by disease background (3)
U-test
Adacolumn(11)
Drug(9)
Adacolumn(29)
Drug(32)
Adacolumn(13)
Drug(11)
First attack type Relapse, refractory type Relapse, non-refractory type
72.766.7
51.7
31.3
61.5 63.6P < 0.05
Use
fuln
ess
(ver
y u
sefu
l an
d u
sefu
l)
0
20
40
60
80
100
%
ns ns
n
Classification based on UC status
Adacolumn Clinical Study in Patients with UC
Usefulness (safety + efficacy) by disease background (4)
U-test
Adacolumn(12)
Drug(12)
Adacolumn(31)
Drug(28)
Adacolumn(10)
Drug(12)
Pseudo-polyposis type Atrophic type Mixed type
50.0
25.0
58.153.6
70.0
41.7
Use
fuln
ess
(ver
y u
sefu
l an
d u
sefu
l)
0
20
40
60
80
100
%
P < 0.05
n
ns ns
Classification based on colonoscopy
Adacolumn Clinical Study in Patients with UC
Usefulness (safety + efficacy) by disease background (5)
U-test
Daily Steroid Dose in the Adacolumn and Control Group during the Clinical Study
Changes in mean dosage of steroid in responder patients (results in very useful and useful cases)
Groupn mean SE
Pretreatmentmean SE
During treatment
AdacolumnContol (drug)
5352
24.426.3
3.603.05
21.555.4
3.179.95
Adacolumn vs. drug group P = 0.377 P < 0.001 U test
0 10 20 30 40 50 (day)10
20
25
30
35
40
45
Do
sag
e o
f st
ero
id
(mg
/day
)
Drug (n=22)
Adacolumn (n=31)
Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001; Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
15
1st day of clinical study
-10
7,8
4,9
0
1
2
3
4
5
6
7
8
Mean frequency of stool
Baseline after Adacolum apheresis
Fre
qu
ency
(%
)Clinical Efficacy - Ulcerative Colitis
84,9
38,5
0
10
20
30
40
50
60
70
80
90
Blood in stool (macrosc. visible)
Pat
ien
ts (
%)
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999(p < 0.001) (p < 0.001)
Baseline after Adacolum apheresis
2,08
1,55
0
0,5
1
1,5
2
2,5
Malaise
Baseline after Adacolumn apheresis
Clinical Efficacy - Ulcerative Colitis
1,77
1,35
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
Ulcer
Baseline after Adacolumn apheresis
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
(p < 0.001) (p < 0.001)
Fre
qu
ency
Fre
qu
ency
1,8
1,3
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
Mucopus
Baseline after Adacolumn apheresis
Clinical Efficacy - Ulcerative Colitis
1,92
1,59
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
2
Erosion
Baseline after Adacolumn apheresis
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
(p < 0.001) (p < 0.001)
Fre
qu
ency
Fre
qu
ency
Adacolumn apheresis induced suppression of LECAM-1 (CD62L, L-selectin) expression and enhanced expression of Mac-1 (CD11b/CD18) in 21 patients with
active ulcerative colitis.
0
500
1000
1500
2000
p <0.01
inflow outflow
LE
CA
M-1
[CD
62L
], %
Po
siti
ve x
MF
I
0
1000
2000
3000
4000
5000
6000
p <0.001
inflow outflow
Mac
-1[
CD
11b
], %
Po
siti
ve x
MF
I
Sixty minutes after start of apheresis, blood samples were taken at the Adacolumn inflow and outflow points and the expression of LECAM-1 and Mac-1 on blood leukocytes was investigated by flow cytometry. The expression index was calculated as % of LECAM-1 or Mac-1 positive cells x MFI (mean fluorescence intensity).
h t t p : / / w w w . a d a c o l u m n . c o m
C h a n g e s i n P r o i n f l a m m a t o r y C y t o k i n e P r o d u c t i o n b y A d a c o l u m n A p h e r e s i s ( U C p a t i e n t s , n = 1 3 )
**
* ** *
*
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
0
5 0 0 0
1 0 0 0 0
1 5 0 0 0
2 0 0 0 0
3 0 m i n 6 0 m i n 6 0 m i nb a s e l i n e i n f l o w o u t f l o w
3 0 m i n 6 0 m i n 6 0 m i nb a s e l i n e i n f l o w o u t f l o w
3 0 m i n 6 0 m i n 6 0 m i nb a s e l i n e i n f l o w o u t f l o w
T N F α ( p g / m L ) I L - 1 β ( p g / m L ) I L - 6 ( p g / m L )
Cyt
okin
e P
rod
uctio
n b
y P
erip
he
ral B
loo
d L
eu
kocy
te
* p < 0 . 0 5 , * * p < 0 . 0 1 , c o m p a r e d w i t h b a s e l i n e b y W i l c o x o n s i g n e d - r a n k t e s t .
http://www.adacolumn.com
0
2
4
6
8
10
12
Baseline 3 wk 5 wk post2wk
CRP (mg/dL) Stool Frequency (times/day)
0
2
4
6
8
10
12
14
16
18
20
Baseline2 3wk 4wk 5wk post2wk
** *** *** ********* *** ***
**p<0.01, ***p<0.001, Compared with baseline byWilcoxonsigned-rank test
Changes in Plasma CRP and Stool Frequency in 31 Responder Cases
0
10
20
30
40
50
60
70
80
Moderate UC Severe UC Refractory UC
Adacolumn > 1 Year Standard therapy > 1 Year
Adacolumn > 2 Years Standard therapy > 2 Years
Pat
ien
ts (
%)
Clinical Efficacy - Ulcerative ColitisPersistence of remission from ongoing follow-up-phase and post-
surveillance observation
Data on file
Adacolumn therapy: n=129 Standard therapy: n=84
Adverse Reactions
Adacolumn Drugs
8
Circulatory andrespiratory organs
• Headache• Dizziness on standing• Dizziness
111
Digestive organs• Nausea• Duodenal perforation
11
Hypersensitivity • Fever• Flushing
22
Liver disorder • Liver disorder (mild)• Liver disorder
42
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
Therapy
Total 40
Adverse Reactions
Adacolumn Drugs
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
Therapy
Musculoskeletalsymptoms
• Osteoporosis• Reduced bone mass• Compressed fracture of lumber vertebra
33
2
Lipid and protein metabolism disorders
• Moon face• Hypoproteinaemia• Hypercholesterolaemia
10 2 1
Dermatological disorders
• Acne• Pyoderma gangrenosum
51
Others 6
Safety - Ulcerative Colitis
5
24
8
40
03
0
5
10
15
20
25
30
35
40
Patients with AE Number of AE Drop out due to AE
Adacolumn (n=59) Standard therapy (n=52)(n)
Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999
Pat
ien
ts
Adacolumn Summary
Indication: Adacolumn is indicated for the treatment of UC (and potential other autoimmune diseases
which are under investigation)
Pathophysiology: 1) Reduction of granulocytes and monocytes2) Changes of granulocyte adhesion
Clinical findings: 1) Remission and improvement of clinical symptoms2) Superiority vs. standard therapy - especially
in severely affected patients3) Reduction of steroid doses
Tolerability: 1) Superior to standard therapy (less and milder side-effects)
Pyoderma Gangrenosum (UC)
Before treatment After 5th treatment
T. Kanekura, et. al., J. American Academy of Dermatology (2002 in press)
38 year old male. Duration of disease = 3 years.
top related