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Adacolumn. Device for Granulocyte and Monocyte Apheresis. Otsuka / JIMRO www.otsuka.de www.adacolumn.com. Legal Status. Adacolumn is indicated for induction of remission in patients suffering from active Ulcerative Colitis

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Adacolumn

Adacolumn

Device for Granulocyte and Monocyte Apheresis

Otsuka / JIMRO

www.otsuka.de

www.adacolumn.com


Legal status

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“


Adacolumn

Adacolumn

+

Adacircuit

www.adacolumn.com

Adamonitor

Adastand


Adacolumn

dacolumn

Granulocyte and Monocyte Apheresis Therapy

Carrier

Cellulose acetate beads

Carrier weight

220g

Main Body

Polycarbonate

Size

60mmØ ×206mm

Filling solution

Physiological saline

Column void volume

130mL

Sterilization method

Autoclave at high vapor pressure


Adacolumn apheresis system

Adacolumn Apheresis System

Flow rate: 30mL/minute

Apheresis time: 60 minutes

Total apheresis volume:1800mL

P

Adacolumn

Vein

Blood return

Blood draw

Vein

Anticoagulant port


Basics

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 d ouble e dged c ellular s pecies

Granulocytes: ADouble-Edged Cellular Species

Stem cell

Differentiation in differentimmuno-competent cells

Microorganisms

Active superoxide

Tissuedamage

Neutrophil

Neutrophil

Proteases,

inflammatory cytokines

Phagocytosis and degradation of infectious microorganisms

Loss of Function

Tissue Damage

Defense of body against infection

Pro-inflammatory function


Adacolumn

Basics

  • Adsorption of complementfragments 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)


Adacolumn

Granulocyte/Monocyte adsorbed on the beads


In vitro determination of human granulocyte and lymphocyte adsorption efficiency

6-Nylon

Glass

Glass

PETF

PETF

Control

Control

6-Nylon

Polystyrene

Polystyrene

Cellulose Acetate

Cellulose Acetate

In vitro Determination of Human Granulocyte and Lymphocyte Adsorption Efficiency

Granulocytes

Lymphocytes

40

40

35

35

30

30

% Adsorption

25

25

20

20

15

15

10

10

5

5

0

0

Heparinized blood was incubated with each type of beads (3mm in diameter) at 37 °C for 60 minutes


Adacolumn

Adsorption Selectivity of Adacolumn Carriers

Data from 59 patients with active Ulcerative Colitis

Number of cells adsorbed (×109)

Adsorption efficiency (%)

Erythrocytes

36.4±10.83

0.5±0.15

Platelets

33.7±7.87

5.7±1.35

Granulocytes

2.5±0.24

24.9±1.90

Monocytes

0.1±0.02

19.5±2.47

Lymphocytes

0.2±0.04

6.6±1.27

The results show that the Adacolumn carriers

selectively adsorb granulocytes and monocytes


Adacolumn

Preclinical

  • 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

Healthy

Arthritis

35

30

25

20

Adsorbed cells (%)

15

10

5

0

Adsorbed CD11b+

p < 0.05

Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997


Adacolumn

Preclinical

  • 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)

Without apheresis

Post apheresis

3.5

3

2.5

2

Adsorbed cells (%)

1.5

1

0.5

0

Monocytes

T-cells

Infiltrated cells in the joint

Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997


Adacolumn

Preclinical

  • 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

Arthritic rabbits without apheresis

Arthritic rabbits with placebo apheresis

Arthritic rabbits with Adacolumn apheresis

4

3,5

3

2,5

2

1,5

Swelling of joint (mm)

1

0,5

0

0

1

2

3

4

5

6

7

Days after the induction of the arthritis

Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997


Adacolumn

Preclinical

Production of LECAM-1-marker on arthritic rabbits before and after an apheresis with Adacolumn (p < 0.05)

Decreased adhesion of granulocytes to inflammated tissue

Saniabadi, A.; Jpn. J. Apheresis 16 (1): 173-178, 1997


Adacolumn

Tokyo

Tokyo Women's Medical University

Tokyo University

International Medical Center of Japan

Odate Municipal Hospital

Hirosaki University

Niigata University

Hyogo College of Medicine

Gunma University

Tohoku University

Fukushima Medical University

Jichi Medical School

Chiba University

Hamamatsu University School of Medicine

Oita Medical University

Adacolumn Clinical Study Sites(14 Institutions)


Adacolumn

Summary of Adacolumn Clinical Study Protocol

in 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 patients

Prednisolon, 5-ASA, SASP

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Clinical efficacy ulcerative colitis

Clinical Efficacy - Ulcerative Colitis

  • 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

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Adacolumn

Clinical Efficacy - Ulcerative Colitis

  • 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)

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Adacolumn

Adacolumn Clinical Study Protocol in Patients with Ulcerative Colitis (UC)

Conventional

Drugs*

Adacolumn

(1 apheresis/wk × 5 wks)

-2

1

2

3

4

5

6

7

Time (week)

Overall assessment

*Expert Committee on IBD, the Ministry of Health and Welfare of Japan

Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001


Assessment of the efficacy of adacolumn

Assessment of the Efficacy of Adacolumn

  • 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)

Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001


Adacolumn

Usefulness of Adacolumn vs.

Conventional Drugs

All cases

n=52

Drugs

P=0.045

Adacolumn

n=53

n=19

Severe cases

P=0.030

n=19

Refractory cases

n=33

P=0.016

n=29

0

10

20

30

40

50

60

% Usefulness (safety + efficacy)

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Clinical efficacy ulcerative colitis1

Clinical Efficacy - Ulcerative Colitis

Adacolumn

Drug therapy

n = 29

51,7%

Refractory cases

p = 0,016

30,3%

n = 33

n = 19

52,6%

Severe cases

p = 0,030

n = 19

21,1%

0

10

20

30

40

50

60

% Clinical usefulness

(efficacy and safety of the therapy)

Shimoyama, T. J. Clin. Apheresis 18:117-131, 1999


Adacolumn

Adacolumn Clinical Study in Patients with UC

Usefulness (safety + efficacy) by disease background (1)

Classification based on severity

%

100

Severe

Fulminant

Moderate

80

P < 0.05

ns

ns

61.8

57.6

60

52.6

Usefulness (very useful and useful)

40

21.1

20

0

0

0

Adacolumn

(0)

Drug

(0)

Adacolumn

(19)

Drug

(19)

Adacolumn

(34)

Drug

(33)

U-test

n


Adacolumn

Adacolumn Clinical Study in Patients with UC

Usefulness (safety + efficacy) by disease background (2)

Classification based on disease location

%

100

Left-sided colitis

Total colitis

ns

ns

80

75.0

60

51.4

48.6

Usefulness (very useful and useful)

40

33.3

20

0

Adacolumn

(16)

Drug

(15)

Adacolumn

(37)

Drug

(37)

U-test

n


Adacolumn

Adacolumn Clinical Study in Patients with UC

Usefulness (safety + efficacy) by disease background (3)

Classification based on clinical course

(%)

100

First attack

Relapsing-remitting

Chronic continuous

ns

ns

ns

80

75.0

71.4

70.0

60

53.8

Usefulness (very useful and useful)

42.9

40

22.2

20

0

Adacolumn

(10)

Drug

(7)

Adacolumn

(39)

Drug

(35)

Adacolumn

(4)

Drug

(9)

U-test

n

YA 22791-08


Adacolumn

Adacolumn Clinical Study in Patients with UC

Usefulness (safety + efficacy) by disease background (4)

Classification based on UC status

%

100

First attack type

Relapse, refractory type

Relapse, non-refractory type

ns

ns

80

72.7

P < 0.05

66.7

63.6

61.5

60

51.7

Usefulness (very useful and useful)

40

31.3

20

0

Adacolumn

(11)

Drug

(9)

Adacolumn

(29)

Drug

(32)

Adacolumn

(13)

Drug

(11)

U-test

n


Adacolumn

Adacolumn Clinical Study in Patients with UC

Usefulness (safety + efficacy) by disease background (5)

Classification based on colonoscopy

%

100

Pseudo-polyposis type

Atrophic type

Mixed type

P < 0.05

ns

ns

80

70.0

58.1

60

53.6

50.0

Usefulness (very useful and useful)

41.7

40

25.0

20

0

Adacolumn

(12)

Drug

(12)

Adacolumn

(31)

Drug

(28)

Adacolumn

(10)

Drug

(12)

U-test

n


Daily steroid dose in the adacolumn and control group during the clinical study

Daily Steroid Dose in the Adacolumn and Control Group during the Clinical Study

Pretreatment

During treatment

Group

n

mean

SE

mean

SE

Adacolumn

Contol (drug)

53

52

24.4

26.3

3.60

3.05

21.5

55.4

3.17

9.95

Adacolumn vs. drug group

P=0.377

P < 0.001

U test

Changes in mean dosage of steroid in responder patients (results in very useful and useful cases)

45

40

Drug (n=22)

35

1st day of clinical study

30

Dosage of steroid (mg/day)

25

20

15

Adacolumn (n=31)

10

(day)

-10

0

10

20

30

40

50

Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001; Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Clinical efficacy ulcerative colitis2

Clinical Efficacy - Ulcerative Colitis

Baseline

after Adacolum apheresis

Baseline

after Adacolum apheresis

7,8

8

90

84,9

7

80

70

6

60

4,9

5

Frequency (%)

50

Patients (%)

4

38,5

40

3

30

2

20

10

1

0

0

Blood in stool (macrosc. visible)

Mean frequency of stool

(p < 0.001)

(p < 0.001)

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Clinical efficacy ulcerative colitis3

Clinical Efficacy - Ulcerative Colitis

Baseline

after Adacolumn apheresis

Baseline

after Adacolumn apheresis

1,77

2,5

1,8

1,6

2,08

2

1,35

1,4

1,55

1,2

Frequency

1,5

Frequency

1

0,8

1

0,6

0,4

0,5

0,2

0

0

(p<0.001)

(p<0.001)

Malaise

Ulcer

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Clinical efficacy ulcerative colitis4

Clinical Efficacy - Ulcerative Colitis

Baseline

after Adacolumn apheresis

Baseline

after Adacolumn apheresis

1,8

1,8

2

1,92

1,6

1,8

1,59

1,6

1,4

1,3

1,4

1,2

1,2

Frequency

1

Frequency

1

0,8

0,8

0,6

0,6

0,4

0,4

0,2

0,2

0

0

(p<0.001)

(p<0.001)

Mucopus

Erosion

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Adacolumn

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.

p

<0.01

p

<0.001

6000

2000

5000

1500

4000

3000

1000

Mac -1[CD11b], %Positive x MFI

LECAM-1[CD62L], %Positive x MFI

2000

500

1000

0

0

inflow

outflow

inflow

outflow

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).


Clinical efficacy ulcerative colitis5

Clinical Efficacy - Ulcerative Colitis

Persistence of remission from ongoing follow-up-phase and post-surveillance observation

Adacolumn > 1 Year

Standard therapy > 1 Year

Adacolumn > 2 Years

Standard therapy > 2 Years

80

Adacolumn therapy: n=129 Standard therapy: n=84

70

60

50

Patients (%)

40

30

20

10

0

Moderate UC

Severe UC

Refractory UC

Data on file


Adacolumn

Adverse Reactions

Adacolumn Drugs

Therapy

Total

8

40

1

1

1

  • Headache

  • Dizziness on standing

  • Dizziness

Circulatory and

respiratory organs

1

  • Nausea

  • Duodenal perforation

Digestive organs

1

  • Fever

  • Flushing

2

2

Hypersensitivity

  • Liver disorder (mild)

  • Liver disorder

4

2

Liver disorder

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Adacolumn

Adverse Reactions

Adacolumn Drugs

Therapy

  • Osteoporosis

  • Reduced bone mass

  • Compressed fracture of lumber vertebra

3

3

Musculoskeletal

symptoms

2

Lipid and protein metabolism disorders

  • Moon face

  • Hypoproteinaemia

  • Hypercholesterolaemia

10

2

1

Dermatological disorders

  • Acne

  • Pyoderma gangrenosum

5

1

Others

6

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Safety ulcerative colitis

Safety - Ulcerative Colitis

Adacolumn (n=59)

Standard therapy (n=52)

(n)

40

40

35

30

24

25

Patients

20

15

10

8

5

5

3

0

0

Patients with AE

Number of AE

Drop out due to AE

Shimoyama, T.; J. Clin. Apheresis 18:117-131, 1999


Adacolumn summary

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 monocytes

2) Changes of granulocyte adhesion

Clinical findings:1) Remission and improvement of clinical symptoms

2) Superiority vs. standard therapy - especially in severely affected patients

3) Reduction of steroid doses

Tolerability:1) Superior to standard therapy (less and milder side-effects)


Adacolumn

Pyoderma Gangrenosum(UC)

38 year old male. Duration of disease = 3 years.

Before treatment

After 5th treatment

T. Kanekura, et. al., J. American Academy of Dermatology (2002 in press)


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