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Device for Granulocyte and Monocyte Apheresis

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Presentation on theme: "Device for Granulocyte and Monocyte Apheresis"— Presentation transcript:

1 Device for Granulocyte and Monocyte Apheresis
Adacolumn Device for Granulocyte and Monocyte Apheresis Otsuka / JIMRO

2 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“

3 Adacolumn + Adacircuit Adamonitor Adastand

4 dacolumn Granulocyte and Monocyte Apheresis Therapy 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

5 Adacolumn Apheresis System
Flow rate: 30mL/minute Apheresis time: 60 minutes Total apheresis volume: 1800mL P Adacolumn Vein Blood return Vein Blood draw Anticoagulant port

6 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.)

7 Granulocytes: A Double-Edged Cellular Species
Stem cell Differentiation in different immuno-competent cells Microorganisms Active superoxide Tissue damage Neutrophil Neutrophil Proteases, inflammatory cytokines Phagocytosis and degradation of infectious microorganisms Tissue Damage Loss of Function Defense of body against infection Pro-inflammatory function

8 Basics 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)

9 Granulocyte/Monocyte adsorbed on the beads

10 In vitro Determination of Human Granulocyte and Lymphocyte Adsorption Efficiency
40 Granulocytes 40 Lymphocytes 35 35 30 30 % Adsorption 25 25 20 20 15 15 10 10 5 5 Control Polystyrene PETF Glass Cellulose Acetate 6-Nylon Control Polystyrene PETF Glass Cellulose Acetate 6-Nylon Heparinized blood was incubated with each type of beads (3mm in diameter) at 37 °C for 60 minutes

11 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

12 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 Adsorbed CD11b+ p < 0.05 Saniabadi, A.; Jpn. J. Apheresis 16 (1): , 1997

13 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 Monocytes T-cells Infiltrated cells in the joint Saniabadi, A.; Jpn. J. Apheresis 16 (1): , 1997

14 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 Swelling of joint (mm) 1,5 1 0,5 1 2 3 4 5 6 7 Days after the induction of the arthritis Saniabadi, A.; Jpn. J. Apheresis 16 (1): , 1997

15 Preclinical  Decreased adhesion of granulocytes to inflammated tissue
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): , 1997

16 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

17 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: , 1999

18 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: , 1999

19 Clinical Efficacy - Ulcerative Colitis
Standard therapy consisted of prednisolone, salazosulphapyridine and 5-amino-salicylic acid Adacolumn apheresis 1x weekly for 5 weeks Patient age: 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: , 1999

20 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

21 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 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

22 Usefulness of Adacolumn vs. % Usefulness (safety + efficacy)
Conventional Drugs All cases n=52 Drugs P=0.045 n=53 Adacolumn Severe cases n=19 P=0.030 n=19 Refractory cases n=33 P=0.016 n=29 10 20 30 40 50 60 % Usefulness (safety + efficacy) Shimoyama, T.; J. Clin. Apheresis 18: , 1999

23 Clinical Efficacy - Ulcerative Colitis
Adacolumn Drug therapy n = 29 51,7% Refractory cases p = 0,016 n = 33 30,3% n = 19 52,6% Severe cases p = 0,030 n = 19 21,1% 10 20 30 40 50 60 % Clinical usefulness (efficacy and safety of the therapy) Shimoyama, T. J. Clin. Apheresis 18: , 1999

24 Classification based on severity Usefulness (very useful and useful)
Adacolumn Clinical Study in Patients with UC Usefulness (safety + efficacy) by disease background (1) Classification based on severity % 100 Fulminant Severe Moderate 80 P < 0.05 ns ns 61.8 57.6 60 52.6 Usefulness (very useful and useful) 40 21.1 20 Adacolumn (0) Drug (0) Adacolumn (19) Drug (19) Adacolumn (34) Drug (33) n U-test

25 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 80 ns ns 75.0 60 51.4 Usefulness (very useful and useful) 48.6 40 33.3 20 Adacolumn (16) Drug (15) Adacolumn (37) Drug (37) n U-test

26 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 70.0 71.4 60 53.8 Usefulness (very useful and useful) 42.9 40 22.2 20 Adacolumn (10) Drug (7) Adacolumn (39) Drug (35) Adacolumn (4) Drug (9) U-test n YA

27 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 66.7 P < 0.05 63.6 61.5 60 51.7 Usefulness (very useful and useful) 40 31.3 20 Adacolumn (11) Drug (9) Adacolumn (29) Drug (32) Adacolumn (13) Drug (11) U-test n

28 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 80 ns ns 70.0 58.1 60 53.6 50.0 Usefulness (very useful and useful) 41.7 40 25.0 20 Adacolumn (12) Drug (12) Adacolumn (31) Drug (28) Adacolumn (10) Drug (12) U-test n

29 1st day of clinical study Dosage of steroid (mg/day)
Daily Steroid Dose in the Adacolumn and Control Group during the Clinical Study Group Pretreatment During treatment 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 Dosage of steroid (mg/day) 30 25 20 15 Adacolumn (n=31) 10 -10 10 20 30 40 50 (day) Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001; Shimoyama, T.; J. Clin. Apheresis 18: , 1999

30 Clinical Efficacy - Ulcerative Colitis
Baseline after Adacolum apheresis Baseline after Adacolum apheresis 8 7,8 90 84,9 7 80 6 70 4,9 60 5 Frequency (%) 50 4 Patients (%) 38,5 40 3 30 2 20 1 10 Blood in stool (macrosc. visible) Mean frequency of stool (p < 0.001) (p < 0.001) Shimoyama, T.; J. Clin. Apheresis 18: , 1999

31 Clinical Efficacy - Ulcerative Colitis
Baseline after Adacolumn apheresis Baseline after Adacolumn apheresis 2,5 1,77 1,8 2,08 1,6 2 1,4 1,35 1,55 1,2 Frequency 1,5 Frequency 1 0,8 1 0,6 0,5 0,4 0,2 Malaise (p < 0.001) Ulcer (p < 0.001) Shimoyama, T.; J. Clin. Apheresis 18: , 1999

32 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 1,4 1,6 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 Mucopus (p < 0.001) Erosion (p < 0.001) Shimoyama, T.; J. Clin. Apheresis 18: , 1999

33 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 2000 6000 5000 1500 4000 1000 3000 Mac -1[CD11b], %Positive x MFI LECAM-1[CD62L], %Positive x MFI 2000 500 1000 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).

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36 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= Standard therapy: n=84 70 60 50 Patients (%) 40 30 20 10 Moderate UC Severe UC Refractory UC Data on file

37 Adverse Reactions Therapy Adacolumn Drugs Total 8 40 Headache
Dizziness on standing Dizziness 1 Circulatory and respiratory organs Nausea Duodenal perforation 1 Digestive organs 1 Fever Flushing 2 Hypersensitivity Liver disorder (mild) Liver disorder 4 2 Liver disorder Shimoyama, T.; J. Clin. Apheresis 18: , 1999

38 Adverse Reactions Therapy Adacolumn Drugs Osteoporosis 3
Reduced bone mass Compressed fracture of lumber vertebra Musculoskeletal symptoms 3 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: , 1999

39 Safety - Ulcerative Colitis
Adacolumn (n=59) Standard therapy (n=52) (n) 40 40 35 30 25 24 Patients 20 15 10 8 5 5 3 Patients with AE Number of AE Drop out due to AE Shimoyama, T.; J. Clin. Apheresis 18: , 1999

40 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)

41 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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