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Adacolumn Device for Granulocyte and Monocyte Apheresis Otsuka / JIMRO www.otsuka.de www.adacolumn.com.

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Presentation on theme: "Adacolumn Device for Granulocyte and Monocyte Apheresis Otsuka / JIMRO www.otsuka.de www.adacolumn.com."— Presentation transcript:

1 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 Adamonitor Adacolumn + Adacircuit Adastand

4 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

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

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 10 3 granulocytes/µL Ulcerative Colitis:6,4 0,4 x 10 3 granulocytes/µL Rheumatoide Arthritis:5,5 0,3 x 10 3 granulocytes/µL Carcinoma (progressed stadium):5,2 0,7 x 10 3 granulocytes/µL Rationale for using granulocyte and monocyte apheresis in autoimmune diseases (e.g. Crohns disease, Ulcerative Colitis, etc.)

7 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 Tissue damage

8 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

9 Granulocyte/Monocyte adsorbed on the beads

10 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 Control Polystyrene PETF Glass Cellulose Acetate 6-Nylon Granulocytes % Adsorption Control Polystyrene PETF Glass Cellulose Acetate 6-Nylon

11 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 Granulocytes Monocytes Lymphocytes 36.4± ± ± ± ±0.04 Number of cells adsorbed (×10 9 ) 0.5± ± ± ± ±1.27 Adsorption efficiency (%)

12 Preclinical Adsorbed CD11b+ HealthyArthritis Adsorbed cells (%) 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): , 1997

13 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 MonocytesT-cells Without apheresisPost apheresis Saniabadi, A.; Jpn. J. Apheresis 16 (1): , 1997 Infiltrated cells in the joint Adsorbed cells (%)

14 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, Arthritic rabbits without apheresis Arthritic rabbits with placebo apheresis Arthritic rabbits with Adacolumn apheresis Swelling of joint (mm) Days after the induction of the arthritis Saniabadi, A.; Jpn. J. Apheresis 16 (1): , 1997

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

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 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: , 1999

19 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) Clinical Efficacy - Ulcerative Colitis Shimoyama, T.; J. Clin. Apheresis 18: , 1999

20 * Expert Committee on IBD, the Ministry of Health and Welfare of Japan Adacolumn (1 apheresis/wk × 5 wks) Time (week) Overall assessment Adacolumn Clinical Study Protocol in Patients with Ulcerative Colitis (UC) Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001 Conventional Drugs*

21 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

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

23 Clinical Efficacy - Ulcerative Colitis 21,1% 30,3% 52,6% 51,7% 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 Shimoyama, T. J. Clin. Apheresis 18: , 1999 Adacolumn

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

25 Classification based on disease location Adacolumn (16) Drug (15) Adacolumn (37) Drug (37) Left-sided colitisTotal colitis Usefulness (very useful and useful) % ns n Adacolumn Clinical Study in Patients with UC Usefulness (safety + efficacy) by disease background (2) U-test

26 YA Adacolumn (10) Drug (7) Adacolumn (39) Drug (35) Adacolumn (4) Drug (9) First attackRelapsing-remitting Chronic continuous Usefulness (very useful and useful) (%) n ns Classification based on clinical course Adacolumn Clinical Study in Patients with UC Usefulness (safety + efficacy) by disease background (3) U-test

27 Adacolumn (11) Drug (9) Adacolumn (29) Drug (32) Adacolumn (13) Drug (11) First attack typeRelapse, refractory typeRelapse, non-refractory type P < 0.05 Usefulness (very useful and useful) % ns n Classification based on UC status Adacolumn Clinical Study in Patients with UC Usefulness (safety + efficacy) by disease background (4) U-test

28 Adacolumn (12) Drug (12) Adacolumn (31) Drug (28) Adacolumn (10) Drug (12) Pseudo-polyposis typeAtrophic typeMixed type Usefulness (very useful and useful) % P < 0.05 n ns Classification based on colonoscopy Adacolumn Clinical Study in Patients with UC Usefulness (safety + efficacy) by disease background (5) U-test

29 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) Group nmeanSE Pretreatment meanSE During treatment Adacolumn Contol (drug) Adacolumn vs. drug group P = 0.377P < U test (day) Dosage of steroid (mg/day) Drug (n=22) Adacolumn (n=31) Shimoyama, T.; J. Clin. Apheresis 16:1-9, 2001; Shimoyama, T.; J. Clin. Apheresis 18: , st day of clinical study -10

30 7,8 4, Mean frequency of stool Baselineafter Adacolum apheresis Frequency (%) Clinical Efficacy - Ulcerative Colitis 84,9 38, Blood in stool (macrosc. visible) Patients (%) Shimoyama, T.; J. Clin. Apheresis 18: , 1999 (p < 0.001) Baselineafter Adacolum apheresis

31 2,08 1,55 0 0,5 1 1,5 2 2,5 Malaise Baselineafter 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 Baselineafter Adacolumn apheresis Shimoyama, T.; J. Clin. Apheresis 18: , 1999 (p < 0.001) Frequency

32 1,8 1,3 0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 Mucopus Baselineafter 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 Baselineafter Adacolumn apheresis Shimoyama, T.; J. Clin. Apheresis 18: , 1999 (p < 0.001) Frequency

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 inflowoutflow LECAM-1[CD62L], %Positive x MFI p<0.001 inflowoutflow Mac -1[CD11b], %Positive x MFI 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 Moderate UCSevere UCRefractory UC Adacolumn > 1 YearStandard therapy > 1 Year Adacolumn > 2 YearsStandard therapy > 2 Years Patients (%) Clinical Efficacy - Ulcerative Colitis Persistence of remission from ongoing follow-up-phase and post- surveillance observation Data on file Adacolumn therapy: n=129 Standard therapy: n=84

37 Adverse Reactions Adacolumn Drugs 8 Circulatory and respiratory organs Headache Dizziness on standing Dizziness Digestive organs Nausea Duodenal perforation 1 1 Hypersensitivity Fever Flushing 2222 Liver disorder Liver disorder (mild) Liver disorder 4242 Shimoyama, T.; J. Clin. Apheresis 18: , 1999 Therapy Total 40

38 Adverse Reactions Adacolumn Drugs Shimoyama, T.; J. Clin. Apheresis 18: , 1999 Therapy Musculoskeletal symptoms Osteoporosis Reduced bone mass Compressed fracture of lumber vertebra Lipid and protein metabolism disorders Moon face Hypoproteinaemia Hypercholesterolaemia Dermatological disorders Acne Pyoderma gangrenosum 5151 Others 6

39 Safety - Ulcerative Colitis Patients with AENumber of AEDrop out due to AE Adacolumn (n=59)Standard therapy (n=52) (n) Shimoyama, T.; J. Clin. Apheresis 18: , 1999 Patients

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) Before treatmentAfter 5 th treatment T. Kanekura, et. al., J. American Academy of Dermatology (2002 in press) 38 year old male. Duration of disease = 3 years.

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