Genmab A/s · OMXCOP:GMAB

Genmab A/s — Technical Presentation (2006)

40 slides from Genmab A/s's technical presentation, Oct 21, 2006

  1. Slide 1: Novel antibody therapeutic approach for rheumatoid arthritis

    Novel antibody therapeutic approach for rheumatoid arthritis Mikkel Østergaard Department of Rheumatology Copenhagen University Hospital at Hvidovre, Denmark

  2. Slide 2: Investigators

    Investigators M Østergaard Copenhagen University Hospital at Hvidovre, Denmark B Baslund Rigshospitalet, Copenhagen, Denmark MS Hansen Copenhagen University Hospital at Herlev , Denmark PT Dawes The Haywood Hospital, Stoke on Trent, UK BL Hazleman Addenbrooke’s Hospital, Cambridge, UK I McInnes Univ

  3. Slide 3: ACR Treatment Algorithm for RA

    ACR Treatment Algorithm for RA Diagnosis and Initial Evaluation of RA •Establish Diagnosis of RA Early Initiate Therapy •Document Baseline Disease Activity and Damage •Patient Education •Estimate Prognosis •Start DMARD(s) within 3 months •Consider NSAID •Consider local or low-dose systemic steroids

  4. Slide 4: Approved biologic agents in RA

    Approved biologic agents in RA • TNFα inhibitors ƒ infliximab, adalimumab, etanercept • IL1 inhibitors ƒ anakinra • CD20 antibodies ƒ rituximab

  5. Slide 5: CD20 B cell differentiation antigen

    CD20 B cell differentiation antigen Function - Ca++ channel - Associates with other membrane proteins: MHCII, CD40, CD53, CD81, CD82

  6. Slide 6: Steps in the Maturation of B Cells

    Steps in the Maturation of B Cells Cell Stem Pro B Pre B Immature Activated Memory Plasma surface cells antigens CD10 CD19 CD20 CD24 CD38 CD39

  7. Slide 7: The roles of B cells in the pathophysiology of RA

    The roles of B cells in the pathophysiology of RA •Secretion of pro-inflammatory cytokines •Antigen presentation •T-cell activation •Auto-antibody production

  8. Slide 8: ACR definition of improvement (ACR20, ACR50, ACR70)

    ACR definition of improvement (ACR20, ACR50, ACR70) ≥ 20 (50, 70) % improvement in tender joint count ≥ 20 (50, 70) % improvement in swollen joint count and ≥ 20 (50, 70) % improvement in 3 of following 5 assessments: ƒ Patient Pain Assessment (VAS) ƒ Patient Global Assessment (VAS) ƒ Physician Glob

  9. Slide 9: Rituximab Clinical Trials in RA

    Rituximab Clinical Trials in RA Responses at week 24, % of patients Phase IIa Phase IIb DANCER Phase III N = 465 REFLEX N = 161 N = 499 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 MTX 38 13 5 RTX 2x1g 65 33 15 RTX 2x1g + 76 41 15 CTX RTX 2x1g + 73 43 23 MTX Placebo 28 13 5 RTX 2 x0.5g 55 3

  10. Slide 10: HuMax-CD20

    HuMax-CD20 HuMax-CD20 (fully human) compared to rituximab (chimeric): ƒ Better binding; slower off rate (Dissociation from surface CD20: T½: 180 min vs 90 min) ƒ Stronger complement activation (Complement dependent cytotoxicity higher in tested tumor cell lines) ƒ More efficient tumor lysis [whole b

  11. Slide 11: Previous clinical experience

    Previous clinical experience • Follicular Lymphoma ƒ 4 cohorts of 10 patients with CD20+ refractory or relapsed non-Hodgkin’s Lymphoma grade 1-2 treated with 4 weekly infusions of HuMax- CD20 up to 1000 mg • Chronic Lymphocytic Leukemia ƒ 3 cohorts of 3, 3 and 27 patients with relapsed or refractory

  12. Slide 12: Follicular Lymphoma B cell depletion

    Follicular Lymphoma B cell depletion 9 patients 10 patients 500 500 mg 3135 27678 500 300 mg infusion infusion 400 CD45+CD19+ (*10^6/L) 400 CD45+CD19+ (*10^6/L) 300 300 200 200 100 100 0 0 screening 4 11 19 26 40 54 screening 4 11 19 26 40 54 weeks from start of treatment weeks from start of treatme

  13. Slide 13: Follicular Lymphoma objective response

    Follicular Lymphoma Objective response Objective responses according to Cheson criteria achieved in all dose groups; response rate up to 63%

  14. Slide 14: Chronic Lymphocytic Leukemia leukemic B cell depletion

    Chronic Lymphocytic Leukemia Leukemic B cell depletion Group C, N=27 260 infusion 240 220 CD19+CD5+ count (*10^9/L) 200 180 160 140 120 100 80 60 40 20 0 screening 4 11 19 26 weeks from start of treatment

  15. Slide 15: Chronic Lymphocytic Leukemia

    Chronic Lymphocytic Leukemia 46% objective response rate in the highest dose group Number of patients 27 Nodular partial response 2 12 / 26 Partial response 10 Progressive disease 13 Death 1 Not evaluable 1

  16. Slide 16: Safety profile

    Safety profile Follicular Lymphoma; Chronic Lymphocytic Leukemia • Reversible infusion related events including rigor, pyrexia, fatigue, rash and flushing • Adverse events predominantly reported during first infusion

  17. Slide 17: HuMax-CD20 in RA

    HuMax-CD20 in RA First Clinical Results of HuMax-CD20 fully human monoclonal IgG1 antibody Treatment in Rheumatoid Arthritis

  18. Slide 18: Patient population

    Patient population • A diagnosis of RA of at least 6 months duration • Active disease ƒ ≥ 6 swollen joints (of 28 joints) ƒ ≥ 6 tender joints (of 28 joints) ƒ ESR ≥ 22 mm/h or CRP ≥ 10mg/L • Failure to at least one DMARD • Previous exposure to biological agents allowed except for anti-CD20 antibodie

  19. Slide 19: Study design

    Study design Double blind, randomized, placebo controlled, dose escalation, multi center, 24 week, phase I/II clinical trial 300mg 700mg 1000mg/placebo 1000mg 700mg/placebo placebo 300mg/placebo Part A (30 patients) Part B (200 patients)

  20. Slide 20: Study design

    Study design • 2 infusions of either HuMax-CD20 (300, 700 or 1000 mg) or placebo 2 weeks apart • Premedication with paracetamol and antihistaminics; glucocorticosteroids by amendment • Allowed continuation of ongoing therapy with stable doses of methotrexate and low dose corticosteroid • Patients fo

  21. Slide 21: Primary objective, part A

    Primary objective, part A • To evaluate the safety of HuMax-CD20 in patients with active RA Endpoints ƒ Adverse events and ƒ ACR20, ACR50, ACR70 ƒ CD19+ and CD20+ B cell depletion

  22. Slide 22: Demographics

    Demographics Placebo 300 mg 700 mg 1000 mg No of patients 7 12 10 10 Age, median 60 53 50 57 Duration of RA, years, median 7 6 14 12 Sex male/female 0/7 1/11 1/9 2/8 Methotrexate, no of patients 7 12 7 6 weekly dose, mg, median 20 13 18 15 Glucocorticoids, no of patients 7 12 10 10 daily dose, mg, m

  23. Slide 23: Patient disposition

    Patient disposition Randomised 300 mg: 15 4 withdrawn (AE) Randomised 700 mg: 12 1 withdrawn (AE) Randomised 1000 mg: 12 1 withdrawn (AE) 26 active treatment Completed dosing: 33 7 placebo

  24. Slide 24: B cell depletion

    B cell depletion CD19+ (/mm3) 7 patients Placebo CD19+ (/mm3) 8 patients 300 mg CD19+ / mm3 infusion infusion 1531 700 700 600 600 500 500 400 400 300 108 300 309 11 107 200 206 200 301 104 103 100 203 100 105 113 101 111 0 0 -2 2 6 10 14 18 22 26 30 34 38 -2 2 6 10 14 18 22 26 30 34 38 weeks from s

  25. Slide 25: Infusion related reactions

    Infusion related reactions Dose group Event Premedication by amendment 300 mg Bronchospasm (grade 3 non-serious) Anaphylactoid reaction (SAE) Corticosteroids 50 mg i.v. on infusion day Urticaria (SAE) 1 mg Antihistamine p.o. on day before infusion Corticosteroids to 100 mg i.v. on infusion day 700 m

  26. Slide 26: Adverse events

    Adverse events Reported in ≥ 4 patients No of patients with event / No of events Active treatment Placebo N = 32 N=7 Urticaria NOS 5/5 1/1 Rash NOS 5/7 Nausea 5/5 4/6 Dyspnoea 4/5 Fatigue 4/7 4/4 Pyrexia 5/5 1/1 Hypotension NOS 7/7 Flushing 4/7

  27. Slide 27: Adverse events

    Adverse events The majority occurred at the first infusion 100 90 Grade 4 80 Grade 3 Grade 2 % of patients 70 Grade 1 60 50 40 30 20 10 0 Placebo 300 700 1000 Placebo 300 700 1000 Dose group, mg 1st infusion 2nd infusion

  28. Slide 28: ACR definition of improvement (ACR20)

    ACR definition of improvement (ACR20) ≥ 20 % improvement in tender joint count ≥ 20 % improvement in swollen joint count and ≥ 20 % improvement in 3 of following 5 assessments: ƒ Patient Pain Assessment (VAS) ƒ Patient Global Assessment (VAS) ƒ Physician Global Assessment (VAS) ƒ Patient Self-Assess

  29. Slide 29: ACR responses, intention-to-treat population

    ACR responses at 24 weeks Intention-to-treat population 90 80 70 70 70 % of patients 63 60 50 50 40 40 40 34 30 25 20 20 17 16 10 10 N=7 N=12 N=10 N=10 N=32 Placebo 300mg 700mg 1000mg Total Active ACR20 ACR50 ACR70

  30. Slide 30: ACR responses, patients receiving full dose

    ACR responses at 24 weeks Patients receiving full dose 90 80 78 78 73 70 % of patients 63 60 50 44 44 40 38 30 25 22 20 15 13 11 10 N=7 N=8 N=9 N=9 N=26 Placebo 300mg 700mg 1000mg Total Active ACR20 ACR50 ACR70

  31. Slide 31: Conclusions

    Conclusions • Satisfactory safety profile; AEs predominantly infusion related reported at first infusion • Immediate, profound and long lasting B-cell depletion at all dose levels • ACR20 responses achieved in all groups treated with HuMax-CD20 (50 – 70 %) vs 0 % in placebo group (ITT) • Overall ACR

  32. Slide 32: backups

    backups

  33. Slide 33: Rituximab Phase IIa: ACR Responses

    Rituximab Phase IIa: ACR Responses at 48 Weeks 80 p<0.0001 70 65 60 p=0.01 % of patients 49 50 p=0.002 40 33 p=0.01 35 30 27 20 p=0.03 20 15 15 10 10 10 5 0 0 MTX Rituximab Rituximab + CTX Rituximab + MTX ACR 20 ACR 50 ACR 70 P-values from Fisher’s exact test, comparing the MTX group with each Ritux

  34. Slide 34: Rituximab Phase IIb: DANCER

    Rituximab Phase IIb: DANCER ACR Response at 24 Weeks 60 55 54 * * 50 40 % of Patients 33 34 * * 28 Placebo 30 Rituximab 2 x 500 mg 20 * Rituximab 2 x 1000 mg 20 § 13 13 10 5 0 ACR20 ACR50 ACR70 *p ≤ 0.0001 RTX vs placebo (logistic regression: contrast test in RF-positive patients [ITT population]) §

  35. Slide 35: Rituximab Phase III: REFLEX

    Rituximab Phase III: REFLEX ACR Responses at Week 24 60 p<0.0001 51 50 40 % Patients p<0.0001 27 Placebo (N=201) 30 18 Rituximab (N=298) 20 p<0.0001 12 10 5 1 0 ACR20 ACR50 ACR70 Good efficacy data even in anti-TNF failures Cohen S, et al. ACR/ARHP Annual Scientific Meeting; November 2005; San Diego

  36. Slide 36: HuMax-CD20 triggers efficient complement dependent cytotoxicity

    HuMax-CD20 triggers efficient complement dependent cytotoxicity SU-DHL-4 Daudi Raji 100 80 % lysed cells 60 HuMax-CD20 rituximab 40 20 0 0.01 0.1 1 10 100 0.01 0.1 1 10 100 0.01 0.1 1 10 100 mAb (µg/ml) Complement resistance

  37. Slide 37: Daudi-Luc xenografts in SCID mice

    Daudi-Luc xenografts in SCID mice late treatment (day 14)

  38. Slide 38: Depletion B cells from Cynomolgus blood

    Depletion B cells from Cynomolgus blood CD20low lowCD40high high CD20lowCD23+CD40high B-cells / µl 800 550 5 mg/kg 300 50 20 0 0 50 100 150 CD20lowCD23+CD40high B-cells / µ l 800 550 HuMax-CD20 300 25 mg/kg 50 20 rituximab 0 0 50 100 150 CD20low CD23 +CD40 high B-cells / µ l 800 550 300 50 mg/kg 50

  39. Slide 39: Mapping CD20 mAb epitopes with synthetic peptides

    Mapping CD20 mAb epitopes with synthetic peptides

  40. Slide 40: B cell depletion CD20+

    B cell depletion 7 patients 12 patients CD20+ (/mm3) Placebo CD20+ (/mm3) 300 mg infusion infusion CD20+ / mm3 1515 700 700 600 600 500 108 500 400 400 300 114 206 300 309 200 200 301 203 115 104 100 103 100 111 107 106 105101 110 113 109 112 102 0 0 -2 2 6 10 14 18 22 26 30 34 38 -2 2 6 10 14 18 22

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