John D Isaacs Professor of Clinical Rheumatology Director, Wilson Horne Immunotherapy Centre Newcastle University, UK 1 Rheumatoid arthritis Targeting T-cells Targeting B-cells Costimulation blockade Novel cytokine targets 2 3 The screen versions of these slides have full details of copyright and acknowledgements 1
Chronic inflammation of synovial membrane 1% prevalence in Western world Female preponderance (2-3:1) Peak onset in 5 th decade Genetic predisposition HLA-DRB1, PTPN22 Environmental triggers Smoking,?infectious, dietary, stress 4 Joint pain Joint swelling Early morning joint stiffness Fatigue Joint damage and deformity Impaired joint function and disability Extra-articular disease (nodules, lungs, vaculitis etc.) 5 BONE JOINT SPACE JOINT CAPSULE INFLAMED SYNOVIUM INVADING CARTILAGE AND BONE SYNOVIUM CARTILAGE BONE 6 The screen versions of these slides have full details of copyright and acknowledgements 2
Strong genetic linkage to HLA-DRB1 Lymphocytic infiltrate in synovium Circulating autoantibodies (rheumatoid factor, anti-ccp) Familial association with other autoimmune diseases (diabetes, thyroiditis etc.) 7 8 Panayi GS, Rheumatology 25;44 (S2):ii3-ii7 9 The screen versions of these slides have full details of copyright and acknowledgements 3
Control symptoms and signs Prevent joint damage Maintain function Maintain QOL Prevent secondary complications (e.g., ischaemic heart disease) 1 Rheumatoid arthritis Targeting T-cells Targeting B-cells Costimulation blockade Novel cytokine targets 11 Depleting therapies Non-depleting therapies FIRST ATTEMPTS AT THERAPEUTIC TOLERANCE IN HUMAN AUTOIMMUNITY 12 The screen versions of these slides have full details of copyright and acknowledgements 4
First humanised therapeutic antibody Human IgG1 Anti-CD52 Potent target cell lysis (complement, ADCC) Targets T-, B-, NK cells and monocytes 13 Removing T-cells will reset the autoreactive immune system 14 JS clinical progress 3 2 1 Long-term benefit from short-term therapy Ritchie Joint score 1 2 3 Day 15 The screen versions of these slides have full details of copyright and acknowledgements 5
Lower limit of normal range Isaacs JD, et al., Arthritis Rheum 21;44:1998-28 16 1..75 Controls.5 Cases.25. 1 2 3 4 Analysis time (days) Isaacs JD, et al., Arthritis Rheum 21;44:1998-28 17 Common with CAMPATH-1H Chills, rigors, high fever Urticarial skin rash Hypotension in severe cases Dose-related, minimized with glucocorticoid prophylaxis Cytokine release from NK cells following Fcγ R cross-linking 18 The screen versions of these slides have full details of copyright and acknowledgements 6
CYTOKINES CAM PATH-1H CD16 TARGET CELL Wing et al., J Clin Invest 1996;98:2819-26 NK CELL 19 Short-term benefit Persisting lymphopenia, first-dose reaction No major effect on mortality over the medium term Reconstitution defects may relate to Impaired thymic function 1 Impaired IL7 regulation 2 1 Ponchel F, et al., Blood. 22;1(13):455-6 2 Ponchel F, et al., Arthritis Res Ther. 25;7(1):R8-92 2 Multiple mabs and trials in 199s Double blind randomised controlled trials did not confirm apparent benefits from open studies Depletion a common unwanted effect, even with genetically engineered mabs Some suggestion that efficacy associated with coating of synovial fluid CD4 T-cells Choy E, et al., Arthritis Rheum 1996:52-6 Mason, U, et al., J Rheumatol 22;29:22-9 21 The screen versions of these slides have full details of copyright and acknowledgements 7
Wrong disease? Wrong stage of disease? Wrong target (e.g., CD4 vs. CD8 vs. CD28 etc.)? Wrong epitope? Inappropriate dose? Inappropriate duration? Lack of surrogate response markers 22 We are seeking long-term outcomes from brief interventions Treatments not necessarily anti-inflammatory, so there may not be short-term benefit Mechanisms of therapeutic tolerance poorly understood No biomarkers of tolerance induction 23 Rheumatoid arthritis Targeting T-cells Targeting B-cells Costimulation blockade Novel cytokine targets 24 The screen versions of these slides have full details of copyright and acknowledgements 8
Autoantibody production Cytokine and chemokine production Antigen presentation to T-cells Co-stimulation of T-cells Synovial structure and organisation Silverman GJ & Carson DA. Arthritis Research & Therapy 23;5 (suppl 4):S1-S6 Panayi GS. Rheumatology 25;44 (suppl2):ii3-ii7 Weyand CM, Seyler TM, Goronzy JJ. Arthritis Research & Therapy 25;7:S9-S12 25 Takemura et al., J Immunol 21;167:172-8 26 Stem cells Pro-B cells Pre-B cells Immature B cells Activated B cells Memory B cells Plasma B cells CD1 Cell surface antigens CD19 CD2 CD24 CD38 CD39 Roitt I et al., Immunology. London, UK: Mosby; 22; Sell S et al., Immunology, Immunopathology, and Immunity. Washington DC: ASM Press; 21; Silverman GJ et al., Arthritis Rheum 23;48:1484 1492 27 The screen versions of these slides have full details of copyright and acknowledgements 9
297-amino acid phosphoprotein (33 37 kda) found on the surface of B cells Highly expressed on B cells but not on stem cells or plasma cells Function unknown Binding of anti-cd2 mab to CD2 does not: Down-modulate expression of CD2 Cause shedding of CD2 from the plasma membrane Good target for cell lysis (CDC, ADCC, apoptosis) 28 Chimeric anti-cd2 mab Murine V-region, human IgG1 C-region Potent B-cell depletion Licensed for use in non-hodgkin s lymphoma Recently licensed for RA in USA License pending in Europe, UK 29 Phase II Study Design and Treatment Groups MTX inadequate responders R A N D O M I Z E D (1g x 2) MTX (>1 mg/wk) N=4 Baseline Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 MTX (>1 mg/wk) N=4 (1g x 2) N=4 (1g x 2) Cytoxan (75 mg x 2) N=41 17 day corticosteroid regimen in all arms 48 weeks 3 The screen versions of these slides have full details of copyright and acknowledgements 1
Sex Patient Demographics Female Male MTX (n=4) 8% 2% (n=4) 73% 27% + CTX (n=41) 83% 17% + MTX (n=4) 75% 25% Age (years) 54 54 53 54 Previous DMARDs (mean) 2.6 2.5 2.6 2.5 Pts receiving concomitant corticosteroids Pts. receiving NSAIDs or COX 2 inhibitors 41% 48% 45% 45% 9% 9% 83% 88% 31 Patients Baseline Disease Characteristics MTX (n=4) (n=4) + CTX (n=41) + MTX (n=4) Disease duration (years) 11. 9.3 9.8 11.5 SJC (mean) 19 21 19 23 TJC (mean) 32 34 33 32 RF (median, IU/ml) 2 159 198 149 CRP (mean mg/l) 32 26 4 29 ESR (mean mm/h) 52 47 55 53 DAS28 6.9 6.8 6.9 6.8 32 % patients 8 7 6 5 4 3 2 1 ACR Responses at 24 Weeks 38 13 5 P=.25 65 P=.1 76 P=.3 73 P=.59 41 P=.5 P=.5 43 33 P=.48 23 15 15 MTX + CTX + MTX ACR2 ACR5 ACR7 P-values from Fisher s Exact test, comparing the MTX group with each rituximab group 33 The screen versions of these slides have full details of copyright and acknowledgements 11
ACR Responses at 48 Weeks 8 7 P<.1 65 % pati ents 6 5 4 3 2 1 2 5 33 P=.1 49 P=.1 27 15 1 1 P=.2 35 P=.3 15 MTX + CTX + MTX ACR2 ACR5 ACR7 P-values from Fisher s Exact test, comparing the MTX group with each rituximab group All withdrawals considered non-responders 34 Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 35 Circulating B-cell Counts (Median) Median CD19 (Cells x1^3/ul) 5 45 4 35 3 25 2 15 1 5 1 2 3 4 5 Time (weeks) MTX R R+CTX R+MTX Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 36 The screen versions of these slides have full details of copyright and acknowledgements 12
2 Median Change (IU/L) -2 1 2 3 4 5-4 -6-8 -1-12 -14-16 Time (Weeks) M TX R R+CTX R+MTX Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 37 16 Mean IgG (ng/ml) 14 12 1 8 6 Lower normal limit 4 2-5 5 15 25 35 45 55 Time (Weeks) MTX R R+CTX R+MTX Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 38 2.5 Mean IgM (ng/ml) 2 1.5 1.5 Lower normal limit -5 5 15 25 35 45 55 Time (Weeks) MTX R R+CTX R+MTX Edwards JCW, et al., New Engl J Med 24; 35:2572-2581 39 The screen versions of these slides have full details of copyright and acknowledgements 13
Dose-ranging Assessment: INternational Clinical Evaluation of in RA (DANCER) Objectives Compare two doses of Study different glucocorticoid pre-medication regimes Emery, P et al., Arthritis Rheum 26; 54:139-4 4 Randomised N= 465 patients 2 x 1 mg Placebo N=149 N=192 2 x 5 mg N=124 All groups received 2 doses 2 weeks apart + no glucocorticoids + IV premedication only a + IV premedication plus oral b + no glucocorticoids + IV premedication only a + IV premedication plus oral b + no glucocorticoids + IV premedication only a + IV premedication plus oral b Primary endpoint: % patients with ACR2 at week 24 Baseline 24 weeks All arms received weekly MTX -25 mg (p.o or patenteral) a Methylprednisolone 1 mg iv on days 1 and 15; b Methylprednisolone 1 mg iv on days 1 & 15 plus oral prednisone, 6 mg/day on days 2 7 and 3 mg on days 8 14 41 % patients 6 5 4 3 2 1 ACR Responses at 48 Weeks 28 55 54 13 33 34 Placebo (n=122) 2x5 mg (n=123) 2x1 mg (n=122) p=.29, p.1 vs. placebo 5 13 2 ACR2 ACR5 ACR7 RF +ve patients, ITT population n=367 42 The screen versions of these slides have full details of copyright and acknowledgements 14
1 st infusion 2 nd infusion Variable Placebo 2x5 mg 2x1 mg Placebo 2x5 mg 2x1 mg Placebo % 14 32 37 8 5 6 GC iv % 19 19 GC iv + po % 16 12 9 29 7 2 8 43 No difference in ACR2/5 response rate between doses 1 mg methylprednisolone appears to be an appropriate GC premedication regime GC do not contribute to efficacy (data not shown) No difference in AEs between doses (data not shown) 44 QOL Function Damage Responders relapse from 6 months onwards Outstanding questions RhF positive vs. RhF negative RA? Repeated courses? Predictors of relapse? (B-cells, RhF) Long-term safety with repeated courses? 45 The screen versions of these slides have full details of copyright and acknowledgements 15
Rheumatoid arthritis Targeting T-cells Targeting B-cells Costimulation blockade Novel cytokine targets 46 APC M HC C D 4 B 7. 1/2 TCR C D 4 L C D 2 8 C TL A -4 T-cell 47 CTLA4 (CD152) IgG1 CTLA4-Ig external Cell Membrane internal Cytotoxic T Lymphocyte-Associated Antigen 4 48 The screen versions of these slides have full details of copyright and acknowledgements 16
Patients with Inadequate Response to Methotrexate Abatacept (N = 433) Double-blind Open-label Treated (N = 652) Changes 1 in DMARDs mg/kg Methotrexate continued Placebo (N = 219) allowed Other DMARDs washout Day 1 6 Months 1 Year Screening Randomization Co-primary endpoint ACR2 Co-primary endpoint Physical Function Structural damage Infusions d1, d15, d3 then monthly Kremer JM, et al., Arthritis & Rheumatism 25; 52: 2263-71 49 Patients with Inadequate Response to Methotrexate Mean Number of tender joints Number of swollen joints Abatacept N = 433 31 21 Placebo N = 219 32 22 Physical function, HAQ score CRP, mg/dl DAS-28 (ESR) Percent Patients with Erosions 1.7 3.3 6.8 > 99 1.7 2.8 6.8 1 5 Patients with Inadequate Response to Methotrexate % Responders 8 7 6 5 4 3 2 ^ Primary Endpoint 1 Abatacept (N = 424) Placebo (N = 214) 1 15 29 57 85 113 141 169 225 281 365 Visit Days p <.1 ^p <.1 p <.5 ITT analysis; All patients who D/C are considered non-responders Infusions d1, d15, d3 then monthly 51 The screen versions of these slides have full details of copyright and acknowledgements 17
Patients with Inadequate Response to Methotrexate % Responders 35 3 25 2 15 1 Abatacept (N = 424) Placebo (N = 214) ^ Infusions d1, d15, d3 then monthly 5 115 29 57 85 113 141 169 225 281 365 p <.1 Visit Days ^p <.1 ITT analysis; All patients who D/C are considered non-responders 52 Patients with Inadequate Response to Methotrexate Mean Change from Baseline 3 2 1 Abatacept (N = 391) Placebo (N = 195) ^.63 1.14.58 1.18 1.21 2.32 p <.1 ^ p <.1 Erosion JSN JSN = Joint Space Narrowing Total 53 p <.1 ^ p <.1 p <.5 % Responders (decrease.3) (Decrease in HAQ.3) Patients with Inadequate Response to Methotrexate 8 7 6 5 4 3 2 1 ^ 1 15 29 57 85 113 141 169 225 281 365 ITT analysis; All patients who D/C are considered non-responders Infusions d1, d15, d3 then monthly Visit Days Abatacept (N = 424) Placebo (N = 214) 54 The screen versions of these slides have full details of copyright and acknowledgements 18
Effective in RA Symptoms and signs Quality of life Function Retardation of joint damage Good safety profile 55 Effective for signs and symptoms, function, QOL, slowing of joint damage More effective when co-administered with methotrexate Good safety record so far Low incidence of anti-globulins Also effective in patients that have failed anti-tnf therapy Combination with anti-tnf (or each other) not advised Current licenses for advanced disease only 56 Rheumatoid arthritis Targeting T-cells Targeting B-cells Costimulation blockade Novel cytokine targets 57 The screen versions of these slides have full details of copyright and acknowledgements 19
Physician s global assessment (-1 mm) CRP (mg/dl) Tender joints Patient s global assessment (-1 mm) ESR (mm/hr) Swollen joints placebo 4 mg/kg MRA (tocilizumab) 8 mg/gk MRA (tocilizumab) Every 4 weeks for 3 months No DMARDs allowed Palm score (-1 mm) Week MHAQ score Week Nishimoto N, et al., Arthritis Rheum 24; 5: 1761-9 58 placebo 4 mg/kg MRA (tocilizumab) 8 mg/kg MRA (tocilizumab) Every 4 weeks for 3 months Nishimoto N, et al., Arthritis Rheum 24; 5: 1761-9 59 n = 36 MRA (tocilizumab) 8 mg/kg every 4 weeks for 52 weeks vs. standard DMARD therapy (not leflunomide/anti-tnf) Outcomes: ACR response Van der Heijde modified Sharp score Nishimoto N, et al., American College of Rheumatology AGM, 25 6 The screen versions of these slides have full details of copyright and acknowledgements 2
At baseline: Mean disease duration, 2.3 years Mean DAS28, 6.9 Mean CRP, 4.8 mg/dl Mean total Sharp score, 3. Nishimoto N, et al., American College of Rheumatology AGM, 25 61 MRA DMARD Significance Xray progression 2.3 ± 5.6 6.1 ± 11.4 p =.1 ACR2 89% 35% p <.1 ACR5 7% 14% p <.1 ACR7 47% 6% p <.1 AEs 96% 87% SAEs 19% 13% Nishimoto N, et al., American College of Rheumatology AGM, 25 62 Improves symptoms and signs Functional benefit Retards joint damage No safety signal (?lipids) Currently in phase III 63 The screen versions of these slides have full details of copyright and acknowledgements 21
Several mab therapies are licensed, or in trial, for rheumatoid arthritis Target T-cells, B-cells, and cytokines Effective for symptoms and signs, as well as x-ray progression So far they have a good safety record New paradigms for therapy Set new challenges remission now the target Therapeutic tolerance still elusive 64 65 The screen versions of these slides have full details of copyright and acknowledgements 22