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Were do we stand with solid evidence for biologics               in Crohn’s Disease         Evidence                   Cli...
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
Dissecting mechanisms of inflammation in IBD by ex-vivo studies              MacDonald TT & Monteleone G, Science 2005;307...
Therapeutic pipeline in Crohn’s disease                      e                    in s                  ok or             ...
Learning from other chronic inflammatory disorders   Presumed pathogenetic pathways involved in rheumatoid arthritis
Inhibition of IL-17A by anti-IL-17A monoclonal antibodysecukinumab is ineffective in moderate to severe Crohn’s disease   ...
Augmentation of Tregs to treat human autoimmunity:In vivo and ex vivo approaches to enhance the relative numbers of Tregs
Different type cytokines are mutually antagonistic, and one or the other subtype may be dominant    at any one time during...
Inhibition of IFN-γ enhances Th2 and Th17-type cytokines                                    Th2                           ...
Inhibition of IL-17A enhances Th1-type cytokines                                Th2                          Th2          ...
Targeting immune pathways in IBD:               lessons from unsuccessful data       Redundancy of soluble                ...
Biologics for Crohn’s Disease Chimeric              Humanmonoclonal           monoclonal antibody             antibody    ...
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
Were do we stand with solid evidence for biologics               in Crohn’s Disease   Disease                             ...
UNMET NEEDS FOR AN EBM BASED THERAPY IN CD                      Measuring  Biomarkers          intestinal                 ...
AVALABLE TOOLS FOR DISEASE ASSESSMENT IN CDDefining disease subtypes and treatment goals                                  ...
IS THE “VISUAL” APPROACH ADEQUATEFOR DEFINING TREATMENT OPTIONS AND         OUTCOME MEASURES?
Management Must Be Tailored to the Individual Patient     IBSEN: disease course in Crohn’s disease over 10 years          ...
Long-term evolution of Crohn’s disease behaviour                                           Start therapy                  ...
Evolution of Crohn’s disease behaviour over 10 yearsBehaviour categories of the Vienna classification according to site   ...
Remission and response from control arms of trials ofbiological therapies for active luminal Crohn’s disease       18 % re...
When to Intervene early with aggressive therapy: Poor Prognosis PatientsWe must intervene with immunosoppresive drugs earl...
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
What is Deep Remission?
Decision patterns in Crohn’s Disease   Based on 479 consecutive CD patients attendances                 GROSS             ...
Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD  patients The “ideal„ definition of...
A new therapeutic end point in the management of                       CD                   Deep RemissionIs a recently i...
Mucosal Healing in CDbefore anti TNF-α              after anti TNF-α
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ?      Early disease                 Chronic uncomplicated    ...
DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ?      Early disease                 Chronic disease course   ...
Inflammatory Activity and Progression of Damage in a            Theoretical Patient with CD                               ...
Infliximab Improves Clinical Remission and         Allows for Mucosal Healing                                    All rando...
Patients with Corticosteroid-free ClinicalRemission and Mucosal Healing at Week 26         Colombel JF et al N Engl J Med ...
EXTEND:                                             Deep Remission with Adalimumab                                        ...
EXTENDDeep Remission at Week 12 is Associated with Better Quality                   of Life at Week 52                    ...
Mucosal Healing                                after 1 Year and Risk of Surgery                                           ...
Infliximab Scheduled Therapy Results in        Fewer Surgical Procedures                                 P<0.05           ...
Adalimumab:      Reduction in Hospitalisation Risk                                    78% reduction in Crohn’s-related hos...
Clinical Practice Experience: Leuven CD Real-Life Data                                  CD Cohort:                      63...
Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change ...
Clinical trial patients                    Adult age and virtually any                        disease duration            ...
DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ?      Early disease                 Chronic uncomplicated    ...
Immune cells: key players of the IBD-associated tissue damage                                                           De...
Star wars                                Naive T cell                        CD4 -                        CD8 -           ...
COMBINING EX VIVO DATA WITH CLINICAL EVIDENCE   EARLY CD                             LATE CD                              ...
Infliximab prevents Crohn’s disease recurrence after ileal                       resectionEndoscopic score after 1 year of...
Range          15-54%Gisbert JP and Panes J. Am J Gastroenterol 2009
Maintenance of Remission Among Patients With Crohn’sDisease on Antimetabolite Therapy After Infliximab Therapy IsStopped  ...
TREAT Registry: Serious Infections     Logistic Regression Data (Multivariate)                                 Odds Ratio ...
Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis      ...
Cost Distribution for Crohn’s DiseaseA Minority of patients Account for the Majority of Costs            100              ...
Yanai H and Hanauer SB. Am J Gastroenterol 2011
5-ASABrand name Cover                            Release                   Site          Asacol                           ...
Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD  patients The “ideal„ definition of...
Clinical Practice Experience:  Leuven CD and UC Real-Life Data            CD Cohort:                                      ...
Clinical trial patients                    Any adult age and virtually any                          disease duration
CHARM / ADHERE:                         Remission Sustained through 3 Years                               CHARM           ...
D’Haens G, et al. Lancet 2008
Colombel JF et al NEJM 2010
Discontinuation of Infliximab in Patients in Stable                   Remission on Combination Therapy                    ...
NATURAL HISTORY OF CROHN’S DISEASE       A decades long history    Early disease
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
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Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®

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Gastrolearning I lezione
Impatto della terapia biologica sul decorso clinico della M. di Crohn - Prof. F. Pallone (Università di Roma Tor Vergata)
www.gastrolearning.it

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Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®

  1. 1. Were do we stand with solid evidence for biologics in Crohn’s Disease Evidence Clinical relevance Biological plausibility
  2. 2. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  3. 3. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  4. 4. Dissecting mechanisms of inflammation in IBD by ex-vivo studies MacDonald TT & Monteleone G, Science 2005;307:1920-5
  5. 5. Therapeutic pipeline in Crohn’s disease e in s ok or m t he hibi C n cytokine i blockers ulator omod Cell adhesion molecule n InhibitorsImmu JAK rInh ibito TNF Stem Cell blockers therapies Adapted from Danese et al GUT 2012
  6. 6. Learning from other chronic inflammatory disorders Presumed pathogenetic pathways involved in rheumatoid arthritis
  7. 7. Inhibition of IL-17A by anti-IL-17A monoclonal antibodysecukinumab is ineffective in moderate to severe Crohn’s disease Secukinumab 2 x 10 mg/kg i.v. Placebo 50 50 (>100 points drop in CDAI Remission at week 6 (%) Response at week 6 (%) 40 40 (CDAI < 150) 30 30 30 20 20 18 10 10 15 10 0 0 Hueber et al. Gut 2012
  8. 8. Augmentation of Tregs to treat human autoimmunity:In vivo and ex vivo approaches to enhance the relative numbers of Tregs
  9. 9. Different type cytokines are mutually antagonistic, and one or the other subtype may be dominant at any one time during immune responses Th2 Th2Th2 IL-4 IFN/TNF IL-17 Monteleone G et al Trends in Pharmacology 2011
  10. 10. Inhibition of IFN-γ enhances Th2 and Th17-type cytokines Th2 Th2 Th2 IL-4Fontolizumab Th17 Th1 IFN-γ IL-17 Th17 Th1 Th1 Th17 Monteleone G et al Trends in Pharmacology 2011
  11. 11. Inhibition of IL-17A enhances Th1-type cytokines Th2 Th2 Th2 IL-4 Secukinumab Th17 Th1 IFN-γ IL-17 Th17Th1 Th1 Th17 Monteleone G et al Trends in Pharmacology 2011
  12. 12. Targeting immune pathways in IBD: lessons from unsuccessful data Redundancy of soluble Block multiple signals cytokines, chemokines simultaneously or and inflammatory pathways sequentially Positive effect of an anti-cytokine neutralizing strategy Reconsider the use of in mice may not necessarily murine models of be translated in humans colitisSuccess of currently avaliable biologics in CD is mostly Target of available dependent on their killing biologics are cells action against pro- (T cells/ macrophages), inflammatory cells not soluble cytokines
  13. 13. Biologics for Crohn’s Disease Chimeric Humanmonoclonal monoclonal antibody antibody Fc IgG1Infliximab Adalimumab mAb mAb
  14. 14. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  15. 15. Were do we stand with solid evidence for biologics in Crohn’s Disease Disease Diseaseheterogeneity complexity Uncertainty Disagreement
  16. 16. UNMET NEEDS FOR AN EBM BASED THERAPY IN CD Measuring Biomarkers intestinal damage Disease & bio-profiling behaviour Do all pts Tailored need therapy treatment?
  17. 17. AVALABLE TOOLS FOR DISEASE ASSESSMENT IN CDDefining disease subtypes and treatment goals LC PTV 05 a “VISUAL” approach DB PTV 07
  18. 18. IS THE “VISUAL” APPROACH ADEQUATEFOR DEFINING TREATMENT OPTIONS AND OUTCOME MEASURES?
  19. 19. Management Must Be Tailored to the Individual Patient IBSEN: disease course in Crohn’s disease over 10 years 43% 19% Disease activity 3% 32% 0 Years 10 0 Years 10Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 Missing data, 3%
  20. 20. Long-term evolution of Crohn’s disease behaviour Start therapy 100 Cumulative probability of remaining free of 90 80 70 complications (%) 60 Penetrating 50 40 Inflammatory 30 Stricturing 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240Patients at risk: Monthsn= 2,002 552 229 95 37 Cosnes J, et al. Inflamm Bowel Dis 2002;8:244–50
  21. 21. Evolution of Crohn’s disease behaviour over 10 yearsBehaviour categories of the Vienna classification according to site AT DIAGNOSIS AFTER 10 YEARS L1 L2 L3 L1 L2 L3 B1 76.9 72.1 69.7 B1 37.3 28 22.9 B2 14.9 1.5 15.2 B2 43 20 17 B3 8.3 26.5 15.2 B3 19.6 52 60 L1 pure ileal B1 non stricturing-non penetrating L2 pure colonic B2 stricturing L3 ileo-colonic B3 penetrating adapted from Louis E et al Gut 2001;49:777–782
  22. 22. Remission and response from control arms of trials ofbiological therapies for active luminal Crohn’s disease 18 % remission 33 % response Tinè F et al Aliment Pharmacol Ther 27, 1210–1223
  23. 23. When to Intervene early with aggressive therapy: Poor Prognosis PatientsWe must intervene with immunosoppresive drugs early in: • Extensive small bowel disease • Severe upper GI disease • Severe rectal disease • Younger patients • Patients with perianal lesions • Patients with early stricturing / penetrating disease • Patients with deep colonic (rectal) ulcers
  24. 24. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  25. 25. What is Deep Remission?
  26. 26. Decision patterns in Crohn’s Disease Based on 479 consecutive CD patients attendances GROSS CLINICAL HUMORAL CHANGES “ACTIVITY” * “ACTIVITY” §Pattern 1 − − − optimalPattern 2 − − +Pattern 3 + − − enoughPattern 4 + − + acceptable ?Pattern 5 − + −Pattern 6 − + +Pattern 7 + + −Pattern 8 + + +* + = CDAI > 150 or Simple Index > 3 § + = CRP > 1.5 mg/dl and/or ESR > 25 Torsoli A et al, Ital J Gastroenterol, 1983, 15, 138-139
  27. 27. Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD patients The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD No endoscopic indices have validated a cut-off value for MH Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010 Armuzzi A et al. JCC 2012
  28. 28. A new therapeutic end point in the management of CD Deep RemissionIs a recently introduced end point, which includes corticosteroid free remission and mucosal healingIt has been introduced and applied to patients with CD on biologics or immunomodulators who have no symptoms and objective signs of inflammation Rutgeerts P et al. Gastroenterology 2012
  29. 29. Mucosal Healing in CDbefore anti TNF-α after anti TNF-α
  30. 30. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  31. 31. DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic uncomplicated disease course Complicated disease
  32. 32. DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic disease course free of either complications and major symptoms Complicated disease
  33. 33. Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD Stricture Surgery Inflammatory activity (CDAI, CDEIS, CRP)Digestive damage Fistula/abscess Stricture Disease Diagnosis Early onset disease Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
  34. 34. Infliximab Improves Clinical Remission and Allows for Mucosal Healing All randomized patients Week 54 results Clinical remission Complete mucosal healingACCENT I – Hanauer SB, et al. Lancet 2002
  35. 35. Patients with Corticosteroid-free ClinicalRemission and Mucosal Healing at Week 26 Colombel JF et al N Engl J Med 2010;362:1383-95.
  36. 36. EXTEND: Deep Remission with Adalimumab Adalimumab, induction-only (placebo) 25 Adalimumab, every other week p<0.001 Patients with deep remission (%) p=0.34 19.4 20 16.1 15 9.8 10 5 6/61 10/62 0/61 12/62 0 Week 12 Week 52 Deep remission defined as clinical remission (Crohn’s Disease Activity Index [CDAI] <150) and mucosal healing (absence of mucosal ulceration)Colombel JF, et al. J Crohn’s Colitis 2010;4:S11
  37. 37. EXTENDDeep Remission at Week 12 is Associated with Better Quality of Life at Week 52 IBDQ remission at week 52 75 Week 52 IBDQ remission (%) 64 Patients achieving deep remission are more likely to have IBDQ remission 50 (p<0.05) 26 25 7/11 14/53 0 Deep remission Non-deep remission1 (Wk 12) (Wk 12) 1 Logistic regression adjusted baseline IBDQ score IBDQ remission = IBDQ≥170Colombel JF, et al. UEGW 2010, Barcelona, Spain, October 23-27:OP371
  38. 38. Mucosal Healing after 1 Year and Risk of Surgery ULCERATIVE COLITIS CROHN’S DISEASE HR = 0.34 (0.14-0.86) p=0.02 HR = 0.42 (0.20-0.89) p=0.027 1.00 1.0 MHProportion of patients Proportion of patients 0.9 not colectomised 0.96 3.4% MH not resected 0.8 16.9% 0.94 0.7 No MH 0.90 9.7% 0.6 No MH 31.0% 0.5 0.86 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years since 1-year visit Years since 1-year visit Soldberg IC, et al. Scand J Gastroenterol 2009
  39. 39. Infliximab Scheduled Therapy Results in Fewer Surgical Procedures P<0.05 P<0.05 N=143 N=139 N=99 N=96* Surgery major enough to categorise a patient as a treatment failure in the trial, excluding drainage of abscesses, seton placement and stricture dilation. Lichtenstein GR, et al. Gastroenterology 2005
  40. 40. Adalimumab: Reduction in Hospitalisation Risk 78% reduction in Crohn’s-related hospitalisation at 3 months The difference was apparent 2 weeks after randomisation 57% relative risk reduction at 12 months 30 Placebohospitalisation risk (%) Adalimumab Crohn’s-related 20 Week 2 Log-rank test: risk was significantly different (p<0.01) 10 n=499; CHARM 0 0 50 100 150 200 250 300 350 Days since randomisation Feagan BG, et al. Gastroenterology 2007;
  41. 41. Clinical Practice Experience: Leuven CD Real-Life Data CD Cohort: 63.4% With Sustained Clinical Benefit Median Follow-up 55 Months1 63.4%1 Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
  42. 42. Biologic plausibility, pipelineDo all patient equally benefit from available biologicsGoals of therapyDo biologics change the course and natural history of CDProblems and pitfalls in biologics therapy for CD
  43. 43. Clinical trial patients Adult age and virtually any disease duration Clinical activity (symptoms scoring) SOP responsive/refractor y Concomitant treatment
  44. 44. DO BIOLOGIS IMPACT ONTHE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic uncomplicated disease course Complicated disease
  45. 45. Immune cells: key players of the IBD-associated tissue damage Dendritic cell T0 TLRs T MHC-1/2 B7 T- 3 IL-4 -2 be IL TSLP, t TGF-β, IL-15 TH2 T2 T1 TH1 Macrophage T2 TH2 MMP RA T17 TH17 T2 TH2 TH1 TH1 T1 T1 TLRs IL-8 TH17 TH17 T17 T17 IL-5 NOD2 CD103+ mTNF sis IL-8 Ulcer/ pto IL-13 IFN-γ TIMP fistula po TNF-α ↓a IL-12 IL-17 T T1 T 1 ↑collagen TH1 Treg TH1 H1 TH1 T1 T1 T1 TH1 TH1 TH1 deposition T1 T TH1T T TH1 H1 TH1 T1 1 1 TH1 TH1 T T1 T Scar H1 1 Fibrosis TH1 T1 tissue T H1 TH T H1 1 T cells Blood vessel TLRs CD40
  46. 46. Star wars Naive T cell CD4 - CD8 - IL-2 IL-12 IFN-γ CD4+ STAT4 Th0 IL-10IFN-γ Th1 CD4+/CD25+ TGF-βIL-2 IL-18 FOXP3 IL-23 IL-13 IL-17 Th2 IL-4 Th17 IL-22 IL-5 IL-6
  47. 47. COMBINING EX VIVO DATA WITH CLINICAL EVIDENCE EARLY CD LATE CD IL17A IL1β,IL6,IL23 Th17 IL17F ? APC Th1/Th17 IFNγ IL17 IL1 TNFα 2 IL1β IL6 Th1 IL18 IFNγ TNFα IL21 Zorzi F et al FISMAD 2011
  48. 48. Infliximab prevents Crohn’s disease recurrence after ileal resectionEndoscopic score after 1 year of resection Grade 0-1 Grade 2-4 11/13 10/11 10 10 2/13 1/11 INFLIXIMAB PLACEBO INFLIXIMAB PLACEBO Regueiro M et al GASTROENTEROLOGY 2009;136:441–450
  49. 49. Range 15-54%Gisbert JP and Panes J. Am J Gastroenterol 2009
  50. 50. Maintenance of Remission Among Patients With Crohn’sDisease on Antimetabolite Therapy After Infliximab Therapy IsStopped 52 relapses in 115 patients Median (±SE) follow up 21 ± 1 mo LOUIS E et al GASTROENTEROLOGY 2012;142:63–70
  51. 51. TREAT Registry: Serious Infections Logistic Regression Data (Multivariate) Odds Ratio 95% CIAge (years) 1.01 0.99-1.03Female 1.24 0.81-1.90Moderate or severe CD 2.11 1.10-4.05*Current use of infliximab 1.40 0.95-2.07Current use of 6MP/AZA/MTX 0.88 0.61- 1.27Current use of corticosteroids 2.21 1.46- 3.34*Current use of narcotic 2.38 1.56- 3.63*analgesics *P < .05 Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2006
  52. 52. Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease
  53. 53. Cost Distribution for Crohn’s DiseaseA Minority of patients Account for the Majority of Costs 100 100% 90 90% 80 80% 70 70% 60 60% % Cost 50 50% 40 41% 30 31% 20 20% 10 12% 5% 0 0 10 20 30 40 50 60 70 80 90 100 % All Patients Feagan BG et al. Am J Gastroenterol. 2000;95:1955.
  54. 54. Yanai H and Hanauer SB. Am J Gastroenterol 2011
  55. 55. 5-ASABrand name Cover Release Site Asacol Eudragit S pH>7 Colon ± terminal ileumSalofalk Eudragit-L pH>6 Colon + ileumMesasal Eudragit-L pH>6 Colon + ileumPentasa Ethylcellulose Time and Colon + ileum+ jejunum pH-dependentMesavancol MMX pH Colon Immunomodulators Corticosteroids Drugs AZA Oral Intravenous Topical (suppository, foam, enema) Prednisolone Hydrocortisone Hydrocortisone 6-MP Prednisone Metyl-prednisolone Prednisolone metasulfobenzoato Budesonide Budesonide 6-TG Beclomethasone Beclomethasone diproprionate dipropionate Biological agents
  56. 56. Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD patients The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD No endoscopic indices have validated a cut-off value for MH Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010 Armuzzi A et al. JCC 2012
  57. 57. Clinical Practice Experience: Leuven CD and UC Real-Life Data CD Cohort: UC Cohort:63.4% With Sustained Clinical Benefit 68% With Sustained Clinical Response Median Follow-up 55 Months1 Median Follow-up 33.4 Months2 68% 63.4% 1 Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
  58. 58. Clinical trial patients Any adult age and virtually any disease duration
  59. 59. CHARM / ADHERE: Remission Sustained through 3 Years CHARM 6 mo 12 mo 24 mo 36 mo baseline Open label extension (OLE) 100 100 100 85 with remission (%) 78 81 84 83 77 80 72 64 Patients 60 40 20 145 145 113/145 118/145 111/145 123/145 105/145 122/145 93/145 120/145 0 Week 56 Week 24 Week 48 Week 60 Week 108 CHARM ADHERE ADHERE ADHERE ADHERE All adalimumab, NRI All adalimumab, LOCFPts randomised to ADA, in remission (CDAI<150) at week 56 of CHARM, and enrolled in OLE ITT (n=145).LOCF: last observation carried forward; NRI: non-responder imputation.467 patients enrolled in the open-label extension (ADHERE) Panaccione R, et al. J Crohn’s Colitis 2009;3:S69-70
  60. 60. D’Haens G, et al. Lancet 2008
  61. 61. Colombel JF et al NEJM 2010
  62. 62. Discontinuation of Infliximab in Patients in Stable Remission on Combination Therapy (Azathioprine Maintained) 79±4% 56±5% 50±5% 52 relapses in 115 patients Median (±SE) follow up 21 ± 1 mo # at risk : 115 102 79 63 51 47 39 27 20 12 9Louis E et al. Gastroenterology ,2009;136(Suppl 1):A-146, Gastroenterology epub 2011.
  63. 63. NATURAL HISTORY OF CROHN’S DISEASE A decades long history Early disease

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