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Emergence of New Biologic Agents in IBD: Top down vs Step-up Approach.

Disclosure. Grant SupportNational Institutes of HealthCrohn's and Colitis Foundation of AmericaProctor

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Emergence of New Biologic Agents in IBD: Top down vs Step-up Approach.

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    1. Emergence of New Biologic Agents in IBD: “Top down” vs “Step-up” Approach.

    2. Disclosure Grant Support National Institutes of Health Crohn’s and Colitis Foundation of America Proctor & Gamble Pharmaceuticals Speaker’s Bureau Centocor Honoraria Prometheus Laboratories, Abbott laboratories, AstraZeneca, UCB Pharma, Proctor & Gamble, Salix Pharmaceuticals, Axcan Pharma Off label discussion of Drugs Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    4. Overview: I. New Biologic Agents for IBD Anti-TNF-alpha agents Anti-IL-12/anti-IL23 Natalizumab II. The “Top down vs step up” protocol for Crohn’s disease (CD). III. Is “Top down” therapy a good idea for all CD patients? Heterogeneity of CD. Disease modifying therapy in early CD IV. A rational approach for biologic therapy in IBD Who should be treated with biologics Risk/benefit assessment Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    5. I. New biologic agents for IBD Anti-TNF-alpha agents Anti-IL-12/anti-IL23 Natalizumab Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    6. Molecular and cellular mechanisms in IBD

    7. Molecular and cellular mechanisms in IBD

    8. Biologics Under Investigation in IBD Anti-TNF Strategies Chimeric antibodies “Humanized” antibodies “Fully human” antibodies Antibody fragments Antisense compound TNF-BP1 Thalidomide Cytokine strategies Il-1ra (anakinra) Antibodies to Il-4, Il-6, Il-8, Il-12, Il-15, Il-16, Il-18, Il-23 Il-10, Il-11 Anti-cell adhesion molecules Antibodies to ICAM-1, VCAM-1, VLA-4, ?-4 (natalizumab), ?4?7 Antisense compound to ICAM-1 Anti NF-?B, anti-OX40, anti-ZAP Other approaches rhuGrowth hormone, KGF- (failed in UC trial), rosiglitizone, PAF inhibitor, EGF, RDP, Nu-286 (Wnt agonist)

    9. Crohn’s Disease: 1960’s historical perspective

    10. Biologic era in IBD management: Healing of refractory ulceration/fistula with Infliximab

    11. Construct of Anti-TNF-a Biologic Agents

    12. Clinical Response and Remission with Infliximab

    13. ACCENT I: Maintenance Infliximab for CD in Randomized Responders (N = 335) ACCENT I: Maintenance Infliximab for CD in Randomized Responders (N = 335) Throughout follow-up, patients who responded to initial treatment by week 2 and who continued to receive active treatment showed a greater therapeutic benefit than week 2 responders who subsequently received placebo.1 At week 30, the proportion of patients with a clinical response (defined as a reduction in CDAI scores = 70 points and = 25% improvement from baseline) was higher in patients who received maintenance therapy with infliximab 5 and 10 mg/kg (47% and 60%, respectively) than in patients who received placebo (26%; P = 0.0002 and P < 0.0001 vs placebo, respectively). At week 54, clinical response rates had decreased by approximately 10% in each of the treatment arms. However, the response rates were still significantly higher among patients receiving active treatment when compared with the rate in patients receiving placebo (P = 0.0001 for both comparisons). Clinical remission (CDAI scores < 150 points) at 30 weeks was also observed in a higher percentage of patients in the infliximab 5 and 10 mg/kg groups (39% and 45%, respectively) than in the placebo group (25%; P = 0.002 and P = 0.003 vs placebo, respectively). Significant differences were seen as early as week 10. Remission rates at week 54 were approximately 10% lower than the rates observed at week 30, although the percentages of patients achieving remission continued to be significantly higher in the active treatment arms when compared with the percentage of patients achieving remission in the placebo arm (P = 0.002 for both active treatment arms vs placebo). Throughout the 54-week study, the median time to loss of response was longer for patients who received maintenance therapy with infliximab (38 weeks and > 54 weeks for infliximab 5 and 10 mg/kg, respectively; data not shown). These data led the authors to conclude that patients with non-fistulizing CD who respond to an initial dose of infliximab are more likely to be in remission after 54 weeks and to maintain their clinical response for a longer period of time when they received maintenance infliximab therapy every 8 weeks. Reference 1. Hanauer SB, et al. Lancet. 2002;359:1541-9. ACCENT I: Maintenance Infliximab for CD in Randomized Responders (N = 335) Throughout follow-up, patients who responded to initial treatment by week 2 and who continued to receive active treatment showed a greater therapeutic benefit than week 2 responders who subsequently received placebo.1 At week 30, the proportion of patients with a clinical response (defined as a reduction in CDAI scores = 70 points and = 25% improvement from baseline) was higher in patients who received maintenance therapy with infliximab 5 and 10 mg/kg (47% and 60%, respectively) than in patients who received placebo (26%; P = 0.0002 and P < 0.0001 vs placebo, respectively). At week 54, clinical response rates had decreased by approximately 10% in each of the treatment arms. However, the response rates were still significantly higher among patients receiving active treatment when compared with the rate in patients receiving placebo (P = 0.0001 for both comparisons). Clinical remission (CDAI scores < 150 points) at 30 weeks was also observed in a higher percentage of patients in the infliximab 5 and 10 mg/kg groups (39% and 45%, respectively) than in the placebo group (25%; P = 0.002 and P = 0.003 vs placebo, respectively). Significant differences were seen as early as week 10. Remission rates at week 54 were approximately 10% lower than the rates observed at week 30, although the percentages of patients achieving remission continued to be significantly higher in the active treatment arms when compared with the percentage of patients achieving remission in the placebo arm (P = 0.002 for both active treatment arms vs placebo). Throughout the 54-week study, the median time to loss of response was longer for patients who received maintenance therapy with infliximab (38 weeks and > 54 weeks for infliximab 5 and 10 mg/kg, respectively; data not shown). These data led the authors to conclude that patients with non-fistulizing CD who respond to an initial dose of infliximab are more likely to be in remission after 54 weeks and to maintain their clinical response for a longer period of time when they received maintenance infliximab therapy every 8 weeks. Reference 1. Hanauer SB, et al. Lancet. 2002;359:1541-9.

    14. CLASSIC I: Results at Week 4 CLASSIC I: Results at Week 4 There was a linear dose response across the three adalimumab groups at week 4 for the primary endpoint of remission.1 The rates of remission at week 4 were 18%, 24%, and 36% in patients who received induction therapy with adalimumab 40/20 mg, 80/40 mg, and 160/80 mg, respectively, compared with a rate of 12% in patients who received placebo. The difference in remission rates was statistically significant between patients who received induction therapy with the highest doses of adalimumab (160/80 mg) and patients who received placebo (P < 0.05). The percentage of patients with a 70-point decrease from baseline in CDAI score was significantly higher in all three active treatment arms (54%, 59%, and 59% for adalimumab 40/20 mg, 80/40 mg, and 160/80 mg, respectively) when compared with the percentage in the placebo arm (37%; P < 0.05, P = 0.001, and P = 0.007 for each comparison, respectively, vs placebo). A similar dose-dependent trend toward improved outcomes with adalimumab was observed for the secondary endpoint of a 100-point decrease in CDAI score (P < 0.05 for adalimumab 160/80 mg vs placebo). These data demonstrate that adalimumab is superior to placebo for the induction of remission in TNF-naive patients with moderate-to-severe CD. Reference 1. Hanauer, S. et al. Gastroenterology. 2006:130:323-33.CLASSIC I: Results at Week 4 There was a linear dose response across the three adalimumab groups at week 4 for the primary endpoint of remission.1 The rates of remission at week 4 were 18%, 24%, and 36% in patients who received induction therapy with adalimumab 40/20 mg, 80/40 mg, and 160/80 mg, respectively, compared with a rate of 12% in patients who received placebo. The difference in remission rates was statistically significant between patients who received induction therapy with the highest doses of adalimumab (160/80 mg) and patients who received placebo (P < 0.05). The percentage of patients with a 70-point decrease from baseline in CDAI score was significantly higher in all three active treatment arms (54%, 59%, and 59% for adalimumab 40/20 mg, 80/40 mg, and 160/80 mg, respectively) when compared with the percentage in the placebo arm (37%; P < 0.05, P = 0.001, and P = 0.007 for each comparison, respectively, vs placebo). A similar dose-dependent trend toward improved outcomes with adalimumab was observed for the secondary endpoint of a 100-point decrease in CDAI score (P < 0.05 for adalimumab 160/80 mg vs placebo). These data demonstrate that adalimumab is superior to placebo for the induction of remission in TNF-naive patients with moderate-to-severe CD. Reference 1. Hanauer, S. et al. Gastroenterology. 2006:130:323-33.

    15. CHARM: Clinical Remission of CD Over Time With Adalimumab Randomized Responders (n = 499) CHARM: Clinical Remission of Crohn’s Disease Over Time With Adalimumab Randomized Responders (N = 499) In the CHARM study, the difference in clinical remission rates between patients receiving adalimumab 40 mg EOW and those receiving placebo was statistically significant as early as week 6 (P < 0.001), 2 weeks after patients were randomized to maintenance therapy with either adalimumab or placebo.1 At week 8, clinical remission rates were significantly higher in both adalimumab groups when compared with the rate observed in the placebo arm (P < 0.001 and P = 0.005 for adalimumab EOW and weekly, respectively, vs placebo). The significant differences in remission rates observed between patients receiving maintenance therapy with adalimumab and those receiving maintenance therapy with placebo were sustained throughout the 56-week study. These results are similar to the results observed in the ACCENT I study between patients receiving maintenance therapy with infliximab and those receiving maintenance therapy with placebo.2 References 1. Colombel JF, et al. DDW 2006. Abstract 686d. 2. Hanauer SB, et al. Lancet. 2002;359:1541-1549.CHARM: Clinical Remission of Crohn’s Disease Over Time With AdalimumabRandomized Responders (N = 499) In the CHARM study, the difference in clinical remission rates between patients receiving adalimumab 40 mg EOW and those receiving placebo was statistically significant as early as week 6 (P < 0.001), 2 weeks after patients were randomized to maintenance therapy with either adalimumab or placebo.1 At week 8, clinical remission rates were significantly higher in both adalimumab groups when compared with the rate observed in the placebo arm (P < 0.001 and P = 0.005 for adalimumab EOW and weekly, respectively, vs placebo). The significant differences in remission rates observed between patients receiving maintenance therapy with adalimumab and those receiving maintenance therapy with placebo were sustained throughout the 56-week study. These results are similar to the results observed in the ACCENT I study between patients receiving maintenance therapy with infliximab and those receiving maintenance therapy with placebo.2 References 1. Colombel JF, et al. DDW 2006. Abstract 686d. 2. Hanauer SB, et al. Lancet. 2002;359:1541-1549.

    16. PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CD Randomized Responders (N = 428) PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CD Randomized Responders (N = 428) Among patients in the intent-to-treat population in the PRECiSE 2 study, clinical response (decrease from baseline in CDAI score of = 100 points) was attained by 63% of the patients in the certolizumab pegol group at week 26 compared with 36% of patients in the placebo group (P < 0.001).1 A significant difference in clinical response rates between these two groups was apparent beginning at week 12. A similar trend was observed with respect to rates of clinical remission (CDAI < 150 points) at 26 weeks. Remission was achieved by 48% of the patients in the certolizumab pegol group compared with 29% of patients in the placebo group (P < 0.001). Contrary to the results of an earlier phase II study,2 clinical response and remission rates were found to be significantly different between the two treatment groups regardless of baseline levels of C-reactive protein (CRP; ie, < 10 mg/L or = 10 mg/L). These results indicate that maintenance therapy with certolizumab pegol 400 mg every 4 weeks is effective for sustaining clinical response and remission in patients with moderate-to-severe CD and further indicate that treatment with certolizumab pegol is effective in patients with either normal or elevated levels of CRP. References 1. Schreiber S, et al. Gut. 2005;54(Suppl VII):A82. 2. Schreiber S, et al. Gastroenterology. 2005;129:807-818. PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CDRandomized Responders (N = 428) Among patients in the intent-to-treat population in the PRECiSE 2 study, clinical response (decrease from baseline in CDAI score of = 100 points) was attained by 63% of the patients in the certolizumab pegol group at week 26 compared with 36% of patients in the placebo group (P < 0.001).1 A significant difference in clinical response rates between these two groups was apparent beginning at week 12. A similar trend was observed with respect to rates of clinical remission (CDAI < 150 points) at 26 weeks. Remission was achieved by 48% of the patients in the certolizumab pegol group compared with 29% of patients in the placebo group (P < 0.001). Contrary to the results of an earlier phase II study,2 clinical response and remission rates were found to be significantly different between the two treatment groups regardless of baseline levels of C-reactive protein (CRP; ie, < 10 mg/L or = 10 mg/L). These results indicate that maintenance therapy with certolizumab pegol 400 mg every 4 weeks is effective for sustaining clinical response and remission in patients with moderate-to-severe CD and further indicate that treatment with certolizumab pegol is effective in patients with either normal or elevated levels of CRP. References 1. Schreiber S, et al. Gut. 2005;54(Suppl VII):A82. 2. Schreiber S, et al. Gastroenterology. 2005;129:807-818.

    17. Overview of Results of Long-Term Anti-TNF Trials

    18. Infliximab therapy for UC Read slide Read slide

    19. Anti-IL-12 (ABT-874) in Active Crohn’s Disease Patients in Group II (n=39) who received 3 mg/kg of ABT-874 showed significant differences in response rates and remission rates compared to patients who received placebo. At the time of final injection (Week 7), the response rate for this group was 75% and the remission rate was 38%. The effect of ABT-874 was sustained. Twelve weeks after the final injection (Week 19), 50% of patients were in remission, with 69% achieving a clinical response (defined as baseline CDAI decrease of at least 100 points). The response and remission rates for patients receiving ABT-874 in Group I (n=40) were not significantly different from placebo.  Patients in Group II (n=39) who received 3 mg/kg of ABT-874 showed significant differences in response rates and remission rates compared to patients who received placebo. At the time of final injection (Week 7), the response rate for this group was 75% and the remission rate was 38%. The effect of ABT-874 was sustained. Twelve weeks after the final injection (Week 19), 50% of patients were in remission, with 69% achieving a clinical response (defined as baseline CDAI decrease of at least 100 points). The response and remission rates for patients receiving ABT-874 in Group I (n=40) were not significantly different from placebo.  

    20. Adhesion and Recruitment Adhesion and Recruitment Mucosal and Inflammatory Zip Codes The pathogenesis of CD involves persistent recruitment of leukocytes into gut tissue, with resultant inflammation.1 Recruitment is now known to proceed through a stereotypical series of steps that depend on selective adhesion molecules (SAMs). SAMs include integrins, a group of heterodimeric proteins that are present on the cell surface of many types of leukocytes. Integrins with an ?4 chain appear to play an especially important role in the intestine.2 The ?4?1 integrins are present on most leukocytes except neutrophils and effect binding to the vascular adhesion molecule 1 (VCAM-1) on endothelial and dendritic cells.3 In contrast, ?4?7 integrin is expressed on subpopulations of lymphocytes, natural killer cells, and monocytes, and selectively targets them to so-called gut-associated lymphoid tissue.3 Thus, the ?4 integrins mediate tissue-specific transport or “trafficking” of inflammatory cells to the intestine. Experimental evidence has suggested that ?4 integrins are important in the recruitment and activation of cells in IBD, especially since tissues affected by IBD have increased levels of ?4 integrins and their ligands.4 References Feagan BG, et al. N Engl J Med. 2005;352:2499-2507. Hamann A, et al. J Immunol. 1994;152:3282-3293. Podolsky DK. N Engl J Med. 2005;353:18:1965-1968. Koizumi M, et al. Gastroenterology. 1992;103:840-847. Adhesion and RecruitmentMucosal and Inflammatory Zip Codes The pathogenesis of CD involves persistent recruitment of leukocytes into gut tissue, with resultant inflammation.1 Recruitment is now known to proceed through a stereotypical series of steps that depend on selective adhesion molecules (SAMs). SAMs include integrins, a group of heterodimeric proteins that are present on the cell surface of many types of leukocytes. Integrins with an ?4 chain appear to play an especially important role in the intestine.2 The ?4?1 integrins are present on most leukocytes except neutrophils and effect binding to the vascular adhesion molecule 1 (VCAM-1) on endothelial and dendritic cells.3 In contrast, ?4?7 integrin is expressed on subpopulations of lymphocytes, natural killer cells, and monocytes, and selectively targets them to so-called gut-associated lymphoid tissue.3 Thus, the ?4 integrins mediate tissue-specific transport or “trafficking” of inflammatory cells to the intestine. Experimental evidence has suggested that ?4 integrins are important in the recruitment and activation of cells in IBD, especially since tissues affected by IBD have increased levels of ?4 integrins and their ligands.4 References Feagan BG, et al. N Engl J Med. 2005;352:2499-2507. Hamann A, et al. J Immunol. 1994;152:3282-3293. Podolsky DK. N Engl J Med. 2005;353:18:1965-1968. Koizumi M, et al. Gastroenterology. 1992;103:840-847.

    21. Construct of Natalizumab Construct of Natalizumab Natalizumab is a humanized IgG4 monoclonal antibody against ?4 integrins, designed to inhibit interactions between ?4 integrins on the surface of most leukocytes and adhesion molecules (VCAM-1 and MAdCAM-1) on vascular endothelial cells in the gastrointestinal tract.1 These interactions are necessary for the adhesion and subsequent recruitment and migration (“trafficking”) of leukocytes to sites of chronic inflammation. Natalizumab binds to the a4 subunit of a4ß1 and a4ß7 integrins expressed on all leukocytes except neutrophils. Receptors for the family of a4 integrins include VCAM-1 (vascular cell adhesion molecule-1) and MAdCAM-1 (mucosal addressin cell adhesion molecule-1), which are both found in the vascular endothelial cells of the gastrointestinal tract. Binding of natalizumab to leukocytes prevents the interaction of leukocytes with vascular endothelial cells and inhibits transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. Reference 1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925.Construct of Natalizumab Natalizumab is a humanized IgG4 monoclonal antibody against ?4 integrins, designed to inhibit interactions between ?4 integrins on the surface of most leukocytes and adhesion molecules (VCAM-1 and MAdCAM-1) on vascular endothelial cells in the gastrointestinal tract.1 These interactions are necessary for the adhesion and subsequent recruitment and migration (“trafficking”) of leukocytes to sites of chronic inflammation. Natalizumab binds to the a4 subunit of a4ß1 and a4ß7 integrins expressed on all leukocytes except neutrophils. Receptors for the family of a4 integrins include VCAM-1 (vascular cell adhesion molecule-1) and MAdCAM-1 (mucosal addressin cell adhesion molecule-1), which are both found in the vascular endothelial cells of the gastrointestinal tract. Binding of natalizumab to leukocytes prevents the interaction of leukocytes with vascular endothelial cells and inhibits transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. Reference 1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925.

    22. Natalizumab as Maintenance Therapy for Crohn’s Disease: ENACT-2 Trial

    23. Mean CDAI Scores Over 24 Months of Continuous Treatment With Natalizumab Mean CDAI Scores Over 24 Months of Continuous Treatment With Natalizumab As shown in slide 55, patients who had achieved a clinical response in ENACT-1 were re-randomized to receive up to 12 monthly intravenous infusions of natalizumab 300 mg or placebo in ENACT-2.1 In addition, the patients who completed the ENACT-2 trial were eligible to enroll in a 2-year open-label extension (OLE) study. Panaccione and colleagues2 presented data from 87 patients who were in remission and had received 15 months of continuous natalizumab therapy in the ENACT trials, who received an additional 12 months of natalizimab therapy (300 mg IV monthly) in the OLE. Of the 87 patients in the OLE, 22 had been previously exposed to infliximab and 11 had failed infliximab therapy. An analysis of mean CDAI scores during ENACT-1, ENACT-2 and the OLE study are shown in this slide. Mean CDAI scores in the 87 patients who received natalizumab continuously during the 3 studies were maintained below remission levels throughout the 27 months of therapy (CDAI score at ENACT-2 baseline = 90.0; CDAI score at OLE baseline = 72.1; CDAI score at the end of the OLE study = 71.9). Similar results were observed in the subset of 22 patients who had previously received infliximab therapy (CDAI values at OLE baseline = 57.8 and at the end of the OLE study = 64.0). However, the subset of patients who had previously failed infliximab therapy demonstrated a small upward trend in CDAI values at the end of the OLE study, although they remained in remission (ENACT-2 baseline value = 89.5; OLE baseline value = 64.5; end of OLE value = 94.6). It would have been of interest to follow this subset of patients for a longer period of time to determine if their CDAI levels continued to rise, suggesting a gradual loss in response. Unfortunately, this study was halted prematurely due to safety concerns with natalizumab. Treatment-emergent adverse events during the OLE study were similar to those encountered in the ENACT clinical trials; 6% of the patients encountered a serious infection and 5% discontinued therapy due to an adverse event.2 One of the 3 reported cases of progressive multifocal leukoencephalopathy associated with natalizumab was found in a patient in this study.2 Only 2% of patients receiving continuous natalizumab therapy throughout ENACT-1, ENACT-2 and the OLE study developed anti-natalizumab antibodies.3 Indeed, none of the patients who were negative for anti-natalizumab antibodies entering the OLE developed these antibodies regardless of whether they were receiving natalizumab monotherapy or the drug plus concomitant immunomodulators or steroids.2 On the other hand, 9.9% of the patients who had received natalizumab in ENACT-1, were randomized to placebo in ENACT-2, and were then redosed with natalizumab in the OLE study developed anti-natalizumab antibodies.3 Thus, as for some of the TNF antagonists, dose interruption in natalizumab therapy appears to enhance the drug’s immunogenicity. References 1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925. 2. Panaccione R, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S450. Abstract 1152. 3. Plevy S, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S446. Abstract 1143. Mean CDAI Scores Over 24 Months of Continuous Treatment With Natalizumab As shown in slide 55, patients who had achieved a clinical response in ENACT-1 were re-randomized to receive up to 12 monthly intravenous infusions of natalizumab 300 mg or placebo in ENACT-2.1 In addition, the patients who completed the ENACT-2 trial were eligible to enroll in a 2-year open-label extension (OLE) study. Panaccione and colleagues2 presented data from 87 patients who were in remission and had received 15 months of continuous natalizumab therapy in the ENACT trials, who received an additional 12 months of natalizimab therapy (300 mg IV monthly) in the OLE. Of the 87 patients in the OLE, 22 had been previously exposed to infliximab and 11 had failed infliximab therapy. An analysis of mean CDAI scores during ENACT-1, ENACT-2 and the OLE study are shown in this slide. Mean CDAI scores in the 87 patients who received natalizumab continuously during the 3 studies were maintained below remission levels throughout the 27 months of therapy (CDAI score at ENACT-2 baseline = 90.0; CDAI score at OLE baseline = 72.1; CDAI score at the end of the OLE study = 71.9). Similar results were observed in the subset of 22 patients who had previously received infliximab therapy (CDAI values at OLE baseline = 57.8 and at the end of the OLE study = 64.0). However, the subset of patients who had previously failed infliximab therapy demonstrated a small upward trend in CDAI values at the end of the OLE study, although they remained in remission (ENACT-2 baseline value = 89.5; OLE baseline value = 64.5; end of OLE value = 94.6). It would have been of interest to follow this subset of patients for a longer period of time to determine if their CDAI levels continued to rise, suggesting a gradual loss in response. Unfortunately, this study was halted prematurely due to safety concerns with natalizumab. Treatment-emergent adverse events during the OLE study were similar to those encountered in the ENACT clinical trials; 6% of the patients encountered a serious infection and 5% discontinued therapy due to an adverse event.2 One of the 3 reported cases of progressive multifocal leukoencephalopathy associated with natalizumab was found in a patient in this study.2 Only 2% of patients receiving continuous natalizumab therapy throughout ENACT-1, ENACT-2 and the OLE study developed anti-natalizumab antibodies.3 Indeed, none of the patients who were negative for anti-natalizumab antibodies entering the OLE developed these antibodies regardless of whether they were receiving natalizumab monotherapy or the drug plus concomitant immunomodulators or steroids.2 On the other hand, 9.9% of the patients who had received natalizumab in ENACT-1, were randomized to placebo in ENACT-2, and were then redosed with natalizumab in the OLE study developed anti-natalizumab antibodies.3 Thus, as for some of the TNF antagonists, dose interruption in natalizumab therapy appears to enhance the drug’s immunogenicity. References 1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925. 2. Panaccione R, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S450. Abstract 1152. 3. Plevy S, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S446. Abstract 1143.

    24. Summary: Anti-TNF-a Therapy in IBD Effective therapy for induction and remission of active CD and fistulizing CD (infliximab) In the current management paradigm, reserved for patients with more severe disease Mucosal healing with long-term therapy (infliximab) Safety issues Infections Reactivation of latent TB Possible lymphoma risk Hepatosplenic T-cell lymphoma in young patients on infliximab plus concomittant azathioprine (n = 8) Immunogenicity Infliximab: Infusion reactions contributing to loss of response Other anti-TNF-a agents: Immunogenicity occurs; significance is uncertain

    25. Patients With CD Who Developed HSTCL While Receiving Infliximab and Immunomodulators 8 cases of HSTCL have been reported in CD patients receiving infliximab plus azathioprine or 6-mercaptopurine AZA or 6-MP use for 3 to 7 years prior to starting IFX 7 males; 1 female Age range: 12 to 31 years Duration of CD: 2 to 8 years T-cell receptor type at presentation: 3 aß; 5 ?d HSTCL occurred at varying times after IFX exposure-- 5 years after 1 dose of IFX 5 mg/kg (1 case) 2-3 years after 1-3 doses of IFX 5 mg/kg (3 cases) 2-5 years after 10-20 doses of IFX 5-10 mg/kg (4 cases) Outcome: 6 patients died; 1 responded to chemo; 1 starting chemo Incidence – approximately 1 in 1000 Patients With CD Who Developed HSTCL While Receiving Infliximab and Immunomodulators Hepatosplenic T-cell lymphoma (HSTCL) is a very rare form of non-Hodgkin’s lymphoma reported most commonly in adolescent and young adult males.1,2 The background incidence of HSTCL is unknown, since only approximately 150 documented cases have been published in the medical literature since it was first recognized as a distinct lymphoma subtype in the early 1990s.3 The clinical course of the disease is extremely aggressive with a fatal outcome in most patients within 2 years of diagnosis, regardless of the T-cell receptor phenotype (?d or aß) expressed by the tumor.1,2 Cases of HSTCL described in the literature include 3 patients with CD treated with long-term azathioprine1,2,4 and in chronically immunosuppressed, solid organ allograft recipients, many of whom were reported to have received azathioprine in addition to other immunosuppressants.5-13 Eight postmarketing cases of HSTCL have been reported in adolescent and young adult patients with CD who were treated with infliximab.14,15 The details of the cases are outlined in this slide. The patients were all in the United States, ranged in age from 12 to 31 years, and had all received azathioprine or 6-mercaptopurine concomitantly with infliximab. In those patients for whom the duration of infliximab use was reported, exposure ranged from 1 or 2 infusions to approximately 4 years of maintenance therapy. Six of the 8 patients have died as a result of their lymphoma. To date, no additional cases of HSTCL have been reported out of approximately 500,000 patients treated worldwide with infliximab for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis (including those treated with concomitant methotrexate), as well as 10,000 pediatric and 27,000 adult patients with CD. A causative role for infliximab in the development of HSTCL in these 8 patients has not been established. References 1. Mittal S, et al. Eur J Haematol. 2006;76:531-534. 2. Navarro JT, et al. Leuk Lymphoma. 2003;44:531-533. 3. Data on file, Centocor, Inc. 4. Lemann M, et al. Gastroenterology. 1998;114:A1020. 5. Francois A, et al. Am J Surg Pathol. 1997;21:781-790. 6. Kraus MD, et al. Cancer. 1998;82:983-992. 7. Garvin AJ, et al. Am J Surg Pathol. 1988;12:64-70. 8. Roncella S, et al. Haematologia. 2000;85:256-262. 9. Ross CW, et al. Am J Clin Pathol. 1994;102:310-315. 10. Labouyrie E, et al. Mod Pathol. 1995;8:355-359. 11. Albalate M, et al. Nephrol Dial Transplant. 1998;13:3242-3244. 12. Lin WC, et al. Leuk Lymphoma. 1999;33:377-384. 13. Rajakariar R, et al. Am J Transplant. 2004;4:1534-1538. 14. Thayu M, et al. J Pediatr Gastroenterol Nutr. 2005;40:220-222. 15. Centocor, Inc., Press release, May 22, 2006. Patients With CD Who Developed HSTCL While Receiving Infliximab and Immunomodulators Hepatosplenic T-cell lymphoma (HSTCL) is a very rare form of non-Hodgkin’s lymphoma reported most commonly in adolescent and young adult males.1,2 The background incidence of HSTCL is unknown, since only approximately 150 documented cases have been published in the medical literature since it was first recognized as a distinct lymphoma subtype in the early 1990s.3 The clinical course of the disease is extremely aggressive with a fatal outcome in most patients within 2 years of diagnosis, regardless of the T-cell receptor phenotype (?d or aß) expressed by the tumor.1,2 Cases of HSTCL described in the literature include 3 patients with CD treated with long-term azathioprine1,2,4 and in chronically immunosuppressed, solid organ allograft recipients, many of whom were reported to have received azathioprine in addition to other immunosuppressants.5-13 Eight postmarketing cases of HSTCL have been reported in adolescent and young adult patients with CD who were treated with infliximab.14,15 The details of the cases are outlined in this slide. The patients were all in the United States, ranged in age from 12 to 31 years, and had all received azathioprine or 6-mercaptopurine concomitantly with infliximab. In those patients for whom the duration of infliximab use was reported, exposure ranged from 1 or 2 infusions to approximately 4 years of maintenance therapy. Six of the 8 patients have died as a result of their lymphoma. To date, no additional cases of HSTCL have been reported out of approximately 500,000 patients treated worldwide with infliximab for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis (including those treated with concomitant methotrexate), as well as 10,000 pediatric and 27,000 adult patients with CD. A causative role for infliximab in the development of HSTCL in these 8 patients has not been established. References 1. Mittal S, et al. Eur J Haematol. 2006;76:531-534. 2. Navarro JT, et al. Leuk Lymphoma. 2003;44:531-533. 3. Data on file, Centocor, Inc. 4. Lemann M, et al. Gastroenterology. 1998;114:A1020. 5. Francois A, et al. Am J Surg Pathol. 1997;21:781-790. 6. Kraus MD, et al. Cancer. 1998;82:983-992. 7. Garvin AJ, et al. Am J Surg Pathol. 1988;12:64-70. 8. Roncella S, et al. Haematologia. 2000;85:256-262. 9. Ross CW, et al. Am J Clin Pathol. 1994;102:310-315. 10. Labouyrie E, et al. Mod Pathol. 1995;8:355-359. 11. Albalate M, et al. Nephrol Dial Transplant. 1998;13:3242-3244. 12. Lin WC, et al. Leuk Lymphoma. 1999;33:377-384. 13. Rajakariar R, et al. Am J Transplant. 2004;4:1534-1538. 14. Thayu M, et al. J Pediatr Gastroenterol Nutr. 2005;40:220-222. 15. Centocor, Inc., Press release, May 22, 2006.

    27. Natalizumab: Safety Most common AEs (= 10% of patients) were headache, nausea, and nasopharyngitis 8–14% of patients discontinued treatment due to AEs 3 cases of progressive multifocal leukoencephalopathy (PML) have been reported Patients in all clinical trials have been re-evaluated for PML2,3 89% of eligible clinical trial patients participated (N = 3389) No additional, confirmed cases of PML were identified in > 3000 patients PML was excluded in all but 1 patient, where repeat MRI and CSF were not available Estimated risk of PML in this population: 1 per 1000 patients (0.1%; 95% CI: 0.2–2.8 per 1000)3 Incidence in CD: 1 in 1275 Incidence in MS: 2 in 2248 Natalizumab: Safety The safety of natalizumab was evaluated in both the ENACT-1 and ENACT-2 studies.1 The most common AEs (ie, observed in = 10% of the patients) in natalizumab-treated patients were headache (30% and 36% in ENACT-1 and -2 studies, respectively), nausea (17% and 22%), and nasopharyngitis (14% and 23%). Treatment was discontinued due to AEs in 8% and 14% of the natalizumab-treated patients in the ENACT-1 and ENACT-2 studies, respectively. Natalizumab was temporarily withdrawn from the market following 3 reports (2 of which were fatal) of progressive multifocal leukoencephalopathy (PML) in 2 patients with multiple sclerosis who were also receiving interferon-beta and in 1 patient with CD and prior exposure to AZA. Subsequent to this, Yousry and colleagues2 conducted a study of more than 3,000 patients who had received a mean of 17.9 monthly doses of natalizumab to assess the risk for PML. Patient medical histories were reviewed by an independent adjudication committee (IAC), as were magnetic resonance images of the brain and cerebrospinal fluid samples (for determination of JC polyomavirus DNA) obtained specifically for this study. Of the 44 cases referred to the IAC for adjudication, PML was ruled out in 43 patients, and one case was classified as indeterminate because follow-up examinations could not be conducted. The IAC was able to confirm only the 3 initial cases of PML. The IAC therefore estimated the risk for PML to be 1 case per 1000 patients (0.1%) with a 95% confidence limit of 0.2–2.8 cases per 1000 patients. The most recent update to these data was presented at DDW 2006.3 References Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925. Yousry TA, et al. N Engl J Med. 2006;354:924-933. Sandborn WJ, et al. DDW 2006, Abstract 492. Natalizumab: Safety The safety of natalizumab was evaluated in both the ENACT-1 and ENACT-2 studies.1 The most common AEs (ie, observed in = 10% of the patients) in natalizumab-treated patients were headache (30% and 36% in ENACT-1 and -2 studies, respectively), nausea (17% and 22%), and nasopharyngitis (14% and 23%). Treatment was discontinued due to AEs in 8% and 14% of the natalizumab-treated patients in the ENACT-1 and ENACT-2 studies, respectively. Natalizumab was temporarily withdrawn from the market following 3 reports (2 of which were fatal) of progressive multifocal leukoencephalopathy (PML) in 2 patients with multiple sclerosis who were also receiving interferon-beta and in 1 patient with CD and prior exposure to AZA. Subsequent to this, Yousry and colleagues2 conducted a study of more than 3,000 patients who had received a mean of 17.9 monthly doses of natalizumab to assess the risk for PML. Patient medical histories were reviewed by an independent adjudication committee (IAC), as were magnetic resonance images of the brain and cerebrospinal fluid samples (for determination of JC polyomavirus DNA) obtained specifically for this study. Of the 44 cases referred to the IAC for adjudication, PML was ruled out in 43 patients, and one case was classified as indeterminate because follow-up examinations could not be conducted. The IAC was able to confirm only the 3 initial cases of PML. The IAC therefore estimated the risk for PML to be 1 case per 1000 patients (0.1%) with a 95% confidence limit of 0.2–2.8 cases per 1000 patients. The most recent update to these data was presented at DDW 2006.3 References Sandborn WJ, et al. N Engl J Med. 2005;353:1912-1925. Yousry TA, et al. N Engl J Med. 2006;354:924-933. Sandborn WJ, et al. DDW 2006, Abstract 492.

    28. II. Step-up vs Top-down Approach

    29. New Approaches to Therapeutic Intervention in Crohn’s Disease? The “Step-up” vs “Top-down” Trial

    30. Assessment of Top-Down Versus Step-Up Strategies in CD Assessment of Top-Down Versus Step-Up Strategies in CD The prevailing therapeutic strategy in CD has been called a “step-up” approach. That is, treatment progresses from 5-ASA, antibiotics, and topical and/or systemic steroids through immune modulators and culminates with anti-TNF therapy. The premise is that traditional drugs should be used to treat the majority of patients who have mild disease, while those who do not respond to these agents should be switched to the newer and more effective agents. Unfortunately, this strategy focuses on a short time horizon and symptomatic relief, while neglecting the possibility that the disease may progress to a more complicated form because of inadequate response to initial therapy. An alternative strategy, called “top-down” therapy, has been proposed that may result in better patient outcomes earlier in the course of the disease and may delay or even halt progression to more severe forms of the disease. In this case, more potent agents are introduced early in the course of the disease in an effort to arrest inflammation and prevent complications that may, over the long term, result in disability. Data on top-down therapy are beginning to accumulate. For example, a randomized, controlled study was conducted to compare top-down therapy with step-up therapy in 133 patients with moderate-to-severe CD (129 patients were evaluated for efficacy).1 Patients had relatively early, active disease (< 4 years’ duration, CDAI score > 220 points) and were naive to corticosteroids, immunomodulators, and TNF antagonists. Patients were initially randomized to top-down treatment with 3 infusions of infliximab (weeks 0, 2, and 6) and AZA 2-2.5 mg/kg/day or to step-up treatment with topical budesonide 9 mg/day. In the top-down group, patients who relapsed were treated with repeat infliximab infusions and corticosteroids. In the step-up group, patients who failed to respond to budesonide were stepped up to prednisone 40 mg/day. In these patients, AZA was added in the case of repeated need for corticosteroids or if the patient developed a dependency on corticosteroids, and infliximab was only given after failure of AZA. The primary endpoint was remission (CDAI score < 150 points without steroid use and no bowel resection) at month 6 and 12. Secondary endpoints included safety and endoscopic assessment at 24 months. Remission was attained in 60% of patients in the top-down group versus 36% of the patients in the step-up group at 6 months (P < 0.01), and in 62% and 42% of the patients, respectively, at 12 months (P < 0.05). At 6 months, 31% of patients in the step-up group were still receiving corticosteroids (median dose 26 mg/day) compared with none of the patients in the top-down group (P < 0.001). Results were similar at 12 months, with 17% of the patients in the step-up group still receiving corticosteroids (median dose 23 mg) compared with none of the patients in the top-down group (P < 0.001). Reference 1. Hommes D, et al. DDW 2006, Abstract 749.Assessment of Top-Down Versus Step-Up Strategies in CD The prevailing therapeutic strategy in CD has been called a “step-up” approach. That is, treatment progresses from 5-ASA, antibiotics, and topical and/or systemic steroids through immune modulators and culminates with anti-TNF therapy. The premise is that traditional drugs should be used to treat the majority of patients who have mild disease, while those who do not respond to these agents should be switched to the newer and more effective agents. Unfortunately, this strategy focuses on a short time horizon and symptomatic relief, while neglecting the possibility that the disease may progress to a more complicated form because of inadequate response to initial therapy. An alternative strategy, called “top-down” therapy, has been proposed that may result in better patient outcomes earlier in the course of the disease and may delay or even halt progression to more severe forms of the disease. In this case, more potent agents are introduced early in the course of the disease in an effort to arrest inflammation and prevent complications that may, over the long term, result in disability. Data on top-down therapy are beginning to accumulate. For example, a randomized, controlled study was conducted to compare top-down therapy with step-up therapy in 133 patients with moderate-to-severe CD (129 patients were evaluated for efficacy).1 Patients had relatively early, active disease (< 4 years’ duration, CDAI score > 220 points) and were naive to corticosteroids, immunomodulators, and TNF antagonists. Patients were initially randomized to top-down treatment with 3 infusions of infliximab (weeks 0, 2, and 6) and AZA 2-2.5 mg/kg/day or to step-up treatment with topical budesonide 9 mg/day. In the top-down group, patients who relapsed were treated with repeat infliximab infusions and corticosteroids. In the step-up group, patients who failed to respond to budesonide were stepped up to prednisone 40 mg/day. In these patients, AZA was added in the case of repeated need for corticosteroids or if the patient developed a dependency on corticosteroids, and infliximab was only given after failure of AZA. The primary endpoint was remission (CDAI score < 150 points without steroid use and no bowel resection) at month 6 and 12. Secondary endpoints included safety and endoscopic assessment at 24 months. Remission was attained in 60% of patients in the top-down group versus 36% of the patients in the step-up group at 6 months (P < 0.01), and in 62% and 42% of the patients, respectively, at 12 months (P < 0.05). At 6 months, 31% of patients in the step-up group were still receiving corticosteroids (median dose 26 mg/day) compared with none of the patients in the top-down group (P < 0.001). Results were similar at 12 months, with 17% of the patients in the step-up group still receiving corticosteroids (median dose 23 mg) compared with none of the patients in the top-down group (P < 0.001). Reference 1. Hommes D, et al. DDW 2006, Abstract 749.

    31. Top-Down Versus Step-Up Trial Clinical Results at 2 Years Top-Down Versus Step-Up Trial Clinical Results at 2 Years At study onset, 100% of the patients in the top-down group were receiving infliximab whereas none of the patients in the step-up group were receiving infliximab.1 The upper right panel demonstrates that the difference in infliximab use between the two treatment groups decreased dramatically over the first 10 weeks of the study. Infliximab use was essentially the same in both the top-down and step-up groups at 48 weeks after randomization and continued to be the same through 104 weeks. At 6 months, a higher proportion of patients in the top-down group were receiving concomitant immunosuppressant therapy compared with the patients in the step-up group (84% vs 41%; P < 0.001; lower right panel). This trend continued at 12 months with 93% of the patients in the top-down group receiving concomitant immunosuppressant therapy compared with 65% of the patients in the step-up group (P < 0.001). The difference between the top-down and step-up groups in immunosuppressant use began to narrow after 60 weeks as patients in the step-up group began receiving infliximab. After 2 years, 44 of the 133 patients in the study underwent a repeat endoscopy (24 had received top-down treatment and 20 had received step-up treatment), and results were compared with endoscopy findings at diagnosis.2 For the comparison, 5 ileal and colonic segment lesions were scored for each patient as follows: 0 = no ulcer, 1 = aphthoid ulcers, 2 = larger ulcers, and 3 = ulcerated stenosis. Complete ulcer disappearance was observed in 71% of the patients who received top-down treatment and in 30% of the patients who received step-up treatment (P < 0.001; left panel). Mucosal healing at 2 years was more pronounced in the top-down group, with ulcer reductions observed in 88% of the patients in the top-down group compared with 47% in the step-up group (P < 0.001). The mean ulcer score decreased from 5.75 to 0.75 in the top-down group and decreased from 5.40 to 3.25 in the step-up group (P < 0.001 for comparison between the two groups; data not shown). These data suggest that top-down therapy is superior to step-up therapy in achieving clinical remission and in effecting mucosal healing. References Hommes D, et al. DDW 2006, Abstract 749. D’Haens GR, et al. DDW 2006, Abstract 764. Top-Down Versus Step-Up TrialClinical Results at 2 Years At study onset, 100% of the patients in the top-down group were receiving infliximab whereas none of the patients in the step-up group were receiving infliximab.1 The upper right panel demonstrates that the difference in infliximab use between the two treatment groups decreased dramatically over the first 10 weeks of the study. Infliximab use was essentially the same in both the top-down and step-up groups at 48 weeks after randomization and continued to be the same through 104 weeks. At 6 months, a higher proportion of patients in the top-down group were receiving concomitant immunosuppressant therapy compared with the patients in the step-up group (84% vs 41%; P < 0.001; lower right panel). This trend continued at 12 months with 93% of the patients in the top-down group receiving concomitant immunosuppressant therapy compared with 65% of the patients in the step-up group (P < 0.001). The difference between the top-down and step-up groups in immunosuppressant use began to narrow after 60 weeks as patients in the step-up group began receiving infliximab. After 2 years, 44 of the 133 patients in the study underwent a repeat endoscopy (24 had received top-down treatment and 20 had received step-up treatment), and results were compared with endoscopy findings at diagnosis.2 For the comparison, 5 ileal and colonic segment lesions were scored for each patient as follows: 0 = no ulcer, 1 = aphthoid ulcers, 2 = larger ulcers, and 3 = ulcerated stenosis. Complete ulcer disappearance was observed in 71% of the patients who received top-down treatment and in 30% of the patients who received step-up treatment (P < 0.001; left panel). Mucosal healing at 2 years was more pronounced in the top-down group, with ulcer reductions observed in 88% of the patients in the top-down group compared with 47% in the step-up group (P < 0.001). The mean ulcer score decreased from 5.75 to 0.75 in the top-down group and decreased from 5.40 to 3.25 in the step-up group (P < 0.001 for comparison between the two groups; data not shown). These data suggest that top-down therapy is superior to step-up therapy in achieving clinical remission and in effecting mucosal healing. References Hommes D, et al. DDW 2006, Abstract 749. D’Haens GR, et al. DDW 2006, Abstract 764.

    32. What does mucosal healing in Crohn’s disease mean clinically? Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    33. Endoscopic Healing and Reduced Hospitalizations and Surgeries: Infliximab maintenance for Crohn’s disease

    34. Weighing the Value of Top-Down Therapy Weighing the Value of Top-Down Therapy Epidemiological observations have shown that the course of CD, despite conventional treatment, often progresses to the development of severe complications (fibrosis, stricture, fistulas, obstruction) and the need for surgery.1,2 Even corticosteroids are largely ineffective in preventing surgery since the cumulative probability of the need for surgery at 1 year is nearly 40% in CD patients treated with steroids.3 Is it possible to alter the natural history of CD with the “top-down” approach—that is, by introducing the most aggressive and effective therapies early in the course of disease to promote mucosal healing and avoid disease complications and need for surgery? As was seen in previous slides, TNF antagonists are effective for the rapid induction and maintenance of remission in patients with moderate to severe CD, for promoting the healing of fistulas and withdrawal from steroids, for reducing the need for hospitalization and surgery, and for improvement in function and quality of life. On the other hand, biologic agents can be associated with adverse events, including infusion reactions that may lead to treatment failure (infliximab); reactivation of latent TB, increase in opportunistic infections and increased risk for lymphoma (the TNF antagonist class); or for the development of a life-threatening viral infection (natalizumab). In addition, an aggressive approach with biologic agents early in the course of disease may not be necessary in many CD patients who could be effectively treated with milder agents that have a more favorable adverse event profile (eg, aminosalicylates). Unfortunately, a system that allows identification of subgroups of CD patients with differing disease phenotypes and that predicts a patient’s disease course and prognosis is not available at this time. Such a prospective classification system, utilizing specific biomarkers for staging of disease severity and predicting response to therapy, could play a pivotal role in deciding between a step-up or top-down approach in a patient with CD. References 1. Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10(Suppl 2):S2-S10. 2. Caprilli R, et al. Digest Liver Dis. 2005;37:973-979. 3. Faubion Jr WA, et al. Gastroenterology. 2001;121:255-260. Weighing the Value of Top-Down Therapy Epidemiological observations have shown that the course of CD, despite conventional treatment, often progresses to the development of severe complications (fibrosis, stricture, fistulas, obstruction) and the need for surgery.1,2 Even corticosteroids are largely ineffective in preventing surgery since the cumulative probability of the need for surgery at 1 year is nearly 40% in CD patients treated with steroids.3 Is it possible to alter the natural history of CD with the “top-down” approach—that is, by introducing the most aggressive and effective therapies early in the course of disease to promote mucosal healing and avoid disease complications and need for surgery? As was seen in previous slides, TNF antagonists are effective for the rapid induction and maintenance of remission in patients with moderate to severe CD, for promoting the healing of fistulas and withdrawal from steroids, for reducing the need for hospitalization and surgery, and for improvement in function and quality of life. On the other hand, biologic agents can be associated with adverse events, including infusion reactions that may lead to treatment failure (infliximab); reactivation of latent TB, increase in opportunistic infections and increased risk for lymphoma (the TNF antagonist class); or for the development of a life-threatening viral infection (natalizumab). In addition, an aggressive approach with biologic agents early in the course of disease may not be necessary in many CD patients who could be effectively treated with milder agents that have a more favorable adverse event profile (eg, aminosalicylates). Unfortunately, a system that allows identification of subgroups of CD patients with differing disease phenotypes and that predicts a patient’s disease course and prognosis is not available at this time. Such a prospective classification system, utilizing specific biomarkers for staging of disease severity and predicting response to therapy, could play a pivotal role in deciding between a step-up or top-down approach in a patient with CD. References 1. Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10(Suppl 2):S2-S10. 2. Caprilli R, et al. Digest Liver Dis. 2005;37:973-979. 3. Faubion Jr WA, et al. Gastroenterology. 2001;121:255-260.

    35. III. Is “Top-down” treatment a good idea for managing all patients with Crohn’s disease? Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    36. Natural History of IBD Heterogeneity of Crohn’s disease. Severe CD phenotypes. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    37. 1998 - Tale of 2 boys Patient -1 12 year old boy with weight loss and diarrhea Diagnosis – Crohn’s disease of ileum and colon Treated with steroids + immune modifiers

    38. 2003 - Tale of 2 boys Patient -1 He had been in clinical remission for first 2 years Relapse required a short course of steroids Normal growth and timely puberty He has been in remission since then Repeat colonoscopy – all lesions were healed.

    39. Probability of Surgery for Crohn’s Disease

    40. Probability of Surgery for Crohn’s Disease

    41. Predictability of the postoperative course of Crohn's disease. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Gastroenterology. 1990;99:956-963

    42. Rutgeerts Endoscopic Scoring System – neoterminal ileum

    43. Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions

    44. Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions

    45. Rationale for disease modifying therapy in IBD. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    47. Efficacy of AZA as Maintenance Therapy in Patients with Active CD* The Candy-Wright study evaluated the efficacy of azathioprine in the induction of remission when used in conjunction with prednisone on a tapering dose over a period of 12 weeks. In addition, the study evaluated the efficacy of azathioprine over placebo in the maintenance of remission in over a period of 15 months. 63 patients with active CD were treated with a 12 week tapering dose of prednisone and at the same time entered into a randomized, double-blind, 15-month trial of azathioprine 2.5 mg/kg/d or placebo in the maintenance of remission. The proportion of patients in remission at 15 months was 42% in the azathioprine group vs. 7% in the placebo group (P=0.001).The Candy-Wright study evaluated the efficacy of azathioprine in the induction of remission when used in conjunction with prednisone on a tapering dose over a period of 12 weeks. In addition, the study evaluated the efficacy of azathioprine over placebo in the maintenance of remission in over a period of 15 months. 63 patients with active CD were treated with a 12 week tapering dose of prednisone and at the same time entered into a randomized, double-blind, 15-month trial of azathioprine 2.5 mg/kg/d or placebo in the maintenance of remission. The proportion of patients in remission at 15 months was 42% in the azathioprine group vs. 7% in the placebo group (P=0.001).

    48. Duration of Remission With 6-MP in Children With Newly Diagnosed CD

    49. REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD The rates of clinical response and remission at week 10 were 88.4% (95% CI: 82.5%, 94.3%) and 58.9% (95% CI: 49.8%, 68.0%), respectively.1 At week 54, the rates of clinical response and remission were significantly higher in patients who received maintenance therapy with infliximab 5 mg/kg every 8 weeks (63.5% and 55.8%, respectively) than the rates in patients who received maintenance therapy with infliximab 5 mg/kg every 12 weeks (33.3% and 23.5%; P = 0.002 for each comparison). Clinical response rates were similar regardless of age (= 13 years or > 13 years), disease duration (= 1 year or > 1 year), or disease location (colon or small intestine). Antibodies to infliximab (ATI) developed in 3 (2.9%) patients (1 in each active treatment arm and another who was not randomized at week 10). Reference 1. Hyams J, et al. DDW 2006. Abstract 57.REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD The rates of clinical response and remission at week 10 were 88.4% (95% CI: 82.5%, 94.3%) and 58.9% (95% CI: 49.8%, 68.0%), respectively.1 At week 54, the rates of clinical response and remission were significantly higher in patients who received maintenance therapy with infliximab 5 mg/kg every 8 weeks (63.5% and 55.8%, respectively) than the rates in patients who received maintenance therapy with infliximab 5 mg/kg every 12 weeks (33.3% and 23.5%; P = 0.002 for each comparison). Clinical response rates were similar regardless of age (= 13 years or > 13 years), disease duration (= 1 year or > 1 year), or disease location (colon or small intestine). Antibodies to infliximab (ATI) developed in 3 (2.9%) patients (1 in each active treatment arm and another who was not randomized at week 10). Reference 1. Hyams J, et al. DDW 2006. Abstract 57.

    50. Changes in PCDAI Score Following Infliximab Infusion (10 Weeks)

    52. Duration of Response Following Initial Infliximab Infusion: Early vs. Late CD

    53. PRECiSE 2: Week 26 Clinical Response or Remission by Duration of Crohn’s Disease PRECiSE 2: Week 26 Clinical Response or Remission by Duration of Crohn’s Disease An interesting retrospective analysis of the PRECiSE 2 study was recently presented in which the ability of certolizumab to maintain clinical remission and response was assessed in patients with CD of recent onset compared with patients with established disease.1 As shown in this slide, a higher percentage of patients maintained on monthly certolizumab achieved a clinical response or remission earlier in the course of disease than those with more established disease. For example, 90% of certolizumab-treated patients and 37% of placebo-treated patients with disease duration < 1 year (n = 54) demonstrated a clinical response (P < 0.01), compared with 57% of certolizumab-treated patients and 33% of placebo-treated patients with disease duration ? 5 years (P < 0.001; n = 229). Similar results were seen for the incidence of clinical remission in patients with early disease versus established disease (right panel). Overall, maintenance of a clinical response at 26 weeks in CD patients with disease duration of < 3 years was observed in 76% of patients treated with certolizumab and 40% in those receiving placebo (P < 0.001); similarly, maintenance of clinical remission at 26 weeks in CD patients with disease duration of < 3 years was observed in 59% of certolizumab-treated patients and 33% of placebo controls (P < 0.01; data not shown). These data suggest that there is a clear benefit of early intervention with certolizumab for maintenance of clinical response and remission in patients with active CD. Reference 1. Sandborn WJ, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S394. Abstract 1109.PRECiSE 2: Week 26 Clinical Response or Remission by Duration of Crohn’s Disease An interesting retrospective analysis of the PRECiSE 2 study was recently presented in which the ability of certolizumab to maintain clinical remission and response was assessed in patients with CD of recent onset compared with patients with established disease.1 As shown in this slide, a higher percentage of patients maintained on monthly certolizumab achieved a clinical response or remission earlier in the course of disease than those with more established disease. For example, 90% of certolizumab-treated patients and 37% of placebo-treated patients with disease duration < 1 year (n = 54) demonstrated a clinical response (P < 0.01), compared with 57% of certolizumab-treated patients and 33% of placebo-treated patients with disease duration ? 5 years (P < 0.001; n = 229). Similar results were seen for the incidence of clinical remission in patients with early disease versus established disease (right panel). Overall, maintenance of a clinical response at 26 weeks in CD patients with disease duration of < 3 years was observed in 76% of patients treated with certolizumab and 40% in those receiving placebo (P < 0.001); similarly, maintenance of clinical remission at 26 weeks in CD patients with disease duration of < 3 years was observed in 59% of certolizumab-treated patients and 33% of placebo controls (P < 0.01; data not shown). These data suggest that there is a clear benefit of early intervention with certolizumab for maintenance of clinical response and remission in patients with active CD. Reference 1. Sandborn WJ, et al. Am J Gastroenterol. 2006; 101(Suppl 2):S394. Abstract 1109.

    54. Biologic induction for all IBD patients implies episodic dosing for those who will require longterm maintenance. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    55. Serum Concentrations of Infliximab: All Randomized Patients

    56. Antibodies to Infliximab Through Week 54

    58. Analysis of longterm infliximab performance in Crohn’s disease 2nd Analysis: Last maintenance infusion The peak onset of IBD is between 15 and 25 years of age. About 30% of all IBD cases occur between ages 10 and 19 years. Young children represent approximately 2% of all IBD patients. A second peak incidence of IBD occurs between 50 and 65 years of age. From 1970 to 1990, there was a steady increase in the incidence of IBD in industrialized nations.The peak onset of IBD is between 15 and 25 years of age. About 30% of all IBD cases occur between ages 10 and 19 years. Young children represent approximately 2% of all IBD patients. A second peak incidence of IBD occurs between 50 and 65 years of age.

    59. The peak onset of IBD is between 15 and 25 years of age. About 30% of all IBD cases occur between ages 10 and 19 years. Young children represent approximately 2% of all IBD patients. A second peak incidence of IBD occurs between 50 and 65 years of age. From 1970 to 1990, there was a steady increase in the incidence of IBD in industrialized nations.The peak onset of IBD is between 15 and 25 years of age. About 30% of all IBD cases occur between ages 10 and 19 years. Young children represent approximately 2% of all IBD patients. A second peak incidence of IBD occurs between 50 and 65 years of age.

    60. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    61. IV. A rational approach for biologic therapy in IBD Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    63. Summary and conclusions - I Multiple biologic agents targeting TNF-?, IL-12/23 and ?4 integrin are being developed for IBD. Rapid, effective therapy to induce remission has long-term benefit, specifically for mucosal healing in CD. Precedent for disease modifying therapy exists with pediatric CD patients. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    64. Summary and conclusions - II Antibody based biologic therapy for CD is not flexible. Re-starting therapy is associated with immunogenicity, allergy and diminished efficacy. Rapid identification of the high risk subgroup of patients (approximately 25% of CD) who will ultimately require biologic therapy for long-term maintenance of remission remains the ultimate goal. Risk-benefit assessment will favor use of biologic agents in the severe IBD subgroup. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually. Inflammatory bowel disease (IBD) affects1 to 2 million people in the U.S., or 100 cases per 100,000 population. Ulcerative colitis and Crohn’s disease have a similar prevalence. About 10,000 new cases of IBD are diagnosed annually.

    65. Acknowledgments MCW IBD Center Mazen Issa, M.D. Dawn B. Beaulieu, M.D. Jasmohan Bajaj, M.D., M.S. Kia Saeian, M.D., M.S. Ashwin N. Ananthakrishnan, M.D., M.P.H. Lydia Rosenbaum Josh F. Knox, P.A.-C. Sue Skaros, P.A.-C. Sarah Lundeen, A.P.N.P. Sheila Thierfelder, C.C.R.C. Jeanne Emmons, R.N. Victoria Nelson Heather Brandenburg Gary Sudakoff, M.D. Hitoshi Ogawa, M.D., Ph.D. Ossama A. Hatoum, M.D., M.S. Jan Heidemann, M.D. W. Martin Floer, M.D. Murtaza Arif, M.D. Mary F. Otterson, M.D., M.S. Subra Kugathasan, M.D. Parvaneh Rafiee, Ph.D. David G. Binion, M.D.

    66. Estimate of Work Capacity: 10 Years Following IBD Diagnosis

    68. ACCENT II: Cumulative Number of Surgeries Over Time in Responders ACCENT II: Cumulative Number of Surgeries Over Time in Responders The effect of infliximab maintenance therapy on hospitalizations, surgeries, and procedures was evaluated in patients with fistulizing CD who were enrolled in the ACCENT II study.1 The data on the slide illustrate the cumulative number of hospitalizations during the study among patients who responded to induction therapy with infliximab (n = 195). The cumulative number of hospitalizations began to diverge after week 14 when patients were randomized to receive maintenance therapy with placebo or infliximab. Among all patients randomized to maintenance therapy (ie, responders and nonresponders to induction therapy; n = 282), the mean number of hospitalization days per patient through week 54 was 0.8 in patients receiving maintenance therapy with infliximab and 2.4 in those receiving maintenance therapy with placebo (P = 0.110) Among the responders to induction therapy with infliximab (n = 195), the mean number of hospitalization days per patient was significantly lower among patients receiving infliximab maintenance therapy (0.5) than among patients receiving maintenance therapy with placebo (2.5; P < 0.05). Among all patients randomized to maintenance therapy (responders and nonresponders), the rate of hospitalization per 100 patients was significantly lower in those who received infliximab maintenance therapy than the rate in those who received placebo (14 vs 31; P < 0.05). Results were similar among patients randomized as responders (11 vs 31; P < 0.05). Additionally, the mean number of inpatient surgeries and procedures per 100 patients in the infliximab maintenance group was reduced by > 70% in all randomized patients when compared with the mean number in placebo maintenance group (10 vs 45, respectively; P < 0.001) and by > 80% in patients randomized as responders (7 vs 41, respectively; P < 0.01). Reference 1. Lichtenstein GR, et al. Gastroenterology. 2005;128:862-869.ACCENT II: Cumulative Number of Surgeries Over Time in Responders The effect of infliximab maintenance therapy on hospitalizations, surgeries, and procedures was evaluated in patients with fistulizing CD who were enrolled in the ACCENT II study.1 The data on the slide illustrate the cumulative number of hospitalizations during the study among patients who responded to induction therapy with infliximab (n = 195). The cumulative number of hospitalizations began to diverge after week 14 when patients were randomized to receive maintenance therapy with placebo or infliximab. Among all patients randomized to maintenance therapy (ie, responders and nonresponders to induction therapy; n = 282), the mean number of hospitalization days per patient through week 54 was 0.8 in patients receiving maintenance therapy with infliximab and 2.4 in those receiving maintenance therapy with placebo (P = 0.110) Among the responders to induction therapy with infliximab (n = 195), the mean number of hospitalization days per patient was significantly lower among patients receiving infliximab maintenance therapy (0.5) than among patients receiving maintenance therapy with placebo (2.5; P < 0.05). Among all patients randomized to maintenance therapy (responders and nonresponders), the rate of hospitalization per 100 patients was significantly lower in those who received infliximab maintenance therapy than the rate in those who received placebo (14 vs 31; P < 0.05). Results were similar among patients randomized as responders (11 vs 31; P < 0.05). Additionally, the mean number of inpatient surgeries and procedures per 100 patients in the infliximab maintenance group was reduced by > 70% in all randomized patients when compared with the mean number in placebo maintenance group (10 vs 45, respectively; P < 0.001) and by > 80% in patients randomized as responders (7 vs 41, respectively; P < 0.01). Reference 1. Lichtenstein GR, et al. Gastroenterology. 2005;128:862-869.

    69. Natalizumab as Induction Therapy for Crohn’s Disease: ENACT-1 Trial

    70. Anti-Interleukin 12 (ABT-874) in Active Crohn’s Disease

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