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Positioning Our Recent & Future Therapy in Crohn’s disease

Positioning Our Recent & Future Therapy in Crohn’s disease. Ahmad Alfadhli MD, FRCPC Gastroenterology Unite Haya Al- Habeeb Center Mubarak Al- Kabeer Hospital KUWAIT . Modification of long-term course of CD Complete and persistent healing of bowel mucosa

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Positioning Our Recent & Future Therapy in Crohn’s disease

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  1. Positioning Our Recent & Future Therapy in Crohn’sdisease Ahmad Alfadhli MD, FRCPC Gastroenterology Unite Haya Al-Habeeb Center Mubarak Al-Kabeer Hospital KUWAIT

  2. Modification of long-term course of CD Complete and persistent healing of bowel mucosa Avoidance of complications, including stenoses, abscesses, and fistulae Avoidance of hospitalization, surgeries, and ICU stay Improved cost-to-efficacy ratio of treatment Normal bowel function and improved QOL New Therapeutic Goals in CD

  3. Corticosteroid

  4. Steroids for the treatment of Crohn’s Disease – benefit for the patient N = 74 N = 73 prolonged response remission “positive” outcome steroid dependent partial remission “negative” outcome surgery no response Faubion WA et al. Gastroenterology 2001;121:255

  5. TREAT Benefit risk profile of major CD therapies: infections and mortality Multivariate analysis 4.5 Mortality Serious infections 4 3.5 3 HAZARD RATIO 2.5 IFX † AZA 6-MP MTX * AZA 6-MP MTX IFX 2 1.5 Steroids Steroids 1 0.5 0 *p=0.002; †p<0.001 Data on file (Lichtenstein et al. DDW 2007 poster with abstract S1124)

  6. Complication of long term corticosteroid use • Hyperglycemia • Infection • Myopathy • Psychological- dementia • Hypertension • Osteoporosis • Adrenal insufficiency • Hepatic steatosis • Glaucoma • Growth suppression

  7. Azathioprine

  8. Placebo (n=30) AZA 2.5 mg/kg per d (n=33) Placebo (n=30) AZA 2.5 mg/kg per d (n=33) 80 80 60 60 40 40 20 20 0 0 Maintenance of clinical remission with Azathioprine in CD patients Remission induced by prednisolone; tapered over 12 weeks 100 Placebo (n=30) AZA 2.5 mg/kg per d (n=33) 80 60 % patients not failing trial 40 20 ster + AZA AZA 0 0 15 Duration of trial (months) Candy et al. Gut1995;37:674

  9. ContinuousImmunotherapyisRequiredto Treat a ChronicDisease Patients in clinical remission with AZA for at least 3.5 years before randomisation 1.0 7.9 % relapse 0.8 21.3 0.6 Remission (months) mean ± SE Percentage of Patients inRemission 17.3 ± 0.5 0.4 15.9 ± 0.7 Azathioprine 0.2 Placebo 0.0 0 6 12 18 Months after randomisation Lemann et al.Gastroenterol. 2005 Jun;128(7):1812-8.

  10. More frequent use of immunosuppressives did not decrease the need for surgery in CD Analysis of 2573 patients (retrospective, 25 years) 100 Immunosuppressive Use (P<0.001) 90 Resection (P=0.5) 80 70 60 Cumulative percentage 50 40 30 20 10 0 1978-1982 1983-1987 1988-1992 1993-1997 1998-2002 Adapted from Cosnes et al. Gut2005;54:237

  11. Complications from 6-MP/Azathioprine • N = 806 • Pancreatitis – 1.0% • Abn liver tests – 2.4% • Leucopenia – 10.0% • Significant infection – 5.2% • Lymphoma – 0.005% • Malignancy - unclear O’Brien Wt al, gastroenterology 101:39-46, 1991 Khan et al, digestion 62:249-54. 2000

  12. Methotrexate

  13. Methotrexate: Induction & Maintenance of Remission in CD 100 P=0.04 90 80 70 Methotrexate Remission (%) 60 50 Placebo 40 30 0 0 4 8 12 16 20 24 28 32 36 40 Weeks since randomization Feagan BG, et al. N Engl J Med. 2000;342:1627-1632.

  14. Side effects of Methotrexate

  15. InfliximabInflammatory CD

  16. Healing of Colonic UlcerationWith Infliximab Pre-treatment 4 weeks post-treatment van Dullemen HM et al. Gastroenterology. 1995;109:129-135

  17. Mucosal Healing With Infliximab Histologic H&E staining 4 Weeks post- treatment Pre-treatment Courtesy of K. Geboes, MD.

  18. Inflammatory CD Study design • N = 108 • Randomized, double-blind, placebo-controlled, multicenter trial • CD > 6 months duration • CDAI score between 220 and 400, inclusive • Stable concomitant medications allowed by protocol: aminosalicylates, prednisone (< 40 mg/d), 6-MP/AZA Targan SR et al. N Engl J Med. 1997;337:1029-1035

  19. Clinical Remission With Infliximab at 4 Weeks Clinical remission defined as a CDAI score < 150. Targan SR et al. N Engl J Med. 1997;337:1029-1035

  20. Infliximab Fistulizing CD

  21. Infliximab Treatment of Fistulae in CD Study Design • N = 94 • Single or multiple draining enterocutaneous fistulae • Stable concomitant medications permitted (aminosalicylates, corticosteroids, 6-MP/AZA, antibiotics) • Treatment (infusion at Weeks 0, 2, and 6) • Infliximab 5 mg/kg • Infliximab 10 mg/kg • Placebo Present DH et al. Am J Gastroenterol. 1997;92(suppl):A1746. Abstract

  22. Perianal Fistula: Case Study Patient was a 42-year-old man with a draining fistula of 3 to 6 months duration who received infliximab 5 mg/kg. 2 Weeks Baseline

  23. Perianal Fistula: Case Study (cont) 18 Weeks 10 Weeks

  24. Infliximab Treatment of Fistulae in CD: Conclusions • Primary endpoint: 2/3 demonstrated > 50% reduction in draining fistulae • Secondary endpoint: 1/2 demonstrated closure of all fistulae

  25. From Trial to ClinicHow Has Practice Changed?

  26. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD GETAID3 ACCENT I4 Targan5 AZA-failure IS CS 5-ASA SONIC2 AZA/6-MP naïve Previous Drug Exposure SUTD1 1 2 3 4 5 6 7 9 10 11 12 8 Disease Duration (Years) 1D’Haens G, et al.Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

  27. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD Scheduled therapy is better than episodic GETAID3 ACCENT I4 Targan5 AZA-failure IS CS 5-ASA SONIC2 AZA/6-MP naïve Previous Drug Exposure SUTD1 1 2 3 4 5 6 7 9 10 11 12 8 Disease Duration (Years) 1D’Haens G, et al.Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

  28. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD Better results in AZA naïve, ‘bridging’ does not work GETAID3 ACCENT I4 Targan5 AZA-failure IS CS 5-ASA SONIC2 AZA/6-MP naïve Previous Drug Exposure SUTD1 1 2 3 4 5 6 7 9 10 11 12 8 Disease Duration (Years) 1D’Haens G, et al.Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

  29. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD Top-down therapy works GETAID3 ACCENT I4 Targan5 AZA-failure IS CS 5-ASA SONIC2 AZA/6-MP naïve Previous Drug Exposure SUTD1 1 2 3 4 5 6 7 9 10 11 12 8 Disease Duration (Years) 1D’Haens G, et al.Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

  30. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD Remicade®-based treatment strategy is superior for AZA-naïve patients GETAID3 ACCENT I4 Targan5 AZA-failure IS CS 5-ASA SONIC2 AZA/6-MP naïve Previous Drug Exposure SUTD1 1 2 3 4 5 6 7 9 10 11 12 8 Disease Duration (Years) 1D’Haens G, et al.Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

  31. Adalimumab

  32. HUMIRA Crohn’s Development Program CLASSIC II Long-term maintenance CLASSIC I Inductionof clinical remission/response CHARM Maintenanceof clinical remission/response M04-690Long-term follow-up GAIN Infliximab Failures Induction trial Induction Maintenance Long term F/U

  33. Greatest and Most Rapid Remission with 160/80 mg Induction Dose of HUMIRA (Week 4) * Placebo/placebo 40/20 mg 80/40 mg 160/80 mg * n=74 n=74 n=75 n=76 60 57.9 * 54.7 52.7 * 48.7 50 * 40 37.3 35.5 33.8 32.4 30 Percentage of Subjects 24.3 24.0 20 17.6 12.2 10 0 Clinical Remission Clinical Response 100 Clinical Response 70 Hanauer, S. et al. Gastroenterol. 2006, Hanauer, late-breaking abstract, DDW 2004. Panaccione, et al. Oral Presentation UEGW 2005, Data on file. *p<0.05 vs. placebo (ITT population).

  34. Rapid and Significant Δ 70 Response Rates With All doses of HUMIRA 80 Placebo 40/20 mg 70 # ‡ ** 80/40 mg † 60 160/80 mg 50 * 40 Patients achieving 70-point response (%) 30 20 10 0 0 Week 1 Week 2 Week 3 Week 4 As observed; ITT population *p=0.025 80/40 vs PBO **p=0.002 80/40 vs PBO; p=0.038 160/80 vs PBO #p=0.02 40/20 vs PBO; p=0.01 80/40 vs PBO; p=0.003 160/80 vs PBO Based on Hanauer, S. et al. Gastroenterol. 2006

  35. * * 21 21 % of Patients 6 7 6 4 Week Significant Rates of Remission with adalimumab treatment Placebo 160/80 mg 30 25 20 15 10 5 0 0 1 2 3 4 *P<0.001 vs. placebo Full analysis population Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas

  36. SymptomaticInflammation SubclinicalInflammation Disability Complications Health What is “Early”?Which “Outcomes”? DiseasePrevention Prevention ofComplications Prevention ofSymptomatic Disease Prevention ofRelapse

  37. New Approaches to Therapeutic Intervention in CD? +IFX IFX+ AZA +AZA MTX +(episodic) IFX Steroids Steroids Steroids Hommes D, et al. Presented at DDW 2006.

  38. Step-Up Versus Top-Down Trial Treatment Success* From Week 14 Through 2 Years Top Down Step Up CDAI<150 & No Steroids P = 0.19 P < 0.001 P = 0.03 29 50 41 61 60 Steroid Use P < 0.001 P < 0.001 0 0 31 5 17 *Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection. Hommes D, et al. Presented at DDW 2006. [Abstract 749].

  39. Safety Considerations WithTNF Inhibitors • Infections • Lymphoma • Antibodies against the compound • Infusion/injection site reactions • Other • Autoimmunity and autoantibodies • Demyelination • Congestive heart failure (CHF) • Hematologic disorders • Liver toxicity

  40. Evolving Goals in IBD Goals Perspective Society Clinician Patient Improved outcomes Normal laboratory data Remission off steroids Mucosal healing Improved signs, symptoms and quality of life Remission more than symptom control

  41. Accomplishments in IBD • Shift in the treatment paradigm • Optimal use of Anti-TNF • Appropriate patient identification • Raising the bar for treatment standards • Steroid-free remission • Complete mucosal healing • Improved outcomes • Ultimately strive for changing the natural course of disease

  42. Current & Future Landscape : Biologic IBD market map 1998–2018 paediatric CD Pfizer launch tofacitinib (JAK-3) for UC Humira launch for UC Takeda launch vedolizumab IV for CD Abbott launch Humira in CD (US and EU) UCB launch Cimzia for CD (US) Takeda launch vedolizumab IV for UC Launch of infliximabbiosimilars 2004 2011 2012 2018 1999 2006 2008 2009 2000 2013 2014 2015 2016 2017 2001 2002 2003 2005 2007 2010 Simponi launch for UC Janssen (JAK-3) for UC Remicade ulcerative colitis launch Remicade approved for moderate CD US Remicade launch in Crohn’s disease (1998 US) Stelara launch for CD (2015) Remicade paediatric CD launch Remicade approved for paediatric UC GCSO 2013 Business Planning

  43. Looking to The Future

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