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

New Therapeutic Goals in CD 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

Corticosteroid

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

Benefit risk profile of major CD therapies: infections and mortality 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 * IFX AZA 6-MP MTX 2 Safety of Infliximab and Other Crohn’s Disease Therapies – TREAT™ Registry Data with Nearly 20,000 Patient-Years of Follow-Up   GR Lichtenstein, RD Cohen, BG Feagan, WJ Sandborn, BA Salzberg, DM Chen, MP Turner, DR Mink, DL Broussard, RH Diamond Background and Methods: TREAT, a prospective registry, was established to study the long-term safety of infliximab (IFX) and other therapies in Crohn’s disease (CD). Results: 6273 pts were enrolled as of 8/06, of whom 3334 received IFX (10,796 pt-yrs (py)) (86.5% ≥2 infusions) and 2939 received other therapies only (8277 py) with a mean follow-up of 3.4 yrs. More IFX-treated pts had moderate-to-severe (31.1% vs 10.7%, p<0.0001) or severe-fulminant (2.6% vs 0.6%, p<0.0001) CD. Also, more IFX-treated pts had been hospitalized (27.3% vs. 19.0%, p<0.0001) in the year prior to enrollment, and more were taking prednisone (27.1% vs. 15.9%, p<0.0001) or immunomodulators (49.1% vs. 31.6%, p<0.0001) at enrollment. Infusion reactions occurred in 3.7% of 35,189 infusions; severe reactions in 0.09%. Mortality was similar for both IFX- and non-IFX-treated pts (0.52 per 100 py vs 0.50; RR=1.02, 95% CI=0.70-1.50). In an adjusted Cox proportional hazards analysis, the use of prednisone (HR=1.96, CI=1.28-3.00, p=0.002) and narcotics (HR=2.06, CI=1.33-3.21, p<0.001) were the only medications associated with increased risk of mortality. The incidence of malignancies in the two groups was similar (0.39 per 100 py in IFX pts vs 0.53 in non-IFX pts; RR=0.74, 95% CI=0.49-1.12), as was the incidence of lymphoma (0.04 per 100 py in IFX pts vs 0.05 in non-IFX pts; RR=0.8, 95% CI=0.22-2.99). The incidence of serious infections (SI) was 1.19 per 100 py within 3 months of an IFX infusion and 0.67 not within 3 months of an IFX infusion (RR=1.77, 95% CI =1.27-2.46, p=<0.001). However, an adjusted Cox analysis showed IFX was not a predictor of SI (HR=1.28, 95% CI=0.87-1.90). The only medications associated with SI were prednisone (HR=2.04, CI=1.42-2.93, p<0.001) and narcotics (HR=2.17, 95% CI=1.51-3.14, p<0.001). To date, one IFX-treated pt with known latent TB, who did not receive adequate prophylaxis, developed active TB. Conclusions: IFX safety is similar to that of conventional immunomodulators. Despite having more severe CD, IFX pts had similar rates of mortality, neoplasm and lymphoma as pts not treated with IFX. IFX-treated pts have an increased risk of serious infection but Cox proportional hazard analysis suggests that this increased risk is independently associated with prednisone and narcotic use, and not IFX therapy. 1.5 Steroids Steroids 1 0.5 *p=0.002; †p<0.001 Data on file (Lichtenstein et al. DDW 2007 poster with abstract S1124)

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

Azathioprine

Maintenance of clinical remission with Azathioprine in CD patients Remission induced by prednisolone; tapered over 12 weeks 100 80 60 40 20 Placebo (n=30) AZA 2.5 mg/kg per d (n=33) 80 60 40 20 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 60 % patients not failing trial 40 20 ster + AZA AZA 15 Duration of trial (months) Candy et al. Gut 1995;37:674

Continuous Immunotherapy is Required to Treat a Chronic Disease Patients in clinical remission with AZA for at least 3.5 years before randomisation 1.0 7.9 0.8 % relapse 21.3 0.6 Remission (months) Percentage of Patients in Remission mean ± SE 17.3 ± 0.5 0.4 Here, the point should be made that you cannot simply “stop” immune suppression in CD as then the patients relapse. NB: These are patients that have been maintained for 3.5 years and are then discontinued – therefore, the results cannot be compared with Candy! Immune suppression should be maintained for life Azathioprine Withdrawal Trial in Crohn’s Disease (after 5 years main. Aza) 15.9 ± 0.7 0.2 Azathioprine Placebo 0.0 6 12 18 Months after randomisation Lemann et al. Gastroenterol. 2005 Jun;128(7):1812-8.

Analysis of 2573 patients (retrospective, 25 years) More frequent use of immunosuppressives did not decrease the need for surgery in CD Analysis of 2573 patients (retrospective, 25 years) 100 90 Immunosuppressive Use (P<0.001) 80 Resection (P=0.5) 70 60 Cumulative percentage 50 40 30 20 10 1978-1982 1983-1987 1988-1992 1993-1997 1998-2002 Adapted from Cosnes et al. Gut 2005;54:237

Complications from 6-MP/Azathioprine 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

Methotrexate

Methotrexate: Induction & Maintenance of Remission in CD 100 90 P=0.04 80 70 Methotrexate Remission (%) 60 50 Methotrexate is effective in inducing remission in patients with CD. The study by Feagan, et al evaluated methotrexate as a maintenance therapy in patients whose disease was in remission. Once achieving remission with 25 mg methotrexate once weekly, patients were randomly assigned to receive either 15 mg methotrexate once weekly or placebo for 40 weeks. No other treatments for CD were permitted. The primary endpoint was the proportion of patients remaining in remission (defined as a CDAI score of 150 or less) at week 40. Although the number of patients maintaining remission declined over the course of the study, at week 40 a significantly greater proportion of patients in the methotrexate group (65%) were in remission compared with those receiving placebo (39%; P=0.04). Reference Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med. 2000;342:1627-1632. Placebo 40 30 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.

Side effects of Methotrexate Common & mild Uncommon Rare Nausea Abdominal pain Leukopenia Abnormal LFT Fatigue Headache Vomiting Thrompcytopenia Hair loss Stomatitis Fever Dizziness Anorexia pneumonitis

Infliximab Inflammatory CD

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

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

Targan SR et al. N Engl J Med. 1997;337:1029-1035 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

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

Infliximab Fistulizing CD

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

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

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

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

From Trial to Clinic How Has Practice Changed?

Previous Drug Exposure Disease Duration (Years) 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 8 9 10 11 12 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.

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 8 9 10 11 12 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.

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 8 9 10 11 12 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.

Top-down therapy works Previous Drug Exposure Disease Duration (Years) 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 8 9 10 11 12 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.

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 8 9 10 11 12 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.

Adalimumab

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

Percentage of Subjects 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 * 60 n=74 n=74 n=75 n=76 * 57.9 * 54.7 * 52.7 50 48.7 * 40 37.3 35.5 33.8 32.4 Percentage of Subjects 30 24.0 24.3 20 17.6 12.2 10 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).

Rapid and Significant Δ 70 Response Rates With All doses of HUMIRA 80 Placebo 70 40/20 mg # 80/40 mg ** ‡ 60 † 160/80 mg 50 * Patients achieving 40 70-point response (%) 30 20 10 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

Significant Rates of Remission with adalimumab treatment Placebo 160/80 mg Week % of Patients 6 4 7 * 21 30 25 20 15 10 5 Stats table 14.2.1.2.1 run 062906 1 2 3 4 *P<0.001 vs. placebo Full analysis population Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas

What is “Early”? Which “Outcomes”? Disability Health Subclinical Inflammation Symptomatic Inflammation Complications Disease Prevention Prevention of Complications Prevention of Symptomatic Disease Prevention of Relapse

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.

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

Safety Considerations With TNF Inhibitors Infections Lymphoma Antibodies against the compound Infusion/injection site reactions Other Autoimmunity and autoantibodies Demyelination Congestive heart failure (CHF) Hematologic disorders Liver toxicity In clinical trials, the use of all 3 TNF inhibitors was associated with infections requiring treatment. Most infections were minor and were treated with either outpatient antibiotic therapy and/or temporary withdrawal of the drug. Most commonly observed were infections of the urinary and upper respiratory tracts. TNF inhibitors are associated with an increased risk of serious infections compared with the general population, but the rate is similar to RA patients treated with other disease-modifying agents. However, administration of TNF inhibitors has been shown to cause reactivation of TB. Issues relating to the risk of TB reactivation and other infections are discussed in the following slides. Reference Khanna D, McMahon M, Furst DE. Safety of tumour necrosis factor- antagonists. Drug Safe. 2004;27:307-324.

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

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

GCSO 2013 Business Planning Current & Future Landscape : Biologic IBD market map 1998–2018 paediatric CD Pfizer launch tofacitinib (JAK-3) for UC Humira launch for UC Abbott launch Humira in CD (US and EU) Takeda launch vedolizumab IV for CD UCB launch Cimzia for CD (US) Takeda launch vedolizumab IV for UC Launch of infliximab biosimilars 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Simponi launch for UC Remicade ulcerative colitis launch Janssen (JAK-3) for UC 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 26 June 2012 GCSO 2013 Business Planning

Looking to The Future