Rahul A. Nathwani, MD, FACG 7th Middle East Gastroenterology and Hepatology Conference April 13th, 2012 “Crohns disease: Are new Rx guideline algorithms applicable to patients from our area ?” Rahul A. Nathwani, MD, FACG American Board Certified in Internal Medicine American Board Certified in Gastroenterology Consultant Gastroenterologist & Hepatologist Dubai Healthcare City

Evolution of Therapeutic Goals 10 years ago… What has changed today Symptomatic remission Improve quality of life Induction use then treat on flare Reduce steroid use Timely drug intervention Long-term sustainability (scheduled maintenance) Maintain steroid-free remission Complete mucosal healing Reduction in long-term implications of chronic disease Deep remission #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 68/72 Golimumab-Specific Deck: No

Predictors of Disabling CD Steroid Requirement Age <40 Perianal Disease 1 2 3 4 5 Independent factors at diagnosis Odds ratio 2.1 1.8 3.1 P=0.0004 P=0.01 P=0.0001 Retrospective derivation cohort 1123 patients Prospective validation cohort 302 patients Definition disabling (any) ≥2 steroid courses Steroid dependence Hospitalisation Chronic (>12 mo) symptoms Need immunosuppressants Need surgery Beaugerie & cols, took a different approach to identify at diagnosis factors predictive of a subsequent 5-year disabling course The authors defined “disabling disease” as the presence of at least 1 of the criteria of clinical severity was present. The estimate the prevalence of disabling disease they limited the analysis to a retrospective group of 262 individuals diagnosed and followed in their unit. In these patients the estimation bases on a best and worse scenario of disabling disease in patients LTFU was 64.9-80.5%. Among the 1123 patients with follow-up data allowing full 5-year course classification, the rate of disabling disease was 85.2%. Independent factors resent at diagnosis and significantly associated with subsequent 5-year disabling were the initial requirement for steroid use (OR 3.1 [95% CI: 2.2– 4.4]), an age below 40 years (OR 2.1 [95% CI: 1.3–3.6]), and the presence of perianal disease (OR 1.8 [95% CI: 1.2–2.8]). The positive predictive value of disabling disease in patients with 2 and 3 predictive factors of disabling disease was 0.91 and 0.93, respectively. These values were 0.84 and 0.91, respectively, when tested prospectively in an independent group of 302 consecutive patients seen at our institution from 1998. However, these values have to be put into perspective relative to the proportion of patients with disabling disease. In the derivation cohort prevalence of disabling disease was 85%. Therefore, tossing a coin would have a predictive value of .85, and the prevalence of disabling disease in the validation cohort is not clarified in the manuscript. #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 21/72 Golimumab-Specific Deck: No Beaugerie L, et al. Gastroenterology. 2006;130:650-656.

More Than 2 Risk Factors Predict a Disabling Disease Course in CD Score 0 (0 Factors of Disabling Disease) Score 1 (1 Factor) Score 2 (2 Factors) Score 3 (3 Factors) 100 93 91 90 80 67 70 61 60 51 Percentage (%) 50 40 31 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 22/72 Golimumab-Specific Deck: No 30 20 13 5 10 Distribution Positive Predictive Value N=1123 Beaugerie L, et al. Gastroenterology. 2006;130:650-656.

Patient Case 29-year-old female, lawyer Smoker February 2009 Bloody diarrhea (4–6 liquid stools/day) Weight loss (10%) and abdominal pain (moderate) General well-being: poor No ulceration or fistula on perianal exam Blood tests Haemoglobin 9.7 mg/dL, hematocrit 28% Platelet count 540x106 ESR 63 mm/h, CRP 41 mg/L #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 28/72 Golimumab-Specific Deck: No

Crohn’s Disease (CD) Diagnosis Colonoscopy Aphtous and superficial ulcers in the terminal ileum and whole colon Deep ulcers in the low rectum Histology: Granuloma MRI: 50 cm small Bowel involvement in the terminal ileum #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 29/72 Golimumab-Specific Deck: No

Ileum Sigmoid Transverse colon Rectum 11 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 51/72 Golimumab-Specific Deck: No 11

Risk Factors for Progressive Disease in Luminal CD Terminal ileal location1 Young Smoker2,3 Severe endoscopic lesions8 Lawyer #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 31/72 Golimumab-Specific Deck: No 1Solberg IC, et al. Clin Gastroenterol Hepatol. 2007;5:1430-1438; 2Sutherland LR, et al. Gastroenterology. 1990;98:1123-1128; 3Lindberg E, et al. Gut. 1992;33:779-782; 4Reese GE, et al. Am J Gastroenterol. 2006;101:2410-2422; 5Gearry RB, et al. Inflamm Bowel Dis. 2007;13:1220-1227; 6Armuzzi A, et al. Gut. 2003;52:1133-1139; 7Boirivant M, et al. J Clin Gastroenterol. 1988;10:401-405;8Allez M, et al. Am J Gastroenterol. 2002;97:947-953. 12

Clinical question ? What Rx should this pt receive ? 5 ASA + steroid 5 ASA + steroid + AZA introduced during the 2nd course of steroids Steroid + AZA Biologic therapy

Patient Case (Cont.) Patient treated with oral steroids at the dose of 1 mg/kg/day and AZA 2.5 mg/kg/day Patient was clinically well Blood tests 1 month after: Hb 11.5 mg/L, CRP 0.7 mg/L, ESR 25 mm/h, platelet count 390x106 Steroids tapered (5 mg/week) After 4–5 weeks of steroid discontinuation, disease relapsed Again diarrhea, blood, abdominal pain #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 36/72 Golimumab-Specific Deck: No

Patient Case (Cont.) Anti-TNF therapy started AZA continued Symptom-free after 4 weeks Blood tests: Hb 12.5 mg/L, CRP 0.3 mg/L At the moment in steroid-free remission #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 43/72 Golimumab-Specific Deck: No

Endoscopy: Complete Mucosal Healing Patient Case (Cont.) Endoscopy: Complete Mucosal Healing #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 44/72 Golimumab-Specific Deck: No

The Evolution of Therapy: Toward Optimal Treatment of CD Sequential step-up approach Accelerated step-up approach 5-ASA Antibiotics Prednisone Anti-TNF Surgery AZA/6-MP Budesonide MTX Prednisone Budesonide MTX Anti-TNF and AZA/6-MP Surgery? 17

Limitations for Conventional Therapy Steroids Complications of prolonged steroid exposure Relapse off steroids is high and will require maintenance treatment (immunosuppressant) Azathioprine (AZA) Slow onset of action of AZA may preclude its use for active disease1 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 33/72 Golimumab-Specific Deck: No 1Dignass A, et al. J Crohn’s Colitis. 2010;4:28-62.

The Evolution of Therapy: Accelerating Steps in CD Treatment Disability Complications Anti-TNF Infliximab or adalimumab Disease Progression MTX Disease Control Prednisone Budesonide and AZA/6-MP 19

Advancing Outcomes in CD 5-ASA Antibiotics Prednisone Anti-TNF Surgery AZA/6-MP Budesonide MTX Evolving approach Classical approach Panaccione R, et al. Aliment Pharmacol Ther. 2008;28 :674-688.

Step Up vs Top Down Therapy D’Haens etal. Lancet 2008;371:660-667

Clinical Remission Without Corticosteroids at Week 26 SONIC Clinical Remission Without Corticosteroids at Week 26 Primary End Point 100 P<0.001 80 P=0.009 P=0.022 56.8 60 Proportion of Patients (%) 44.4 40 30.6 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########## Presentation updated on Tuesday, 2 March, 2010 by SILE ########## ########## Presentation updated on Friday, 20 February, 2009 by WEBO ########## ########### Presentation updated on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 55/72 Golimumab-Specific Deck: No ########### Presentation 'SONIC ACGabstract Deck_10OCT2008 .ppt' created on Friday, 10 October, 2008 ########### Author: MedAdv QC&C: 10-Oct-08 Review By: 10-Mar-09 Medical Review: No Slide: 10/15 20 52/170 75/169 96/169 AZA + placebo IFX + Placebo IFX+ AZA Colombel JF, et al. J Crohn’s Colitis. 2009;3(1):S45-46; Data on File. Centocor, Inc.

Mucosal Healing at Week 26 SONIC Mucosal Healing at Week 26 100 Secondary End Point P<0.001 80 P=0.023 P=0.055 60 Proportion of Patients (%) 44 At week 26, more patients experienced complete mucosal healing while receiving infliximab monotherapy (30%; P=0.023) and infliximab-plus-AZA combination therapy (44%; P<0.001) than AZA monotherapy (17%). There was no significant difference between the 2 infliximab groups (P=0.055). Reference Colombel JF, Rutgeerts P, Reinisch W, et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. J Crohn’s Colitis. 2009;3:S45-S46. #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 56/72 Golimumab-Specific Deck: No 40 30 17 20 18/109 28/93 47/107 AZA + Placebo IFX + Placebo IFX + AZA Colombel JF, et al. J Crohn’s Colitis. 2009;3:S45-S46; Data on file. Centocor, Inc.

Natural Course of Crohns Disease Effective therapy Loss of bowel function

Evidence-based CD Treatment Algorithm Surgical interventions Anti-TNF+ AZA/ 6-MP AND/OR Complex Fistulising Disease After 6-12 months with stable remission†, stepping down to Anti_TNF monotherapy may be an option for some patients Delayed (> 6 months) Remission Taper to AZA monotherapy Relapse Early (<6 months) Steroids Plus AZA/6-MP No Remission CD Diagnosis Anti-TNF+/- AZA/6-MP Luminal CD with Risk Factors Risk factors can include: Smoker Extensive disease (>40cm ileal disease) Deep ulcerations Systemically unwell (hemoglobin, albumin, Weight loss) High “gut” damage (multiple surgeries [≥2]) Steroid dependence Disease location (gastro duodenal, rectal, perianal) Elevated CRP Serological markers #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 46/72 Golimumab-Specific Deck: No Luminal CD † Normal CRP, steroid-free clinical remission with mucosal healing.

Evidence-based CD Treatment Algorithm IFX Evidence-based CD Treatment Algorithm Evidence-based CD Treatment Algorithm IFX + AZA/ 6-MP AND/OR Complex Fistulising Disease Surgical interventions No Remission After 6-12 months with stable remission, stepping down to Anti-TNF monotherapy may be an option for some patients Anti-TNF +/- AZA/6 MP Risk factors can include: Smoker Extensive disease (>40cm ileal disease) Deep ulcerations Systemically unwell (hemoglobin, albumin, Weight loss) High “gut” damage (multiple surgeries [≥2]) Steroid dependence Disease location (gastro duodenal, rectal, perianal) Elevated CRP Serological markers #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 47/72 Golimumab-Specific Deck: No † Normal CRP, steroid-free clinical remission with mucosal healing. †Normal CRP, steroid-free clinical remission with mucosal healing. 28

Evidence-based CD Treatment Algorithm Surgical interventions Anti-TNF + AZA/ 6-MP AND/OR Complex Fistulising Disease CD Diagnosis Luminal CD With Risk Factors* Risk factors can include: Smoker Extensive disease (>40cm ileal disease) Deep ulcerations Systemically unwell (hemoglobin, albumin, Weight loss) High “gut” damage (multiple surgeries [≥2]) Steroid dependence Disease location (gastro duodenal, rectal, perianal) Elevated CRP Serological markers #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 24/72 Golimumab-Specific Deck: No Luminal CD

IFX Evidence-based CD Treatment Algorithm Complex Fistulising Disease Surgical interventions Ant-TNF+ AZA/ 6-MP AND/OR Anti-TNF + AZA/6MP And/or Surgical ___interventions CD Diagnosis Luminal CD with Risk Factors* Risk factors can include: Smoker Extensive disease (>40cm ileal disease) Deep ulcerations Systemically unwell (hemoglobin, albumin, Weight loss) High “gut” damage (multiple surgeries [≥2]) Steroid dependence Disease location (gastro duodenal, rectal, perianal) Elevated CRP Serological markers #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 25/72 Golimumab-Specific Deck: No Luminal CD 30

Fistula Response at Week 54 ACCENT II Fistula Response at Week 54 Responders P=0.001 P=0.009 23/98 42/91 19/98 33/91 Sands BE, et al. N Engl J Med. 2004; 350: 876-885.

Effect of Infliximab on Hospitalisations in Fistulising CD ACCENT II Effect of Infliximab on Hospitalisations in Fistulising CD Responders Proportion of patients hospitalised P<0.05 P<0.05 Page 865, Figure 3 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 18/72 Golimumab-Specific Deck: No All Randomised Patients Week 14 Responders Lichtenstein GR, et al. Gastroenterology. 2005;128:862-869.

Effect of Infliximab on Surgeries in Fistulising CD ACCENT II Effect of Infliximab on Surgeries in Fistulising CD Responders Most frequent surgeries Resection of the bowel Fistula-related surgeries Ostomy placement or revision Cumulative number of surgeries P<0.05 Page 865, Figure 3 #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 19/72 Golimumab-Specific Deck: No Lichtenstein GR, et al. Gastroenterology. 2005;128:862-869.

Natural history of Crohns disease 80% of Crohns disease patients will require surgery during their lifetime Of these 70% will go on to a further operation

Factors determining applicability to our patients Incidence Diversity of pt population Natural history of the disease Patient compliance Insurance related issues

The global map of inflammatory bowel disease

Factors determining applicability to our patients Incidence Diversity of pt population Natural history of the disease Patient compliance Insurance related issues

Proportion of patients with colectomy through 54 weeks ACT 1 & ACT 2 Proportion of patients with colectomy through 54 weeks p=0.035 Why are the results significant in ACT II only: the proportion of placebo patients who received commercial remicade as a a rescue therapy was higher than that for combined-infliximab patients in ACT 1, but similar in ACT II. This may have counfounded the outcome in ACT 1. There was a strong positivie trend for the 5mg/kg dose. The 5mg and 10mg group separately wre not powered to show a statistically significant difference. The discrepancy in patients receiving commercial Remicade in different subgroups is also important here. n=36/244 n=46/484 Sandborn et al. UEGW 2007 Abstract OP-G-115. Data on file, Centocor

Factors determining applicability to our patients Incidence Diversity of pt population Natural history of the disease Patient compliance Insurance related issues

Summary Treat beyond symptom control to achieve deep remission Risk stratify patients early in disease and identify patients with poor prognosis early Patients with luminal disease + risk factors May benefit from accelerating through the treatment algorithm to receive biologic therapy Consider top hold to biologics Biologic therapy +/- immunomodulator therapy first line for fistulizing disease Early treatment may alter disease progression and lead to improved outcomes #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 45/72 Golimumab-Specific Deck: No

Summary Ileostomy is a protective factor for post-op recurrence Colonoscopy at 12 months is procedure of choice to diagnose post-op recurrence Apthous ulcers in the neo-terminal ileum is the earliest endoscopic lesion predictive of recurrence Risk stratify in post-op setting as well - Metronidazole in all pts for 3 months (if pt can tolerate) - Immunomodulator therapy is modestly effective - Use biologics for pts at high risk for disease recurrence #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 64/72 Golimumab-Specific Deck: No

Summary Incidence of Crohn’s in the Middle East is low but rapidly increasing Diversity of population, aggressiveness of disease progression, pt compliance and insurance approvals may affect implementation of Rx guidelines in our pts Tailor Rx based on each individual pts disease Emirates Society of Gastroenterology should develop consensus guidelines in keeping with our pts disease spectrum #### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! #### ########### Presentation 'MSD ECCO Symposium slides 2-25-10 FINAL.ppt' created on Tuesday, 2 March, 2010 ########### Author: SILE Purpose: Support for scientific events including MSD clinical observation programs QA: N/A Review By: N/A Review Type: Local MSD Review req'd Slide: 64/72 Golimumab-Specific Deck: No