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Stephen B. Hanauer, MD

Stephen B. Hanauer, MD. Professor of Medicine & Clinical Pharmacology Chief, Gastroenterology University of Chicago. Credentials. Clinician with 6000+ patient database Crohn’s & Colitis Foundation of America Scientific Cabinet, Chair Clinical Research Alliance, Research Initiatives

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Stephen B. Hanauer, MD

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  1. Stephen B. Hanauer, MD Professor of Medicine & Clinical Pharmacology Chief, Gastroenterology University of Chicago

  2. Credentials • Clinician with 6000+ patient database • Crohn’s & Colitis Foundation of America • Scientific Cabinet, Chair Clinical Research Alliance, Research Initiatives • American Gastroenterological Association • Ex-Chair Immunology, Inflammation, IBD Section • Ex-Chair Clinical Practice Section • Chair, Consensus Conference on Biologics (Gastroenterology July 2007) • American College of Gastroenterology • Governing Board • International Organization for Inflammatory Bowel Disease • Chairman • FDA GI Advisory Board • Ex-Chair &Member

  3. Elan/Biogen Consultant & Clinical Research Millenium Consultant Centocor Consultant, Clinical Research, Lectures Abbott Consultant, Clinical Research, Lectures UCB Consultant, Clinical Research Genentech Consultant, Clinical Research BMS Consultant, Clinical Research PDL Consultant, Clinical Research GSK Consultant, Clinical Research Novartis Consultant P&G, Shire, Prometheus Labs, Salix, TAP, Astra Zeneca Consultant, Clinical Resarch, Lectures Conflicts of Interest

  4. Presentation Summary • Crohn’s Disease • Crohn’s Patients • Therapeutic Need • Therapeutic Risks • Likely Prescribers

  5. The Spectrum of IBD1-2 Million Americans ULCERATIVE COLITIS • Continuous inflammation • Colon only • Superficial inflammation • Variable involvement • Risk of cancer • Strictures (cancer) • Extraintestinal manifestations CROHN’S DISEASE • Patchy inflammation • Mouth to anus involvement • Full-thickness inflammation • Variable involvement • Fistulas • Strictures • Extraintestinal manifestations Indeterminate colitis 10-15%

  6. Common Symptoms of Crohn’s Disease • Diarrhea • Abdominal pain and tenderness • Loss of appetite and weight • Fever • Fatigue • Rectal bleeding and anal ulcers • Stunted growth in children

  7. Crohn’s Disease:Colonoscopic Appearance Discrete Ulcer Cobblestone Stricture (Narrowing)

  8. Crohn’s Disease:Intestinal Complications Cancer Perforation Stricture Fistula Abscess

  9. Genetic, Serologic, and Biochemical Profiles: Genetic Markers Serum Immune Markers Cytokine Profile Enzyme Activity Metabolite Levels Individualized “Reagent Grade” Intervention 1 3 2 Traditional Clinical Parameters: + CD UC CD/UC IBD Subtype: 1 4 2 3 4 1 3 2 “Crohn’s Diseases” & “Ulcerative Colitides”:

  10. CD Activity Course Active 25% Clinical Activity 53% 22% Inactive Diagnosis 3 8 Years Munkholm et al. Scand J Gastroenterol. 1995;30:699-706.

  11. Long-term Evolution of Disease Behavior in CD 100 90 Progression Toward Surgery 80 70 60 Penetrating 50 Cumulative Probability (%) 40 Inflammatory 30 Stricturing 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: 95 2002 552 229 37 N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

  12. ± 2 SD Cumulative Probability of Surgical Intervention in CD 100 80 60 Probability (%) 40 20 0 0 Dx 2 5 8 11 14 17 20 Years Events (no.)122 26 15 7 7 4 8 1 8 2 2 2 3 2 1 Munkholm P et al. Gastroenterology. 1993;105:1716.

  13. 100 80 60 Patients With Recurrence (%) 40 Radiologic/endoscopicrecurrence Symptomaticrecurrence 20 0 0 1 2 3 4 5 6 Years Postsurgical Recurrence of CD N=76. McLeod RS, et al. Gastroenterology. 1997;113:1823.

  14. Crohn’s Patients

  15. The Crohn’s Disease Activity Index Liquid stools- 5x7 days=35x2 =70 Abdominal pain-2x7=14=5 =70 Well being-avg 3/d=21x7 =147 Perianal Fistula =20 TOTAL =307 CDAI moderate CD 10 Liquid stools Moderate Pain Abdominal Mass Arthralgias, Weight loss, Anemia= 450 CDAI

  16. Moderate-Severe Non-responders to treatment for mild-moderate disease Fever, significant weight loss Abdominal pain/tenderness Intermittent nausea/vomiting without obstruction Anemia Severe-Fulminant Persistent symptoms despite outpatient oral corticosteroids High fever, persistent vomiting Obstruction, rebound tenderness Muscle mass wasting Abscess Toxic megacolon Fever, distention, frequent bloody bowel movement Definitions of CD Activity Hanauer et al. Am J Gastroenterol. 2001;96:635-643.

  17. SF-36 Scale Scores for Medical Conditions(Standardized Scales) * + Ware JE, JR., Kosinski M. SF-36(r) PHYSICAL AND MENTAL HEALTH SUMMARY SCALES: A MANUAL FOR USERS OF VERSION 1. 2ND ed, Lincoln, RI: QualityMetric Incorporated, 2001. * Baseline ENCORE data +Baseline AFFIRM data

  18. Surgery Anti-TNF MTX AZA/6-MP Systemic Steroids Budesonide Antibiotics 5-ASA Current “Therapeutic Pyramid” Crohn’s Disease Severe Moderate Mild

  19. Clinical Remission Rates in CD Patients with Conventional Therapies • Aminosalicylates • Mild-Moderate Disease ~45-55% • Antibiotics • Few controlled trials • Mild-Moderate Disease ~50% • Budesonide • Mild-Moderate Disease ~65-75% • Corticosteroids • Moderate to Severe Disease~70-80%

  20. Corticosteroids: Short & Long Term Efficacy in Crohn’s Disease None 16% (n=12) Partial 26% (n=19) Complete 58% (n=43) 30-Day Responses (n=74) Steroid Dependent 32% (n=24) Prolonged Response 28% (n=21) Surgery 38% (n=28) 1-Year Responses (n=74)* Faubion WA Jr., et al. Gastroenterology. 2001;121:255-260. *One patient lost to follow-up

  21. Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids 100 80 60 Cumulative Probability (%) 40 20 0 60 0 30 90 182 365 Days N=77 Faubion WA Jr et al. Gastroenterology. 2001;121:255.

  22. Infliximab vs. Placebo in Induction and Maintenance of Remission of CD Gap Remission NNT = 3 NNT = 5 NNT = number needed to treat. Adapted from Bebb JR, et al. Ailment Pharmacol Ther. 2004;20:151-9.

  23. Moon face Acne Ecchymoses Hypertension Hirsutism Petechial bleeding Striae Diabetes Infection Osteonecrosis** Osteoporosis** Myopathy Cataracts Glaucoma Psychosis Corticosteroid ToxicityDose/Duration

  24. Lymphoma Risk in IBD Patients on AZA/6MPMeta-Analysis Study Setting N Obs Exp SIR (95% CI) Kinlen U.K. 321 2 0.16 12.5 (1.2 - 46) Connell London 755 0 0.52 0 Farrell Dublin 238 2 0.05 37.5 (3.5 - 138) Fraser Oxford 626 3 0.65 4.6 (0.9 - 13.7) Korelitz New York 486 3 0.61 4.9 (0.9 - 14.5) Lewis* GPRD 1465 1 0.64 1.6 (0.001 - 9) Pooled 3891 11 2.63 4.2 (2.1 - 7.5) Sensitivity analyses: when papers with highest or lowest SIRs were excluded, results remained significant (range, 3.5 - 5.2) * : population-based study Kandiel et al, Gut 2005

  25. Opportunistic infections and anti-TNF therapies : Ex: from Risk Factors for Opportunistic Infections in IBDA Case-Control Study of 100 Patients (1998-2003) Toruner M, et al. Presented at DDW 2006.

  26. Warning n°2 : Meta-analysis: Risk of Malignancy in RA • Systematic review of pooled data from 9 clinical trials • 3,493 RA patients treated with adalimumab or infliximab compared with 1,512 placebo controls • Malignancy: pooled OR = 3.3 (95% CI: 1.2-9.1) • 11 lymphomas or leukemia • 14 solid tumors • 10 basal or squamous cell carcinomas • The potential risks for these events are reflected in the product labeling for all TNF antagonists Bongartz T, et al. JAMA. 2006

  27. Standard Gamble: Utility Scores in CD >20% life trade-off Gregor JC et al. Inflammatory Bowel Dis.1997;3:265-276; unpublished data. *Median with interquartile range.

  28. Indications & Prescribers • Patients with persisting moderate-severe symptoms with confirmed active inflammation (CRP +/- endoscopy) not responding to conventional & anti-TNF biologics • Prescribers are most likely to be experienced IBD & Tertiary Centers willing to pursue active safety & efficacy monitoring

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