Standard of Care for the Treatment of Ulcerative Colitis

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1 Standard of Care for the Treatment of Ulcerative Colitis Bruce E. Sands, MD, MS Dr. Burrill B. Crohn Professor of Medicine Chief of the Dr. Henry D. Janowitz Division of Gastroenterology Mount Sinai School of Medicine New York, NY

2 Standard therapies in ulcerative colitis Aminosalicylates Corticosteroids Thiopurines (azathioprine, mercaptopurine) Infliximab Cyclosporine Surgery (especially ileal pouch anal anastomosis)

3 Conventional treatment strategy for UC is sequential Disease Severity Severe Anti-TNF Cyclosporine Surgery Anti-TNF Thiopurine Moderate Corticosteroid Aminosalicylate Thiopurine Aminosalicylate Aminosalicylate Mild Step-Up according to severity or failure at prior step Induction Maintenance Courtesy of Dr. Stephen Hanauer

4 5-ASA agents: platform therapy for UC Sulfasalazine COOH N NHSO 2 N N=N 5-ASA CH Mesalamine Rectal suspension enema/ Suppository/Foam Mesalamine Delayed-release capsules Sulfapyridine 5-ASA 5-ASA Olsalazine ph dependent coating 5-ASA N=N 5-ASA Mesalamine Mesalamine Controlled-release capsules Enteric-coating/pH Balsalazide disodium capsules NaOOC 5-ASA 5-ASA (ABA) inert OH Ethylcellulose microspheres MMX or gastroresistant/extendedrelease technology carrier

5 5-Aminosalicylates for mild to moderate UC Efficacy for induction of response is 50% to 70% Efficacy for induction of remission is 15% to 40% Excellent safety profile Hanauer SB et al. Ann Intern Med. 1996;124:204. Hanauer SB et al. Am J Gastroenterol. 1993;88:1188. Hanauer SB et al. Am J Gastroenterol. 2005;100:2478. Levine DS et al. Am J Gastroenterol. 2002;97:1398. Sninsky CA et al. Ann Intern Med. 1991;115:350.

6 Gastro-resistant/extended release mesalamine in mild to moderate UC Patients in Clinical and Endoscopic Remission at Week 8 (%) Placebo Clinical and endoscopic remission defined as a modified UCDAI score 1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability, 2 and at least a 1-point reduction from baseline in more stringently defined sigmoidoscopy score. 1,2 Kamm g/day in divided doses, 4.8 g/day as a single daily dose Lichtenstein and 4.8 g/day as a single daily dose P=0.01* g/day P<0.001* P=0.007* g/day P=0.009* 29 Delayed-Release Mesalamine *P values represent active treatment vs placebo Kamm MA. Gastroenterology. 2007;132:66. Lichtenstein GR. Clin Gastroenterol Hepatol. 2007;5:95.

7 Oral 5-ASA vs. placebo in UC: Failure to Induce Global/Clinical Remission Sutherland LR, MacDonald JK. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000543

8 Oral 5-ASA vs. placebo in UC: Failure to Maintain Clinical or Endoscopic Remission Sutherland LR, MacDonald JK. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000544

9 Which oral 5-aminosalicylate? Similar in Pharmacokinetics Clinical efficacy Adverse events Different for prodrugs Sulfapyridine Looser stools May differ in cost / insurance adherence

10 Rectal 5-ASA vs. placebo in UC: Symptomatic Improvement Marshall JK, et al. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004115

11 Rectal 5-ASA vs. placebo in UC: Endoscopic Improvement Marshall JK, et al. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004115

12 Oral and Rectal Mesalamine in Distal UC Patients Reporting No Rectal Bleeding (%) Oral (2.4 g/d) Rectal (4 g/d) Combined * 0 6 Weeks *P<0.002 vs oral alone, P=0.04 vs topical alone Adapted from Safdi M et al. Am J Gastroenterol. 1997;92:1867.

13 Oral and Rectal Mesalamine in Extensive Ulcerative Colitis Marteau P, et al. Gut 2005;54:

14 Mortality from a severe attack of ulcerative colitis 40 Mortality (%) * * *Edwards FC and Truelove SC. Gut. 1963;4:299

15 Corticosteroid Therapy in UC Study Disease State Steroid/ Dose Response (%)* Steroid Placebo Truelove 1 (6 weeks) Active Cortisone 100 mg 69 (n=109) 41 (n=101) Lennard-Jones 2 (6 months) Maintenance Prednisone 15 mg 38 (n=32) 40 (n=30) Truelove 3 (5 days) Severely active Prednisolone mg (Total n=49) 73 N/A * Response defined as: Truelove: Patients who improved and/or were in remission Lennard-Jones: Maintenance of remission Truelove: Patients in remission 1. Truelove SC et al. Br Med J. 1955;2: Lennard-Jones JE et al. Lancet. 1965;1: Truelove SC, Jewell DP. Lancet. 1974;1:1067.

16 Corticosteroid Response Rates in UC (Meta-Analysis) Response Colectomy Adults n=1,948 67% (65 69) 27% (26 29) Children n=43 63% (48 76) 16% (24 52) Turner D et al. Clin Gastroenterol Hepatol. 2007;5:103.

17 Corticosteroids: Short- and Long-Term Efficacy for UC 1-month Complete remission Partial remission No response outcomes* 54% 30% 16% (n=63) (n=34) (n=19) (n=10) 1-year outcomes (n=63) Prolonged response 49% (n=31) *30 days after initiating corticosteroid therapy Steroid dependent 22% (n=14) Surgery 29% (n=18) Faubion W et al. Gastroenterology. 2001;121:255.

18 Azathioprine or 6-MP vs. placebo in UC: Failure to maintain remission at 12 months or longer Timmer A, McDonald JWD, MacDonald JK. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000478

19 Azathioprine or 6-MP vs. placebo in UC: Failure to maintain remission at 12 months or longer in successfully induced cases only Timmer A, McDonald JWD, MacDonald JK. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000478

20 Cyclosporine versus Placebo or Steroids in severe UC No induction of remission Need for colectomy Shibolet O, Regushevskaya E, Brezis M, Soares-Weiser K. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD004277

21 Lawson MM,Thomas AG, Akobeng AK. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD Infliximab vs. placebo in UC: Clinical Remission at 8 weeks Endoscopic Remission at 8 weeks

22 Infliximab vs. placebo in UC: Colectomy Lawson MM,Thomas AG,Akobeng AK. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005112

23 Cyclosporine vs. Infliximab in UC Failure rate (%) 100% 80% 60% 40% 20% Difference Cyclosporine vs. Infliximab failure rates: -6% (95%CI: - 25 to 12%) p= % 54% 0% Cyclosporine (n=55) Infliximab (n=56) Laharie D, et al. Gastroenterology. 2011:140(5;Suppl 1):S112.

24 Ileal Pouch Anal Anastomosis Early postoperative small bowel obstruction: up to 15% Pelvic sepsis: up to 20% Small bowel obstruction: up to 30% at 10 years Anastomotic strictures: 8 14% at 10 years) Pouchitis: 50% by 3 4 years Sexual dysfunction Female infertility 3x increased Pouch failure Ordas I, et al. Lancet. Published online Aug 20, 2012

25 Treatment algorithm of UC of various severities Ordas I, et al. Lancet. Published online Aug 20, 2012