Latest Treatment Updates for Ulcerative Colitis: Evolving Treatment Goals

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1 Latest Treatment Updates for Ulcerative Colitis: Evolving Treatment Goals Stephen Hanauer, MD Professor of Medicine Medical Director, Digestive Disease Center Northwestern Medicine Chicago, Illinois

2 Speaker Disclosure Stephen Hanauer, MD has disclosed that he received research support from AbbVie, Janssen Biotech, Inc. and Takeda Pharmaceuticals International, Inc., U.S. Dr. Hanauer has also served as a consultant for AbbVie, Janssen Biotech, Inc., Salix Pharmaceuticals, Inc. and Takeda Pharmaceuticals International, Inc., U.S.

3 Educational Objectives Describe the current overall approach to managing ulcerative colitis, including current data on the relationship between mucosal healing and longer-term outcomes Identify recent advances in the management of ulcerative colitis

4 Treatment Goals c.2014 Induce and maintain remission Mucosal healing Prevent complications Disease Related Therapy Related Improve quality of life Limit surgery?

5 Evolving Approach to Treating UC Near Future Approach Newer therapies with favorable safety and side effect profiles Individualized therapy based on genetics and physiology Treatment to hard endpoints such as mucosal healing or surrogates of it Disease monitoring to prevent relapse Current Approach Assessment of prognosis Optimization of azathioprine/6-mp (dose or metabolites) Adopt biologic therapy earlier in disease Appreciation for the implications of a healed mucosa 6-MP = 6-mercaptopurine

6 Predictors of Poor Response or Colectomy Low serum albumin ESR >30 mm/h Bandemia Prolonged flare Active infection Hospitalization setting Severe endoscopic lesions Disease duration Stool frequency Percentage of bloody stools Body temperature >37.5 Heart rate >90 bpm Increased CRP Toxic megacolon Low hemoglobin <10.5 g/dl CRP=C-reactive protein. Lindgren SC, et al. Eur J Gastroenterol Hepatol. 1998;10: ; Gonzalez-Lama Y, et al. Hepatogastroenterology. 2008;55: Suzuki Y, et al. Dig Dis Sci. 2006;51: ; Cacheux W, et al. Am J Gastroenterol. 2008;103: Ananthakrishnan AN, et al. Am J Gastroenterol. 2008;103:

7 High-Risk Patients Oxford Index identifies patients with a high risk for colectomy Evaluate CRP concentration Evaluate number of bloody bowel movements Biomarkers to identify high-risk patients Serum albumin concentration Fecal calprotectin concentration Endoscopic disease severity is predictive Residual histopathologic inflammation Oxford Index: >8 stools/day or 3-8/day and CRP >45mg.dL on third day of corticosteroid. Travis SP, et al. Gut. 1996;38: ; Ho GT, et al. Aliment Pharmacol Ther. 2004;19: ; Carbonnel F, et al. Dig Dis Sci. 1994;39: ; Sandborn W, et al. 2010;105(Suppl 1):S438.

8 Mucosal Healing as a Surrogate for Longer Term Outcomes Associated with: Better quality of life Fewer hospitalizations Fewer surgeries Longer time to clinical relapse Reduction in dysplasia/cancer Sands, B. ACG-FDA Workshop 2012

9 Mucosal Healing: ACG Guidelines Newer goals of therapy include the induction and maintenance of mucosal (and histological) healing that are beginning to translate into changing the natural history of CD 1 Mucosal healing, a novel end point in CD associated with improved pharmacoeconomic and quality of life outcomes... 1 [In UC] long-term mucosal healing may reduce the risk of dysplasia and predicts a better long-term outcome 2 1. Lichtenstein GR, et al. Am J Gastroenterol. 2009;104: Kornbluth A, et al. Am J Gastroenterol. 2010;105:

10 Mucosal Healing Can Impact the Need for Surgery (IBSEN Study) Population-based cohort of IBD pts followed in Norway 1 Patients treated with conventional therapies not including biologics 1 Among 495 pts available for analysis, mucosal healing observed at 1 year in 50% (UC) and 38% (CD) 1 In UC, mucosal healing was significantly associated with: less inflammation less corticosteroid treatment 5 years after diagnosis 1 fewer surgeries by 5 years 1 When f/u extended to 10 years: significantly fewer surgeries in patients with mucosal healing at 1 year 2 1. Frøslie KF, et al. Gastroenterology. 2007;133: Solberg IC, et al. Gut. 2008;57(Suppl II):A15. Abstract OP070.

11 Proportion of UC Patients Not Colectomized Impact of Mucosal Damage on Subsequent Colectomy in Ulcerative Colitis Patients without endoscopic activity at 1-year visit Patients with endoscopic activity at 1-year visit Time in Years After 1-Year Visit Patients with compromised mucosa 1 year after diagnosis showed a trend toward more surgeries. Frøslie KF, et al. Gastroenterology. 2007;133:

12 Colectomy-free Survival Rate (%) Mucosal Healing in UC Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: A multicenter experience 48% (30/63 patients) achieved mucosal healing P=0.004 Mucosal Healing Year 1 Year 2 Year 3 No Mucosal Healing By multivariate analysis, mucosal healing was the sole prognostic factor associated colectomy-free survival, with an odds ratio of (95%CI: ) Laharie D., et al. ECCO Abstract P278.

13 Percent of Patients The Majority of IBD Patients in Clinical Remission have Mucosal Inflammation Mucosal Inflammation n=47 n=51 n=51 n= Group A: No signs of inflammation endoscopically Group B: Evidence of inflammation endoscopically and histologically Group C: Evidence of inflammation only histologically 2 Group D: Evidence of inflammation only endoscopically Treatment was not changed after the index endoscopy in 88% (n=92) of patients with inflammation Treatment was more frequently altered in group B than in group C (24% vs. 4%; p=0.004) Two years after the index procedure on follow-up endoscopy, 29% of all patients had endoscopic inflammation, and another 27% had only microscopic inflammation Inflamm Bowel Dis Sep;18(9):

14 Treat-to-target approach has been adopted in other therapy areas Treatment targets Diabetes <7% HbA1c Hypertension BP: 140/90 mmhg (135/80 mmhg for diabetic patients) LDL-cholesterol: 70 mg/dl (to lower incidence of cardiac events) Rheumatoid arthritis Remission Low disease activity Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1 98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28: ; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631 7

15 Potential Wider Implications of a Adopting a Treat-To-Target Approach Treatment algorithms are based on treatment targets e.g. achieve absence of disease activity in 3 6 months in RA Frequent monitoring is recommended so that treatment can be optimised e.g. HbA1c monitoring every 3 months in patients with diabetes Modification of the target for high-risk patient groups e.g. lower blood-pressure target of 130/80 mmhg in patients with both hypertension and type 2 diabetes Risk of tight target in ICU setting Early disease states are recognised e.g. pre-hypertension, pre-diabetes Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1 98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28: ; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631 7

16 Evolving Goals of Therapy for IBD: Sustained Deep Remission Goal Response Clinical Parameters Improved symptoms Outcomes Improved QoL Remission No symptoms Decreased hospitalisation Deep remission No symptoms Normal labs Mucosal Healing Avoidance of surgery Minimal/No disability SUSTAINED QoL=quality of life Modified from Panaccione R. Presented at: European Crohn s and Colitis Organization (ECCO) Fifth Annual Congress. Prague, Czech Republic; February

17 Comparison of Goals Current Symptom control (induce and maintain remission) Improve quality of life Minimize drug toxicity Minimize disease complications Optimize surgical outcomes Future Mucosal healing Disease modification Predictive Biomarkers Molecular/Genetic markers predicting course & therapeutic response Find the cause Eliminate or tolerize to environmental factors

18 Sequential Therapies for Ulcerative Colitis Disease Severity at Presentation Severe Anti-TNF +/IS Cyclosporine (UC) Anti-Integrin Anti-TNF/ Thiopurine Moderate Corticosteroid Aminosalicylate/ Thiopurine Mild Aminosalicylate Oral/Topical/Combo Aminosalicylate Oral/Topical/Combo Induction Maintenance Therapy is stepped up according to severity at presentation or failure at prior step

19 Acute Severe (Inpatient) UC Treatment Algorithm If no or partial response to IV steroids for 3 to 5 days IV cyclosporin OR IV infliximab OR Colectomy with Ileostomy or IPAA No or partial response If response, 6-MP or azathioprine IPPA = ileal pouch-anal anastomosis Green JA, et al. Pract Gastroenterol. 2009;XXXIII(5):11-19.

20 Optimize Treatment Regimens 6-TGN monitoring for patients receiving azathioprine and 6-mercaptopurine Combination therapy with biologics Infliximab concentration and HACA monitoring for patients receiving infliximab Position novel therapies HACA = human antichimeric antibody

21 Association of 6-TGN Levels and IBD Activity: A Meta-Analysis Study Odds Ratio (95% CI) % Weight Goldenberg 2004 Belaiche 2001 Achkar 2004 Cuffari 2001 Gupta 2001 Dubinsky 2000 Overall (95% CI) 1.47 (0.47, 4.62) 1.62 (0.26, 10.23) 3.80 (1.17, 12.39) (3.78, 35.72) 1.65 (0.73, 3.75) 5.07 (2.62, 9.83) 3.27 (1.71, 6.27) 15.8% 8.9% 15.3% 16.1% 20.7% 23.4% Odds Ratio Osterman MT, et al. Gastroenterology. 2006;130(4):

22 6-TGN levels at Time 1 (pmol/8x10 8 RBC) Correlation Between 6-MP/AZA Dose and 6-TGN Concentration Responders Non-responders 6-TGN correlates with dose for responders (P = 0.026), but not nonresponders (P = 0.5) MP/AZA Dose at Time 1 (mg/kg/d) Dubinsky MC, et al. Gastroenterology. 2002;122(4):

23 UC SUCCESS: Corticosteroid-free Remission in Early UC P= % 40% 35% 30% 25% 20% 15% 10% 5% 0% P=0.032 P=0.813 Panaccione R, et al. Gastroenterology. 2014;146(2): AZA Infliximab Combination

24 UC SUCCESS: Mucosal Healing in Early UC P=0.295 P= % 60% P= % 40% 30% 20% 10% 0% AZA Infliximab Combination Panaccione R, et al. Gastroenterology. 2014;146(2):

25 Complete/partial Response Measuring Infliximab and HACA Concentrations in Patients With IBD: Clinical Outcomes 100% 90% 80% 70% 60% ** * 50% 40% 30% 20% 10% Increase infliximab Change anti-tnf **P < *P < % Detectable HACA Subtherapeutic concentration Afif W, et al. Am J Gastroenterol. 2010;105(5):

26 Addressing Anti-TNF Treatment Failure Scheduled vs episodic treatment Concomitant therapy with immunomodulators Increased serum concentrations Reduced ADAs Monitor adherence Confirm lack of inflammation Therapeutic switching or dose escalation Ben-Horin S, et al. Autoimmun Rev. 2014;13(1):24-30; Lichtenstein GR, et al. Gastroenterology. 2005;128: ; Lémann M, et al. Gastroenterology. 2006;130(4): ; Sokol H, et al. Gut. 2010;59(10):

27 Causes of Treatment Failure With Anti-TNF Agents Poor adherence reported in one-third of patients Suboptimal drug concentrations result from pharmacokinetic (PK) differences Weight-based dosing Measure serum concentrations Antidrug antibodies (ADAs) production Concomitant Infection (C. Diff & CMV) Kane Svet al. Adv Ther. 2009;26(10): ; Fasanmade AA, et al. Eur J Clin Pharmacol.2009;65(12): ; Ben-Horin S, et al. Autoimmun Rev. 2014;13(1):24-30; Farrell RJ, et al. Gastroenterology. 2003;124(4):