Treatment Goals. Current Therapeutic Pyramids Crohn s Disease Ulcerative Colitis 11/14/10

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1 Current Management of IBD: From Conventional Agents to Biologics Stephen B. Hanauer, M.D. University of Chicago Treatment Goals Induce and maintain response/ remission Prevent complications Improve quality of life Restore and maintain nutrition Limit surgery Current Therapeutic Pyramids Crohn s Disease Ulcerative Colitis Severe Surgery Infliximab Surgery MTX AZA/6-MP Systemic Steroids Moderate Cyclosporine Infliximab Budesonide Antibiotics 5-ASA Mild Systemic Corticosteroids Aminosalicylates 1

2 Conventional approach to managing IBD: step-up Disease severity Aminosalicylates Non-systemic corticosteroids Systemic corticosteroids/ Thiopurines/MTX Anti TNF-α therapies Surgery Time Clinical approach to use mildest form of drug therapy to treat patients first Move to next step in non-responders Step-up management approach Advantages Patients attain remission with less toxic therapies Potentially more toxic therapies reserved for more challenging patients Minimizes risk of adverse events Cost sparing Disadvantages Patients have to earn most effective treatments Decrease in quality-of-life before patients obtain optimal therapy Likelihood of surgery is high Treatments is not targeted to underlying cause of disease Disease is not modified Sequential Therapies for IBD Disease Severity at Presentation Severe Anti-TNF Natalizumab Anti-TNF (UC)/ Thiopurine/MTX (CD) Moderate Corticosteroid Aminosalicylate (UC)/ Thiopurine/MTX (CD) Mild Aminosalicylate Aminosalicylate Induction Maintenance Step-Up according to severity at presentation or failure at prior step 2

3 UC: Conventional Treatment Options Mesalamine (5-ASA)/ sulfasalazine Corticosteroids Azathioprine (AZA) 6-mercaptopurine (6-MP) Cyclosporine (CsA) Oral 5-ASA in UC: Available Clinical Trial Data Different formulations of oral 5-ASA Delayed-release mesalamine Controlled-release mesalamine Multi-matrix release mesalamine Pro-Drugs Balsalazide Olsalazine Sulfasalazine Current clinical trial data difficult to compare Different endpoints Different definitions of response and remission Not all trials assessed endoscopic healing Advantages of 5-ASA 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 et al. Am J Gastroenterol. 2002;97:1398. Sninsky CA et al. Ann Intern Med. 1991;115:350. 3

4 Pearls Re: Conventional Therapies Don t Forget Topical Therapy for UC While oral 5-ASAs are effective in leftsided disease Topical 5-ASA is most effective In distal disease As an adjunct in extensive disease Treatment of Distal UC: Oral and Topical Mesalamine Therapy % of Patients Reporting No Rectal Bleeding Oral (2.4 g/d) Rectal (4 g/d) Combined * * * 0 1 Week 2 Weeks 3 Weeks 6 Weeks *P<.002 vs oral alone, P=.04 vs topical alone. Adapted from Safdi M, et al. Am J Gastroenterol. 1997;92: with permission from Blackwell Publishing. 4

5 Topical 5-ASA as Adjunct in Extensive Disease Heal Thy Rectum! Extensive Mild/Moderate UC: Oral and Rectal Mesalamine Therapy Mesalamine 4 g total PO (in divided doses; 2 g BID) + Mesalamine enema 1 g HS (N=71) Mesalamine 4 g total PO (in divided doses; 2 g BID) + Placebo enema HS (N=56) P= % P= % No. of Patients (%) 44% P=NS 34% P= % 64% 43% 68% Remission Improvement Remission Improvement Week 4 Week 8 Marteau P, et al. Gut. 2005;54: Marteau Gut 54:960-5;2005 There is a dose response for 5- ASA in UC Dose-Response applies to: Moderately Severe Disease Inadequate Response in Mild-Moderate Disease 5

6 Dose Response of Mesalamine: Active Mild to Moderate UC % Remission and Improvement Mesalamine (Asacol ) P < Placebo P < P < g g g g 2 Daily Dose 1. Sninsky CA, et al. Ann Intern Med. 1991;115: Schroeder KW, et al. N Engl J Med. 1987;317: Separating Mild from Moderate UC Ulcerative Colitis: Severity at Presentation Less than 10% Present with Severe Disease 100% 80% 60% 40% 20% 0% Severe Activity (9%) Moderate Activity 71% Mild Activity 20% Disease Activity Hendriksen C, Kreiner S, Binder V. Gut 1985;26:

7 % Patients improved ASCEND II Trial: Treatment Success* at Week 6 Mild UC 1 Moderate UC 2 P = P = NS g 4.8 g 2.4 g 4.8 g Daily Mesalamine (Asacol ) Dose Daily Mesalamine (Asacol ) Dose Response Remission *Treatment success = response + remission. Response defined as improvement in PGA and 1 other clinical assessment with no worsening in any other clinical assessment. Remission defined as PGA and all clinical assessments=0 Am J Gastroenterol. 100: ; Gram 5-ASA for Failures at Low Doses MMX mesalamine is highly effective for inducing remission in 5-ASA-naïve and -maintained patients Patients in remission (%) 5-ASA-naïve patients *** ** Patients in remission (%) Patients with prior oral 5-ASA maintenance therapy * (n=84) (n=94) (n=80) (n=88) (n=80) (n=91) *p<0.05, **p<0.01, ***p<0.001 vs placebo at week 8 Kamm, M. UEGW

8 Corticosteroids in UC Oral Cortisone: Mild-to-Severe Active UC, Clinical Response, and Clinical Remission at 6 Weeks P<.001 P<.001 * *Clinical response defined as improved or clinical remission Clinical remission defined as 1 or 2 stools/d without blood Cortisone dosing: 100 mg/d for 6 weeks (N=38) 100 mg/d for 2-3 weeks followed by mg/d until 6 weeks (N=38) >100 mg/d for 6 weeks (N=17) Truelove SC. Br Med J. 1954;4884:375. Oral Cortisone: Mild-to-Severe Active UC, Mucosal Healing at 6 Weeks P=.02 *Defined as normal or near normal (slight hyperemia or granularity) mucosa Truelove SC. Br Med J. 1954;4884:375. 8

9 Corticosteroids: Short & Long Term Efficacy for UC 1-Month Outcomes* (n=63) Complete Remission 54% (n=34) Partial Remission 30% (n=19) No Response 16% (n=10) 1-Year Outcomes (n=63) Prolonged Response 49% (n=31) Steroid Dependent 22% (n=14) Surgery 29% (n=18) *30 days after initiating corticosteroid therapy Faubion W, et al. Gastroenterology. 2001;121:255. Response Rates to IV Corticosteroids in Meta-Analysis Response Colectom Adults n= %(65-69) 27%(26-29) Pediatrics n=43 63%(48-76) 16%(24-52) Turner Clin Gastro Hep 5;103:07 No Dose-Response >1mg/kg MePrednisolone Turner Clin Gastro Hep 5;103:07 9

10 Steroids are the Tipping Point in UC and CD Need for steroids reflects a more complicated disease course Steroid-dependence Surgery Refractory Disease Steroid-Refractory/Dependency is Rule Rather than Exception Conventional Treatment of UC: Immunomodulators Immunomodulators are effective for maintenance of remission, but not induction Blinded, controlled clinical trial data are limited compared to CD 10

11 AZA Withdrawal in Patients With UC Who Required AZA to Achieve Remission P=.04 N=79 Randomized controlled trial of patients who had been receiving AZA for 6 months Hawthorne AB et al. BMJ. 1992;305:20. AZA vs 5-ASA for Steroid-Dependent, Active UC P=.006 N=72 *Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score 1) plus steroid discontinuation Patients treated with concurrent tapering dose of steroids Ardizzone S et al. Gut. 2006;55: g at breakfast and lunch and 1.6 g at dinner Conventional Treatment: CsA CsA is effective for induction of remission in severe UC CsA has demonstrated little efficacy for maintenance of remission Use is limited due to significant safety concerns 11

12 Intravenous CsA: Severe Active Steroid-Refractory UC P<.001 * N=20 *Lichtiger score <10 points for 2 consecutive days Lichtiger S et al. N Engl J Med. 1994;330:1841. CsA Use in Acute UC: Long-Term Experience 65% 42% 90% Oxford 1996 to patients with severe UC 56 responders to CsA Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79. Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis: Clinical Remission ACT 1 ACT 2 P.003 vs placebo P<.001 vs placebo Rutgeerts P et al. N Engl J Med. 2005;353:

13 Conventional Therapeutic Pyramid for Crohn s disease Surgery Severe Biologics MTX AZA/6-MP Systemic Steroids Moderate Budesonide Antibiotics 5-ASA Mild 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% 100 Probability of Surgical Intervention in CD 80 Probability (%) ±2 SD 0 0 D Years Events (no.) Munkholm P et al. Gastroenterology. 1993;105:

14 60% exposed to IS therapy No Change in Surgery Rates Longitudinal Course of CD Preclinical phase: Subclinical inflammation (immune response and histologic lesions) Early Crohn s disease: Inflammation (clinical, biological, endoscopic, radiologic evidence of disease activity) No fistula, abscess, or stricture Time Peyrin-Biroulet L et al. Gut. 2010;59:141. Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression High Potential Low Potential Cumulative Probability (%) Inflammatory Penetrating Stricturing Patients at risk: Months N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:

15 Rationale for Early Intervention in CD Immunopathology supports concept of early intervention in CD Subgroup analyses of large clinical trials suggests TNFα antagonists may be more effective in patients with disease duration < 1-2 years AEs occur less often in early rheumatoid arthritis patients treated with TNFα antagonists Potential for disease modification to prevent transmural complications (surgery/hospitalization) Peyrin-Biroulet L et al. Gut. 2010;59(2):141. Can we predict patients who will have a progressive course? Clinical Predictors of Risk of Progressive/Aggressive Crohn s Disease at Diagnosis Young age Fistulae Need for steroids Deep ulcerations High serologic titers Smoking 15

16 Predictors of Disabling Disease 5-Years after Diagnosis Age at onset <40 years vs. 40 years; P=.0004 Location of disease small bowel + colon vs. small bowel only; P=.002 Smoking status smoker vs. ex- or non-smoker; P=.09 Perianal lesion at diagnosis yes vs. no; P=.01 Required steroids for first flare yes vs. no; P=.0001 Beaugerie L et al. Gastroenterology. 2006;130: Predictors of Rapid Progression to Surgery Factor Odds Ratio (95% CI) Current smoker 3.09 ( ) Abdominal pain 1.82 ( ) Nausea/vomiting 2.07 ( ) Ileal localization only 2.22 ( ) Oral corticosteroid use in 1 st 6months 3.79 ( ) Sands B et al. Am J Gastroenterol. 2003;98: Prognosis of CD Patients with Severe Ulcerations % Colectomy 6% 18% 8% 42% 31% 62% Years SELs defined as deep ulcerations >10% of mucosal area with at least one colonic segment Risk of colectomy associated with severe endoscopic lesions, high CDAI, absence of immunosuppression SEL=severe endoscopic lesions Allez et al. Am J Gastroenterol.2002;97:

17 Probability of non-progressive CD Antibody Sum and Surgery P<.0001 ab_sum=0 ab_sum=1 ab_sum=2 ab_sum=3 N= 47 N= 189 N= 243 N= Time to surgery (months) Dubinsky MC et al. Clin Gastroentrol Hepatol. 2008;6: What do we mean by top down therapy? Early intervention with immunosuppressive Early intervention with biologic Giving our most effective therapy at diagnosis (combination biologic + IS) % Patients Not Failing Trial Efficacy of AZA as Crohn s Disease Maintenance Therapy After Steroids in Adults * *Remission induced by prednisolone tapered over 12 wk Inclusion: Patients were not steroid dependent Duration of Trial (months) AZA 2.5 mg/kg per d Placebo p= % 7% Candy S, et al. Gut. 1995;37(4):

18 Efficacy of 6-MP as Crohn s Disease Maintenance Therapy After Steroids in Steroid-naïve Children 6-MP 91% Control P< % N=55 At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission. Markowitz J et al. Gastroenterology. 2000;119:895. Early Aggressive Biologic Therapy vs Conventional Management of Crohn s Disease Steroids Steroids + AZA MTX Conventional therapy (n=66) Newly diagnosed, antimetabolite, anti-tnf, or steroid-naïve CD patients (n=133) Early aggressive (n=67) + IFX IFX (0,2,6 weeks) + AZA + (episodic) IFX Steroids D Haens G et al. Lancet. 2008;371: Complete Ulcer Disappearance (Mucosal Healing) 73% P=0.003 % 30% Top- Down Step Up D Haens G et al. Lancet. 2008;371:

19 Infliximab: Endoscopic Healing and Reduced Hospitalizations and Surgeries Rate of Hospitalizations and Surgeries (%) % 25% Hospitalization 8% (34*) (4*) (6*) 0% 0% Surgery 0% Patients with no healing (n=74) Patients with healing at 1 visit (10 or 54 wk) (n=16) Patients with healing at both visits (10 and 54 wk) *Number per 100 patients Rutgeerts P et al. Gastroenterology. 2002;123(suppl):43.M2138. SONIC: Mucosal Healing at Week 26 Primary Endpoint 100 Proportion of Patients (%) P=.023 P< P= /109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA Columbel JF et al. N Engl J Med. 2010;362: Comparison of Infliximab Trials: Immunosuppressive Experienced vs. Naïve Patients: ACCENT I vs. SONIC Clinical Remissions p=ns p<0.02 ACCENT I SONIC 19

20 SONIC: Summary of Adverse Events Through Week 50: All Randomized Patients Patients with 1 AE, n (%) Patients with 1 SAE, n (%) AZA + placebo (n=161) IFX + placebo (n=163) IFX + AZA (n=179) 144 (89.4%) 145 (89.0%) 161 (89.9%) 43 (26.7%) 39 (23.9%) 27 (15.1%) Serious infections 9 (5.6%) 8 (4.9%) 7 (3.9%) TB - 1 patient treated with infliximab and azathioprine Colon cancer - 2 patients treated with azathioprine monotherapy Death - Post colectomy, in a patient treated with azathioprine monotherapy Colombel JF et al. N Engl J Med. 2010;362: Who are the patients who are most at risk for serious infections? Older average age = 63 (systematic review); 67 (Mayo) OR 3.0 (95%CI ) for >50 years vs 24 years Multiple co-morbidities Concomitant steroids and/or narcotics Long-standing disease Young healthy patients are not in the clear, but probably less at risk Siegel et al, Clin Gastroenterol Hepatol 2006; 4: Colombel et al, Gastroenterology 2004; 126: Lichtenstein et al, Clin Gastroenterol Hepatol 2006; 4: Toruner et al, Gastroenterology 2008; 134: Safety of Biologic Therapies Consider risks of underlying condition Lymphoma in RA or IBD Consider risks of concomitant medications Corticosteroids Immune suppressants 20

21 The problem with confounding factors Severity of the disease Age Malnutrition Surgery Leucopenia Concomitant use of other medications When to Introduce Early- Aggressive Therapies? The Tipping Point may be need for Corticosteroids? Corticosteroids: Short & Long Term Efficacy in Crohn s Disease 30-Day Responses (n=74) Complete 58% (n=43) Partial 26% (n=19) None 16% (n=12) 1-Year Responses (n=74)* Prolonged Response 28% (n=21) Steroid Dependent 32% (n=24) Surgery 38% (n=28) Faubion WA Jr., et al. Gastroenterology. 2001;121:

22 Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids Cumulative Probability (%) N= Days Faubion WA Jr et al. Gastroenterology. 2001;121:255. So what are the real issues regarding early aggressive therapies? If biologics cost $1.00 we would not be having these discussions Cost of therapy is the overriding issue for all parties Fear of infections/neoplasia Primarily risk of lymphoma in young patients Fear of running out of options Reserving therapy for refractory patients Conflict Resolution: Does One Size Fit All? NO! 22

23 So What Should We Do Assess prognosis at diagnosis Initiate therapy according to disease severity and risk of progression Steroids are a tipping point for complications and poor prognosis Prepare patients for immune suppression PPD, Chest x-ray, vaccinations Monitor patients for risks Early assessment of disease progression &/or complications Current and Future Therapeutic Paradigms Current Bottom-up approach Conservative use of immunomodulators Goals Induce remission Maintain remission Prevent complications Optimize surgical outcomes Future Initiate therapy ~ to prognosis Early-aggressive therapy if bad prognosis Additional goals Disease modification Mucosal healing Pharmacoeconomics Disease prevention! 23