Future comparative effectiveness studies: unanswered questions in the care of IBD patients Jean-Frédéric Colombel Icahn School of Medicine at Mount Sinai New York, USA

Disclosure J-F Colombel has served as consultant, advisory board member or speaker for or received research grants from Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssend and Janssen, Merck & Co., Millenium Pharmaceuticals Inc., Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Sanofi, Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co.

What is comparative effectiveness research (CER) ? The generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to ‘‘assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.’’ Two key elements are 1) the direct comparison of effective interventions 2) The application of these interventions in patients who are typical of day-to-day clinical practice Ratner R , et al. In: Medicine Io.ed Washington DC 2009; Sox HC, et al. Ann Interm Med 2009.

Why do we need CER in IBD ? Clinical trials Clinical practice Defined population Prescribed treatment regimen Follow-up regimented with schedule Uniform primary end-point Efficacy Heterogeneous population Variable treatment regimen with optimization Follow-up not fixed Variable outcomes Effectiveness

Clinical trial IBD population versus real-world IBD population Retrospective study of patients with moderate-severe IBD at a US tertiary referral centre (n=206) 31% of patients were not eligible for participation in a clinical trial of biologic therapy* Reasons for exclusion in CD Strictures or abscesses (62%) Recent exposure or nonresponse to anti-TNF (51%) High-dose steroids (18%) Comorbidities (26%) Reasons for exclusion in UC Current rectal therapy use (57%) Steroid and immunomodulator naive (45%) Newly diagnosed (17%) Colectomy likely (15%) Non-eligible CD patients had a significantly lower response rate to biologics than eligible CD patients (60% vs 89%, p=0.03) *Inclusion criteria based on those published for 9 trials of biologic therapy: ACCENT I, CLASSIC I, CHARM, PRECISE I, ENCORE, ENACT, SONIC, ACT 1, ACT 2 Ha C, et al. Clin Gastroenterol Hepatol 2012.

Patients with CRP 0.8 mg/dL and Lesions on Baseline Endoscopy* The impact of CE studies: SONIC: Corticosteroid-Free Clinical Remission at Week 50 Patients with CRP 0.8 mg/dL and Lesions on Baseline Endoscopy* 100 P=.002 80 P=.016 P=.354 60 50.0 Percent of patients (%) 41.5 40 22.7 20 17/75 27/65 32/64 AZA+ placebo IFX + placebo IFX + AZA * Patients who did not enter the study extension were treated as nonresponders AZA=azathioprine; IFX=infliximab Colombel JF, et al. N Engl J Med. 2010

Setting priorities for CER in IBD: results of an international provider survey, expert rand panel, and patient focus groups Cheifetz AS , et al. Inflam Bowel Dis 2012.

Unanswered questions… Flying Take-off Landing

Unanswered questions… Take-off

Which biologic ?

Comparing biologics agents in IBD IFX CZ ADA The anti-TNFs family

Outcomes in CD patients receiving adalimumab or infliximab therapy Retrospective cohort of US Medicare data (2006–2010) from new users of adalimumab (n=871) and infliximab (n=1,459) Primary outcomes at Week 26 Adalimumab Infliximab Persistence (%) 47 49 OR 0.98, 95% CI 0.81-1.19 Surgery 6.9 5.5 HR 0.79, 95% CI 0.60-1.05 Hospitalisations 15.4 11.8 HR 0.88, 95% CI 0.72-1.07 Primary outcomes according to baseline steroid exposure Adalimumab Infliximab Surgery Steroids 7.2 5.6 HR 0.77, 95% CI 0.51-1.14 No steroids 6.5 5.3 HR 0.82, 95% CI 0.55-1.23 Hospitalisations 17.3 13.1 HR 0.86, 95% CI 0.65-1.12 13.5 10.7 HR 0.90, 95% CI 0.67-1.20 Osterman M, et al. Clin Gastroenterol Hepatol 2013

Vedolizumab in UC: Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population % P=0.0010 21.7 11.6, 31.7 11.5 4.7, 18.3 16.1 6.4, 25.9 95% CI: Feagan B et al New Engl J Med 2013

Comparing biologics agents in IBD Anti- TNFs Anti- Integrins IFX ADA CZ “The key research topic in the area of IBD from the US Institute of Medicine (IOM) report is to compare the effectiveness of competing biologic agents”

Biologic vs surgery ?

The LIRIC -trial

Combo vs mono ?

Steroid-free Remission at Week 26 SONIC Primary End Point 100 P<0.001 80 P=0.009 P=0.022 57 60 Proportion of Patients (%) 44 40 31 20 52/170 75/169 96/169 AZA + Placebo IFX + Placebo IFX+ AZA Steroid-free remission=CDAI <150 points Colombel JF et al. N Engl J Med 2010 18

Impact of concomitant immunomodulator treatment on efficacy and safety of anti-TNF therapy in Crohn’s disease: a meta-analysis of placebo-controlled trials using patient-level data Results: 6 Month Clinical Remission Stratified by anti-TNF agent Adalimumab Certolizumab Infliximab OR 0.88 (0.58-1.35) OR 0.93; (0.65-1.34) OR 1.79 (1.06-3.01) Jones J et al. DDW 2013

Methotrexate with IFX vs IFX alone in CD COMMIT Methotrexate with IFX vs IFX alone in CD Primary end-point: Failure to enter steroid-free remission at week 14 or maintain through week 50 P = 0.83 Highest success rate ever observed At week 14 and 50 there was between the IFX group vs IFX+MTX group All patients on prednisone 15 to 40mg/d P = 0.86 Steroid-free remission MTX Placebo Week 14 Week 50 Feagan B et al. Gastroenterology in press

Step-up vs Accelerated step-up vs Top-down ?

Conventional and evolving treatment strategies in CD Ordás I et al. Gut 2011

Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy RAPID AZTEC Cosnes J et al. Gastroenterology 2013;145: 758-65 Panes J et al. Gastroenterology 2013;145: 766-74

CDAI <150 AND no steroids AND no surgery Early top-down biologic therapy vs conventional management of Crohn’s disease CDAI <150 AND no steroids AND no surgery Patients (%) ** * * Weeks *p<0.01 **p<0.05 D’Haens G, et al. Lancet 2008;371:660-7.

Usual care vs accelerated care : REACT 1 20 practices (1,200 pts) 20 practices (1,200 pts) 60 patients per practice Accelerated care treatment algorithm Usual care Treatment of common diseases such as hypertension and dyslipidemia requires a multidisciplinary approach that includes lifestyle modification in addition to medical therapy. Our challenge as physicians is to identify patients who are at high cardiovascular (CV) risk and prescribe an appropriate treatment program. By performing risk assessment in every patient, we can help to recognize these diseases and treat them effectively to reduce the incidence of heart disease. Therapeutic noncompliance is a common behavior that leads to ineffective treatment and, subsequently, increased health care costs and decreased cost-effectiveness of interventions. Primary endpoint: Proportion in remission (HBI 4 and off steroids) at practice level 12 mo following randomization Patients will be bio-naïve 25 25

Accelerated care therapeutic algorithm for Crohn’s disease 5-ASA Antibiotics Active luminal CD (HBI >4) Without fistula With fistula Steroids (budes vs pred based on disease activity and location) Complex fistula Evaluate in 4 wks – remission? (HBI ≤4) Yes No Yes No MRI, US, EUA to rule out abscess Antibiotics/ fistulotomy Taper steroids Add ADA + AZA or MTX Re-evaluate in 12 wks – remission? Abscess present? Yes No Taper steroids, re-evaluate in 12 wks – remission? Yes No No maintenance therapy ADA + AZA or MTX (steroids prn) Drainage/seton + antibiotics Re-evaluate in 12 wks – remission? Re-evaluate in 4 wks – improved? Yes No Cont combo maint Rx Increase ADA to weekly dose No Re-evaluate in 12 wks – remission? Yes Surgical reassessment Yes No Cont combo maint Rx Switch anti-metabolite Follow algorithm for active luminal CD without fistula Re-evaluate in 12 wks – remission? Yes No Cont combo maint Rx Switch TNF-blocker Re-evaluate in 12 wks – remission? Yes No Cont combo maint Rx Consider resection

Unanswered questions… Flying

Treat to mucosal healing vs treat to symptoms ?

Enhanced care treatment algorithm Step care treatment algorithm Usual care vs enhanced care : REACT 2 15 practices (600 pts) 15 practices (600 pts) 40 patients per practice Enhanced care treatment algorithm Step care treatment algorithm Treatment of common diseases such as hypertension and dyslipidemia requires a multidisciplinary approach that includes lifestyle modification in addition to medical therapy. Our challenge as physicians is to identify patients who are at high cardiovascular (CV) risk and prescribe an appropriate treatment program. By performing risk assessment in every patient, we can help to recognize these diseases and treat them effectively to reduce the incidence of heart disease. Therapeutic noncompliance is a common behavior that leads to ineffective treatment and, subsequently, increased health care costs and decreased cost-effectiveness of interventions. Primary endpt: risk of CD-related complications at one-year, measured at the practice level. CD-related complications include (1) CD-related hospitalizations for CD-related surgeries and non-surgical CD events (such as disease flare, bowel obstruction, excluding hospitalization for side effects of study medication), and (2) Bowel damage events not requiring hospitalization (such as symptomatic bowel obstruction, cutaneous fistula, abscess). 29 29

Enhanced care algorithm Active luminal CD (HBI >4, 1 large ulcer) 5-ASA Antibiotics Initiate combination therapy (adalimumab + AZA or MTX) +/- GCS as required Evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS) Yes No Continue combination maintenance therapy Increase adalimumab to weekly dose +/- GCS as required Taper GCS, re-evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS) Yes No Continue combination maintenance therapy Switch antimetabolite, +/- GCS as required Re-evaluate by ileocolonoscopy in 16 wks – remission? (HBI ≤4, no large ulcers, no GCS) Yes No Continue combination maintenance therapy Switch TNF antagonist, +/- GCS as required

Treat to biomarkers vs treat to symptoms ?

Calprotectin monitoring in CD after IFX withdrawal

Usual care vs tight control using biomarkers: CALM Open-label, multicenter study in Europe and Canada Evaluating two treatment algorithms in CD Conventional CDAI, steroid use Primary endpoint: Mucosal healing 48 weeks after randomisation Prednisone up to 8 weeks Patients naïve to immunomodulators and biologic therapy (n=240) Tight control CDAI, steroid use, high-sensitivity CRP, faecal calprotectin Treatment intensification in both arms: 1) No treatment, 2) Adalimumab every other week, 3) Adalimumab weekly, 4) Adalimumab weekly + azathioprine www.clinicaltrial.gov: NCT01235689

Tight control arm R w9 w21 w33 w45 w56 Treatment may change at weeks 9, 21, 33 and 45 based on success criteria at weeks 8, 20, 32 and 44 Y = No change** Y = No change** N = ADA EOW** N = ADA EOW** Y = No change** Y = No change** N = ADA wkly** At week 9, 21, 33 and 45, did subject meet all objective criteria?: – CDAI <150 – HS-CRP <5mg/L – Calprotectin <250 μg/g – Off steroids starting wk 9 Y = No change** Y = No change* N = ADA wkly** N = ADA EOW** Y = No change** N = ADA wkly Y = ADA EOW** N = ADA wkly AZA** Y = No change** N = ADA wkly** Y = No change** N = 120 Prednisone 8 wks N = ADA wkly Y = No change** Y = ADA EOW** N = ADA N = ADA wkly AZA** Y = No change** Flare = CDAI↑ ≥70 from BL and ≥220, pt continues as non-responder * Flare between wks 9 + 21, ADA started ** Flare between evaluation wks, then next option N = ADA wkly** N = ADA wkly** Y = ADA EOW** N = ADA wkly + AZA Y = ADA EOW AZA** N = ADA wkly AZA** R w9 w21 w33 w45 w56

Treat to trough levels vs treat to symptoms ?

Pk of biologics: What we know already Drug levels of IFX and ADA are associated with outcome in Crohn’s disease Antibody status is not directly associated with outcome but is important in understanding reasons for loss of response (LOR) to anti-TNF Dose escalation can increase drug levels Immunomodulation can decrease antibody production Colombel JF, et al. Inflamm Bowel Dis 2012 Date of preparation September 2013 AXHUG130882am

Individualised therapy vs dose intensification in patients with CD who lose response to anti-TNF Randomised, single-blind, multicentre Danish study in CD (n=69) Patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) or interventions based on serum IFX and IFX antibody levels Co-primary economic endpoint in per protocol populations. Data are average treatment per patient IFX intensification 4 8 12 Study week 2 6 10 Cost per patient, € mean Algorithm * *p<0.001 Intention-to-treat Per protocol -50% -25% 0% 25% 50% True difference IFX intensification better Algorithm better Co-primary clinical endpoint in intention-to-treat and per protocol populations. Dashed lines illustrate the predefined non-inferiority margin Steenholdt C , et al. Gut 2013; gutjnl-2013-305279 [ePub ahead of print]

Biologic Naïve Subjects with active luminal CD (N=120) Optimizing anti-TNF based on trough levels vs clinical symptoms: TAILORIX Biologic Naïve Subjects with active luminal CD (N=120) Ileocolonoscopy at screening Cohort 1 n=40 Cohort 2 n=40 Cohort 3 (control) n=40 Visits Week 0 * IFX 5 mg/kg (0,2,6 then every 8 wks) + AZA 2-2.5 mg/kg (if tolerated) Week 2 * Week 6 * Week 12 Ileocolonoscopy/TL Week 14 * 18 Week 22 * Upon Clinical Relapse and/or TL ↓: † -1st time: IFX 7.5 mg/kg -2nd time: IFX 10mg/kg Upon Clinical Relapse and/or TL ↓: † -IFX 10 mg/kg Only upon Elevated CDAI: -IFX 10 mg/kg 26 Week 30 * 34 Week 38 * 42 Week 46 * 50 Week 54 Ileocolonoscopy * Primary endpoint: steroid-free remission between wk22 and wk54 (CDAI < 150) and endoscopic healing at wk54

Unanswered questions… Landing

Discontinuation of Immunomodulator in Stable Remission on Combination Therapy (Infliximab Maintained) No need for early ‘rescue’ IFX: primary endpoint Median IFX levels, Week 8 to Week 104 combined 1.0 100 Cumulative survival p<0.005 IFX trough levels (μg) 0.8 Log Rank (Cox): 0.735; Breslow: 0.906 0.6 10 0.4 Continued Discontinued 0.2 1 0.0 20 40 60 80 100 Continued Discontinued Time (weeks) 80 patients randomized to continue (+CON , n=40) or to interrupt (++DIS, n=40) immunomodulators (azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV) Van Asche et al, Gastroenterology 2008

Discontinuation of Infliximab in Stable Remission on Combination Therapy (azathioprine maintained) STORI n=52 relapses/115 patients Median follow-up 28+/- 2 months Median time to relapse: 16.4 months Louis E et al. Gastroenterology. 2012;142:63-70.

Predictive Model for Time to Relapse After Stopping IFX and Continuing AZA Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method Deleterious factors: No previous surgery Steroids within 12-6 months before infliximab withdrawal Male gender Hemoglobin ≤14.5 g/dL, Leukocyte count >6x109/L, hsCRP ≥5 mg/L, Fecal calprotectin ≥300 µg/g, CDEIS>0 infliximab trough ≥2 mg/L 0.0 0.4 0.6 0.2 0.8 1.0 6 12 18 24 30 Months since infliximab withdrawal No. deleterious factors <4 4 5-6 >6 Proportion Without Relapse Louis E et al. Gastroenterology. 2012;142:63-70.

A proSpective randomized controlled trial comParing infliximAb-antimetabolites combination therapy to anti-metabolites monotheRapy and infliximab monothErapy in patients with Crohn’s disease in sustained steroid-free remission on combination therapy SPARE CCFA Nycibdc

Screening Randomisation Relapse No remission Study end Scheduled Crohn’s disease patients in steroid-free remission for 6 months and treated with infliximab and anti-metabolites combination therapy for at least 1 year, infliximab being given at 5 mg/Kg /8 weeks for at least 6 months Continuing the combination therapy at the same dosage Intensification of infliximab at 10 mg/Kg/8 weeks Judged as failure per protocol. Managment at the discretion of the investigator Discontinuing infliximab and continuing the anti-metabolite at the same dosage infliximab 5 mg/Kg infusion. If no remission at 4 weeks, reinfusion at 10 mg/Kg If further relapse beyond one year, the same treatment regimen is applied If further relapse within 1 year, the same retreatment regimen is applied and a scheduled treatment with 5 mg/Kg or 10 mg/Kg depending how the remission was recovered, is applied like in group one Discontinuing anti-metabolites and continuing infliximab at the same dosage Infliximab intensification like in first arm. If no remission, anti-metabolite is restarted Colonoscopy Small bowel MRI * * Scheduled visits -3 0 8 16 24 32 40 48 56 64 72 80 88 96 104 Timeline (weeks)

Comparative effectiveness research in IBD A huge opportunity Formidable challenges design recruitment funding …