2. Controversies and challenges in the clinical care of patients with IBD: You can’t always get what you want! Stephen B. Hanauer, MD University of Chicago Medicine

3. Conflicts of Interest  Abbott  Janssen  UCB  Prometheus

4. What I want for Hanukkah/Christmas  Cost-effective therapeutic drug monitoring for biologics  Ability to dose-adjust biologics  A reliable surrogate for mucosal healing

5. Therapeutic Drug Monitoring Clinical Gastroenterology and Hepatology Volume 10, Issue 10, Pages 1079-1087, October 2012 Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel Disease Ingrid Ordás, Brian G. Feagan, William J. Sandborn

7. Effects of absent blood levels  Disease recurs (or no primary response)  Development of antibodies (immunogenicity)  Secondary loss of response

8. Factors Affecting the Pharmacokinetics of Monoclonal Antibodies IMPACT on PK Presence of ADAsDecreases serum [mAbs] Three fold-increased clearance Worse clinical outcomes Concomitant use of ISReduces formation Increases serum [mAbs] Decreases mAbs clearance Better clinical outcomes High Baseline [TNF-α]May decrease [mAbs] by increasing clearance Low AlbuminIncreases clearance Worse clinical outcomes High Baseline CRPIncreases clearance Body sizeHigh BMI may increase clearance GenderMales have higher clearance Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012

9. Effect of Trough Serum Infliximab Concentrations on Clinical Outcome at >52 Weeks Trough serum infliximab Detectable Undetectable Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54 Patients in remission (%) Patients with endoscopic improvement >75% (%) Patients with complete endoscopic remission (%) Patients with CRP <5 mg/dL (%) 100 0 0 0 0 82 6 88 33 76 32 47 19 p<0.001 p=0.03 p<0.001

10. Lower Adalimumab Trough Levels Results in a Lower Rate of Sustained Clinical Response Karmaris Gastro 2009;137:1628–1640

11. Clinical outcomes in UC patients treated with infliximab correlate with detectable trough levels Seow C H et al. Gut 2010;59:49-54 15 69 28 76 55 7 P< 0.001

12. ACT 1+2: Proportion of Patients with Ulcerative Colitis Treated with Infliximab Achieving Clinical Remission by Serum Infliximab Concentration IFX Conc. (% patients) 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile P -values Week 8 <21.3μg/mL (26.3%) ≥21.3-<33μg/mL (37.9%) ≥33-<47.9 μg/mL (43.9%) >47.9 μg/mL (43.1%) P=0.0504 Week 30 <0.11μg/mL (14.6%) ≥0.11-<2.4 μg/mL (25.5%) ≥2.4-<6.8 μg/mL (59.6%) >6.8 μg/mL (52.1%) P<0.0001 Week 54 <1.4μg/mL (21.1%) ≥1.4-<3.6 μg/mL (55.0%) ≥3.6-<8.1 μg/mL (79.0%) >8.1 μg/mL (60.0%) P=0.0066 Reinish W, Sandborn WJ et al., Digestive Disease Week 2012; Abstract # 566

13. Guidance for Patients Losing Response: Based on mAb Blood Levels and anti- mAbs

14. Positive Anti- mAb change to another anti-TNF agent Increase mAb dose if no response, change to Rx with different mechanism of action (non anti-TNF agent) Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139. Potential Treatment Algorithm Based on Therapeutic Anti-TNF Agent Concentrations

15. Sub-therapeutic mAb concentration Increase mAb dose or frequency change to different anti- TNF agent if no response, change to Rx with different mechanism of action (non anti-TNF agent) If no response, change to different anti-TNF agent Potential Treatment Algorithm Based on Therapeutic Anti-TNF Agent Concentrations Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.

16. * Therapeutic mAb concentration endoscopy/CTE with active disease endoscopy/CTE with inactive disease change to Rx with different mechanism of action (non anti-TNF agent) investigate for alternate etiology of symptoms * Patients should have endoscopic or radiologic imaging Potential Treatment Algorithm Based on Therapeutic Anti-TNF Agent Concentrations Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.

17. Clinical Utility of Measuring IFX and HACA Levels in Patients with IBD * 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed * 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed Clinical outcomes in patients with sub-therapeutic concentrations (N = 69)* Afif W, et al. Am J Gastroenterol 2010 May;105(5):1133-9. Complete / Partial Response (%) P<0.004 Complete / Partial Response (%) P<0.016 Clinical outcomes in patients with detectable HACA (N = 35)*

18. Prospective studies of maintaining trough levels and cost effectiveness in progress

19. What about dose adjustments? Major issue (hassle factor) with 3 rd Party Payors

20. Efficacy of Intensification Regimes: Experience of a Single Referral Centre  Objective:  To evaluate the efficacy of intensification regimes of infliximab (IFX) and adalimumab (ADA) in patients with IBD with regard to therapeutic response and ability to return to normal dosing  Methods:  Retrospective review for intensification of therapeutic regimes of biological therapy in patients with IBD treated in center with IFX or ADA between October 2007 and September 2010 19 Lukas M, et al. DDW 2011. Abstract Mo1239.

21. Anti-TNF Therapy for CD: Dose Escalation and Early Discontinuation Infliximab (n=199)Adalimumab (n=136) Mean disease duration10.9 yrs15 yrs % on combined IS64%93% 1 st anti-TNF used--37.5% Required dose escalation38%39% Required dose escalation by 1 yr 14%32% Predictors for dose escalation  by longer disease duration  by stricturing phenotype;  by prior anti-TNF exposure Stopped therapy by 1 yr*29%13% Reasons for stopping therapy Treatment failure, ADRs/drug allergy Naik AS et al. Gastroenterology 2009;136(Suppl 1):A-654. *Patients on combined IS therapy were less likely to stop therapy at 1 yr.

22. Loss of Response to Adalimumab Dose Increase – CHARM Study 27 % over 1 year Approximately half of these maintain benefit and continue at the increased dose Colombel JF et al. Gastroenterology. 2007;132:52 EMEA website

23. Influence of Trough Adalimumab Serum Levels and AAA on Long-term Outcome in Crohn’s Disease  Study design: Patients with CD were treated adalimumab in a single tertiary center  N=176 patients  Follow-up: Median f/u 2 years  Efficacy  71% response @ 4 wks  67% response @ 12 wks  65.4% (102/156) receiving maintenance therapy required dose escalation at end of f/u period  9.2% of patients developed AAA Karmaris Gastro 2009;137:1628–1640 Patients with sustained clinical response without dose escalation

24. Mann-Whitney: p<0.0001 0.0 5.9 Adalimumab Trough Levels and clinical response to dose escalation Karmaris Gastro 2009;137:1628–1640

25. Efficacy of Intensification Regimes: Experience of a Single Referral Centre  Results:  Conclusions:  Intensification of biological therapy restored clinical response in 54% of therapeutic interventions, with shortening of interval in IFX treatment being the most effective  Approximately in half of the cases the normal dosing regime was possible to restore 24 IFXADA Courses of therapy341111 Intensification47 (14%)14 (13%) Interval ↓33 (70%)100% Dose ↑6 (13%)n/a Both8 (17%)n/a Median time to intervention6 mo (3-21)3 mo (1-7) Response after interval ↓22/33 (67%)5/14 (36%) Return to normal dosing50%40% Lukas M, et al. DDW 2011. Abstract Mo1239.

26. WE NEED A COST-EFFECTIVE BIOMARKER FOR MUCOSAL HEALING 25

27. Correlations Between hsCRP, IL-6, Fecal Markers, CDAI, and Endoscopic Activity in Crohn’s Disease (N=164) IL-6CalprotectinLactoferrinCDAISES-CD hsCRP0.650.470.520.160.46 IL-60.450.550.150.43 Calprotectin0.760.230.45 Lactoferrin0.190.48 CDAI0.15 Correlation coefficients highlighted in red were significant (P < 0.05). When stratified by extent, correlation coefficients were highest for colonic disease. hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin 6; CDAI, = Crohn’s Disease Activity Index; SES-CD, = Simple Endoscopic Score for Crohn's Disease. Jones JL, et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.

28. FC levels highly correlate with disease activity in pts on IFX maintenance therapy for UC. DR is associated with very low levels of FC. A flare is associated with high levels (median >300 mg/kg). Two consecutive cp levels of >300 mg/kg predict a flare. Use of fecal calprotectin as marker of disease activity in patients under maintenance treatment with infliximab for ulcerative colitis De Vos et al. ECCO 2012, abstract OP 07 % of Patients # of Patients N=113 UC patients on IFX 5mg/kg in stable remission with 5mg/kg IFX q8. –Fecal calprotectin (FC) measured monthly for 1 year –Deep remission (DR) = normal endoscopy at BL and wk 52 + Mayo score < 3 –Active disease = clinical Mayo score or endoscopic score >2 at wek52 median FC < 50 mg/kg at all measured time points. Median FC 477 mg/kg. Increase in FC observed already 3mo before. Two consecutive FC measurements >300 mg/kg predicted flare 25

29. CRP > 5mg/l and Calpro >250μg/g were associated with relapse in short term After discontinuation of IFX in CD patients, elevated levels of CRP and calpro were associated with increased risk of short term relapse, even with high variability of markers during follow-up Close monitoring of CRP and fecal calprotectin levels to predict relapse in Crohn's disease patients. A sub-analysis of the STORI study N= 113 CD patients in corticosteroid-free remission for ≥ 6mos on IFX and immunosuppressants (IS). - IFX discontinued, CRP and calprotectin measured every 2 mos through 18 mos or clinical relapse. de Suray, et al. ECCO 2012, abstract P274 P = 0.07 P = 0.001

30. Fecal lactoferrin level is an indicator of mucosal healing  85 pts monitored for the complete 12-months  49 pts experienced sustained remission defined by CAI  44 achieved mucosal healing based on Endoscopy Score 0–1  41 did not show any signs of acute histological activity (Riley Score)  FLA was the only biomarker to show a median level above cut-off for active disease defined by endoscopy as well as histology for pts in sustained clinical remission 29 Langhorst J., et al. ECCO 2012. Abstract P095.

31. Fecal lactoferrin level is an indicator of mucosal healing  Fecal lactoferrin (FLA) level is an indicator of mucosal healing in patients with ulcerative colitis: A prospective 12-month monitoring study  85 pts monitored for the complete 12-months  36 pts suffered a flare  49 pts experienced sustained remission defined by CAI. 30 Langhorst J., et al. ECCO 2012. Abstract P095. FlareRemissionP-value Median FLA levels (µg/g)405<0.0001 Median CRP levels (mg/dl)0.60.1<0.001 Median WBC levels7.66.00.01 Mucosal activityMucosal healingP-value Median FLA levels (µg/g)3750.09 Median CRP levels (mg/dl)0.10.20.882 Median WBC levels6.05.90.787 Histologic activityNo histologic activityP-value Median FLA levels (µg/g)14.44.60.198 Median CRP levels (mg/dl)0.20.10.948 Median WBC levels6.0 0.759

32. AuthorPatient popula tion Assessment endoscopic disease activity Lactoferrin (Sensitivity / Specificity) Calprotectin (Sensitivity / Specificity) CRP (Sensitivity / Specificity) Roseth(2004)CD and UC Farup method 100% / 100% Solem (2005)CDStudy specific index 54% / 75% Siponnen (2008)CDCDEIS77% / 100%87% / 100% Siponnen (2008)CDCDEIS66%-71% / 83%-92% 70%-91% / 44%-92% 48% / 91% Siponnen (2010)CDSES-CD80% / 67%80% / 89% D’Inca (2007)CDSES-CD77% / 80%81% / 80% D’Inca (2007)UCMayo score75% / 60%78% / 70% Schoepfer (2009)UCRachmilewitz Index 86% - 93% / 71% - 88% Schoepfer (2010)CDCDEIS 89% / 58%68%/58% Lewis JD. Gastroenterology 2011;13: Calprotectin and Disease Activity

33. Predictive Value of Calprotectin for Clinical Relapse Tibble JA et al. Gastroenterology 2000:119:15-22

34. Calprotectin to Predict Relapse Author PatientsDuration of remission at entry Elevated Level Relapse Rate with Low Calpro Relapse Rate with High Calpro Gisbert*UC>6 mos.>150μg/g9%31% TibbleUC1-4 mos.>50μg/g10%*85%* TibbleCD1-4 mos.>50μg/g15%85% CostaUC1-12 mos.>150μg/g10%81% CostaCD1-12 mos.>150μg/g57%87% D’IncaUC3-36 mos.>130μg/g30%79% SipponenUC+CD> 3mos (51% >12 months) >100μg/g25%39% WalkiewiczCDNot stated>400μg/g11%56% Lewis JD. Gastroenterology 2011;13 * NPV 100% at 12 weeks

35. Monitoring Inflammation  Can Fecal Calprotectin  detect subclinical inflammation?  predict future flares? Gisbert, IBD 2009; 15: 1190. CD and UC in clinical remission Cutoff of 167 Prediction of future flares

36. You Can’t Always Get What you Want….