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Stephen B. Hanauer, MD University of Chicago Medicine

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. Conflicts of Interest. Abbott Janssen UCB Prometheus. What I want for Hanukkah/Christmas.

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Stephen B. Hanauer, MD University of Chicago Medicine

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  1. 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

  2. Conflicts of Interest • Abbott • Janssen • UCB • Prometheus

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

  4. 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

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

  6. Factors Affecting the Pharmacokinetics of Monoclonal Antibodies Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012

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

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

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

  10. ACT 1+2: Proportion of Patients with Ulcerative Colitis Treated with Infliximab Achieving Clinical Remission by Serum Infliximab Concentration Reinish W, Sandborn WJ et al., Digestive Disease Week 2012; Abstract # 566

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

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

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

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

  15. Clinical Utility of Measuring IFX and HACA Levels in Patients with IBD Clinical outcomes in patients with detectable HACA (N = 35)* Clinical outcomes in patients with sub-therapeutic concentrations (N = 69)* P<0.016 P<0.004 Complete / Partial Response (%) Complete / Partial Response (%) * 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 Afif W, et al. Am J Gastroenterol 2010 May;105(5):1133-9.

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

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

  18. 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 Lukas M, et al. DDW 2011. Abstract Mo1239.

  19. Anti-TNF Therapy for CD: Dose Escalation and Early Discontinuation *Patients on combined IS therapy were less likely to stop therapy at 1 yr. Naik AS et al. Gastroenterology 2009;136(Suppl 1):A-654.

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

  21. 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 Patients with sustained clinical response without dose escalation Karmaris Gastro 2009;137:1628–1640

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

  23. 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 Lukas M, et al. DDW 2011. Abstract Mo1239.

  24. WE NEED A COST-EFFECTIVE BIOMARKER FOR MUCOSAL HEALING

  25. Correlations Between hsCRP, IL-6, Fecal Markers, CDAI, and Endoscopic Activity in Crohn’s Disease (N=164) 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.

  26. Use of fecal calprotectin as marker of disease activity in patients under maintenance treatment with infliximab for ulcerative colitis • 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 • Activedisease = clinicalMayoscoreorendoscopicscore >2 at wek52 • median FC < 50 mg/kg at all measured time points. % of Patients # of Patients 25 • Median FC 477 mg/kg. Increase in FC observed already 3mo before. Two consecutive FC measurements >300 mg/kg predicted flare 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. De Vos et al. ECCO 2012, abstract OP 07

  27. 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. P = 0.001 P = 0.07 • 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 de Suray, et al. ECCO 2012, abstract P274

  28. 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   Langhorst J., et al. ECCO 2012. Abstract P095.

  29. 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. Langhorst J., et al. ECCO 2012. Abstract P095.

  30. Calprotectin and Disease Activity Lewis JD. Gastroenterology 2011;13:

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

  32. Calprotectin to Predict Relapse * NPV 100% at 12 weeks Lewis JD. Gastroenterology 2011;13

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

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

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