Robert N. Baldassano, MD Colman Professor of Pediatrics

1. What do we do when the patient loses their response to an anti-TNF: Minor tweaks or major treatment changes? Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania, Perelman School of Medicine Director, Center for Pediatric IBD The Children's Hospital of Philadelphia

2. What is secondary loss of response ? “(1) an increase in the PCDAI of >15 points from the reference PCDAI at week 10 at 2 consecutive visits at least 7 days apart, or (2) the PCDAI was higher than 30 points at any scheduled or unscheduled visit” (Hyams J, Gastro 2007) Symptoms only “Patients who initially respond to anti-TNF therapy and subsequently lost clinical response…with a rise of >70 points of CDAI” (Allez M, ECCO Workshop, J Crohn Colitis 2010) Symptoms + inflammation “Symptomsplus evidence of inflammation” (Regueiro M, Inflam Bowel Dis 2007) “Withdrawal of infliximab and switch of medical therapy or need for surgery” (de Ridder, Inflam Bowel Dis 2008) “Recurrent symptoms necessitating adalimumab dose escalation” Karmiris K, Gastro 2009 Symptoms + Treatment change

3. Intensification & Discontinuationof anti-TNF at 12 months At 12 months: Dose escalation - 23-46% Drug discontinuation - 5-13% Ben-Horin S, Aliment Pharmacol Ther 2011

4. Cumulative rate of loss of responseover time to anti-TNF treatment(adalimumab) 2/3 of patients who lose response to anti-TNF do so within the first 12 months of therapy Alimentary Pharmacology & TherapeuticsVolume 33, Issue 9, pages 987-995, 2011

5. Managing loss of response: Verify the cause of LOR Is it really inflammatory IBD activity ?

6. Uncontrolled IBD inflammation : (Low drug level) Loss of anti-TNF activity due to anti-drug antibodies Relentless TNF-mediated flare ‘consuming’ all anti-TNF Ab Loss of anti-TNF activity due to non-immune drug clearance Non-adherence to therapy Uncontrolled IBD inflammation: (Adequate drug level) Shift of disease pathway away from TNF to other mediators Non-IBD related inflammation: (Adequate drug level, High CRP) Infection ! Other (vasculitis, ischemia) Non-inflammatory mechanisms (Adequate drug level, Normal CRP) Fibrostenotic strictures Cancer IBS Miscellaneous (Amyloidosis, BOG, Bile salt diarrhea, etc) Possible mechanisms of worsening on anti-TNFs Adapted from Allez M, J Crohn Colitis 2010

7. Possible mechanisms of worsening on anti-TNFs Scope, Scope and Scope… Adapted from Allez M, J Crohn Colitis 2010

8. Managing loss of response: Start with prevention…

9. Scheduled vs. Episodic IFX Matters Maser, EA, et al. ClinGastroenterolHepatol2006;4:124854.

10. IFX Trough Levels are Important Outcomes at 1 year on scheduled infliximab therapy Endoscopic Improvement >75% Clinical Remission CRP < 5 mg/dl * * * P<0.001 P<0.001 P<0.001 % of patients Trough Trough Trough Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.

11. Higher trough levels associated with better response SONIC Trial HYPOTHESIS: Optimizing levels with anti-TNF monotherapy could be an alternate to dual therapy Colombel JF, et al. N Engl J Med. 2010;362:1383-1395

12. P < 0.001 Effect of Infliximab Antibody Concentration on Duration of Response 140 120 100 61 days 80 Days Until Subsequent Infusion 60 40 28 days 20 0 Negative 1.8–8.0 µg/mL 8.0–20.0 µg/mL >20.0 µg/mL Concentration of Antibodies to Infliximab Baert F et al. N Engl J Med. 2003;348:601.

13. Relationship Between ATI Concentration and Infusion Reactions 30 28 26 24 22 20 ATI levels 8.0 µg/mL More likely to experience infusion reactions (relative risk, 3.9; 95% CI 1.3 to 11.7; P = 0.04) 18 16 ATI Level (µg/mL) 14 12 10 8 6 4 2 0 No Infusion Reaction Infusion Reaction Miele E et al. J Pediatr Gastroenterol Nutr. 2004;38:502.

14. Rapid IFX Clearance: Mechanism of Non-response in UC Kevans D, et al. DDW 2012

15. Undetectable Serum IFX Trough Predictiveof Colectomy in UC P<0.001 55% Colectomy (% patients) 17% Seow CH et al, Gut 2010;59:49-54

16. Managing loss of response: Dose intensification

17. Managing loss of response – Dose intensification Dose escalation results in ~60% (short-term??) response At 12 months: Regained response - 50-70% % regained response Ben-Horin S, Aliment Pharmacol Ther 2011

18. How to intensify ? Diverse Protocols Abound InfliximabAdalimumab 5mg/kg/6weeks 40mg/EW 7.5mg/kg/8weeks 80mg/EOW 10mg/kg/8weeks 40mg/10 days 5mg/kg/4weeks Re-induction followed by de-escalation

19. 10mg/kg/8w P=0.2 5mg/kg/4w Double dose (10mg/kg/8w) is at least as effective as interval halving (5mg/kg/4w) in loss of response to Infliximab Katz L, Inflamm Bowel Dis, 2012

20. The therapeuticwindow concept increased toxicity? µg/mL 10 3 loss of efficacy 0 0 2 6 14 22 wks. Nesterov I. J Rheumatol 2005

21. Antibody to IFX Can Be Transient • 90 adult IBD patients • 1,232 serum samples • 59% developed ATI • By study design • ATI was transient in 28% Vande Casteele N et al. Am J Gastroenterol 2013

22. Patients with sustained ATI developed significantly higher ATI levels over time compared with patients with transient ATI. Vande Casteele N, Am J Gastroenterol 2013

23. Dose-intensification must increase IFX trough level to regain response Trough level of Infliximab (μg/ml) Vande Casteele N, Am J Gastroenterol 2013

24. Managing loss of response: Add an immunomodulator (6MP, AZA, MTX)

25. Adding immunomodulator to revert immunogenicity Patient 2 Patient 1 Start MTX Start 6-MP Concentration (mcg/ml) Concentration (mcg/ml) Weeks Weeks 10 20 30 40 50 Weeks 0 10 20 30 40 Patient 4 Patient 3 Start AZA Start AZA Concentration (mcg/ml) Concentration (mcg/ml) Weeks Weeks Weeks 0 10 20 30 40 50 Ben Horin S, Clin Gastroenterol Hepatol 2013 0 10 20 30 40 50 60

26. Predictive Value

27. Infliximab Trough May Predict Sustained Response in Crohn Disease • Retrospective adult cohort 84 patients • IFX trough level measured at 14 or 22 wks • Sustained clinical response • IFX Trough level > 3 μg/ml • Increase in ATI • IFX Trough level < 3 μg/ml Bortlik M et al. J Crohns Colitis 2012

28. IFX Trough Levels • Greatest predictor of IFX failure • Any IFX trough < 0.91 μg/ml • IFX trough <2.2 μg/ml at week 14 predicts • Develop ATI (p<0.0001) • Discontinue IFX for LOR/hypersensitivity (p=0.003) • When escalating therapy • ATI > 9.1 U/mL   risk of failure (LR 3.6) • Patients with success had increase in IFX levels Authors suggest: dose escalation if IFX trough <2.2 at week 14 dose escalation can be attempted with low level ATI Vande Casteele N et al. Am J Gastroenterol 2013; epub ahead of print

29. Proposed Treatment Algorithm Increase infliximab or add IM If persistent disease, change to Rx with different mechanism of action (non- anti-TNF agent) ≤ 9 Positive ATI (detectable antibody) no success > 9 Change to another anti-TNF Change to Rx with different mechanism of action (non- anti-TNF agent) Active disease on Endoscopy/radiology Therapeutic IFX conc (>3 mcg/ml trough level) Inactive disease on Endoscopy/radiology Investigate for alternate etiology of symptoms If persistent disease, change to another anti-TNF Sub-therapeutic IFX (<3 mcg/ml trough level) Increase infliximab and/or add IM Adapted from Afif W et al. Am J Gastroenterol 2010; 105:1133-1139