1. Induction and Maintenance Therapies: Lessons from PROTECT Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children's Hospital/Atlantic Health Professor of Pediatrics Icahn School of Medicine at Mount Sinai

2. Disclosures Grant Support: – Abbvie, Astra-Zeneca, Janssen Consultant: – Abbvie, Given, Janssen, Soligenix Honoraria/Speakers’ Bureau – Abbott Nutrition, Abbvie, Prometheus

3. Incidence of IBD is Increasing Dramatically Worldwide Sartor, Nature Clin Prac, 2006 Pathogenesis of IBD

4. GWAS Studies Have Identified over 180 Inflammatory Bowel Disease Susceptibility Loci Lees C W et al. Gut doi:10.1136/gut.2009.

5. EVOLVING CLASSIFICATION (Diabetes as the Model) ULCERATIVE COLITIS Mucosal Continuous CROHNS DISEASE Transmural Discontinuous Oral  Peri-anal Indeterminate Colitis IBD 1IBD 2IBD 3IBD 4IBD5

6. I MMUNE R ESPONSE E NVIRONMENTAL FACTORS T REATMENT G ENETIC S USCEPTIBILITY H OST G ENETICS G ENE E XPRESSION M ICROBIOME S MOKING D IET I NNATE RESPONSE P HARMACOGENOMICS S URGERY B IOLOGICS S TRESS NSAID S A DHERENCE A DAPTIVE RESPONSE IBD patients may have unique signatures that predict complicated or treatment refractory disease F AMILY H ISTORY Large bowelSmall bowel S EROLOGICAL RESPONSE Clinical features: age, location, endoscopy, histology, etc. M ONITORING

7. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient

8. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient

9. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient

10. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient

11. Infliximab Week 2 Responders ACCENT 1 Adalimumab Week 4 Responders CHARM Certolizumab Week 6 Responders PRECiSE 2 Natalizumab Week 10 Responders ENACT-2 Placebo InfliximabAdalimumab Placebo eow Placebo Certolizumab Placebo Natalizumab Patients (%) Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..

12. Infliximab Week 2 Responders ACCENT 1 Adalimumab Week 4 Responders CHARM Certolizumab Week 6 Responders PRECiSE 2 Natalizumab Week 10 Responders ENACT-2 Placebo InfliximabAdalimumab Placebo eow Placebo Certolizumab Placebo Natalizumab Patients (%) Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..

13. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient: – The best combination therapy!

14. IBD: Therapeutic Themes Correct diagnosis! Induction therapies Maintenance therapies “Step in” is better than “step up” Optimization of therapy Treat the whole patient: – The best combination therapy! – Start with how we speak

15. PRO P redicting R esponse t O TEC T S T andardized P E diatric C olitis T herapy 1U01 DK 095745-01

16. Disease Location at Baseline N=379 Enrolled with UC Location Assessed Out of N=379 Macroscopic Disease Microscopic Disease only Cecum343(90.5%)232(67.6%)26(7.6%) Ascending Colon347(91.6%)233(67.1%)35 (10.1%) Transverse Colon354(93.4%)287(81.1%)17(4.8%) Descending Colon371(97.9%)343(92.5%)8(2.2%) Sigmoid376(99.2%)372(98.9%)1(0.3%) Rectum376(99.2%)373(99.2%)3(0.8%)

17. Non-Classical Features at Diagnosis N=379 Enrolled with UC Non-classical Feature% Relative rectal sparing33(8.7%) Macroscopic patchiness35(9.2%) Periappendiceal inflammation27(7.1%) Backwash ileitis28(7.4%) Microscopic gastritis212(55.9%) Non-spec macro gastritis102(26.9%)

19. Initial Therapy By PUCAI: Need to “Right Fit” 2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet. 2 patients had missing data 2 received both Pentasa and steroids at time 0 Baseline PUCAIPentasaOral Steroids IV Steroids Mild (n=90) 78 (87%)9 (10%)2 (2.0%) Moderate (n=164) 48 (29%)81 (49%)30 (18%) Severe (n=119) 2 (2%)33 (28%)81 (68%) n=379

20. Initial Therapy By PUCAI: Need to “Right Fit” 2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet. 2 patients had missing data 2 received both Pentasa and steroids at time 0 Baseline PUCAIPentasaOral Steroids IV Steroids Mild (n=90) 78 (87%)9 (10%)2 (2.0%) Moderate (n=164) 48 (29%)81 (49%)30 (18%) Severe (n=119) 2 (2%)33 (28%)81 (68%) n=379

21. Initial Therapy By PUCAI: Need to “Right Fit” 2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet. 2 patients had missing data 2 received both Pentasa and steroids at time 0 Baseline PUCAIPentasaOral Steroids IV Steroids Mild (n=90) 78 (87%)9 (10%)2 (2.0%) Moderate (n=164) 48 (29%)81 (49%)30 (18%) Severe (n=119) 2 (2%)33 (28%)81 (68%) n=379

22. 24022821620419218016815614413212010896847260483624 12 0 0 10 20 30 40 50 60 70 80 90 100 Cumulative Probability (%) Patients at risk: Months 2002552229 95 37 N = Penetrating Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250. High Potential Low Potential Inflammatory Structuring Impact of Therapy Depends on Degree of Structural Damage and Velocity of Progression Slide Courtesy of the GI Health Foundation

23. Consensus Predictors of Poor Outcome* Deep colonic ulcerations on endoscopy Persistent severe disease despite adequate induction therapy Extensive (pan-enteric) disease Marked growth retardation (> -2.5 height Z scores), Severe osteoporosis Stricturing or penetrating disease (B2 and/or B3 disease behavior) at onset Severe perianal disease *Ruemmele et al. J Crohn’s Colitis ECCO/ESPGHAN Working Group 2014;8:1179

24. Optimizing Outcomes: TREAT TO TARGET: Regular assessment of disease activity using objective clinical and biologic outcome measures Adjust treatment if not accomplishing the goal Enables better outcomes in RA, hypertension, diabetes, hypercholesterolemia Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054

25. LOSS OF RESPONSE TO ANTI-TNF THERAPIES: “GIST” Ben-Horin, Aliment Pharmacol Ther 2011;33:987

26. Strategies to Optimize Durable Biologic Response Regularly scheduled maintenance Concomitant immunomodulator –?duration Monitoring drug/antibody levels –“treat to trough”

27. Proactive Testing in Pediatric IBD: Week 14 IFX Levels and Outcomes Week 54 Outcome (Yes v. No)Median IFX Level (ug/mL) Persistent Remission4.7 versus 2.6* Clinical Remission3.2 versus 2.2 Clinical & Laboratory Remission4.2 versus 3.0 Sustained Durable Remission Week 14 to 54 5.5 versus 3.1* Sustained Durable Remission Week 22 to 54 5.1 versus 3.0* (n=58) * p<0.05 Singh et al. Inflamm Bowl Disease 2014;20:1708

28. IS MUCOSAL HEALING ACHIEVABLE? Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.

29. IS MUCOSAL HEALING ACHIEVABLE? Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85. 67 CD patients underwent 161 endoscopies

30. Summary: Inflammatory Bowel Diseases Chronic intestinal inflammation from a dysregulated immune response to the enteric microbiome in a genetically predisposed host A family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis Accurate diagnosis and staging requires clinical suspicion and appropriate confirmatory testing.

31. Summary: Inflammatory Bowel Diseases Pyramid approach does not change the natural history and disabling outcomes of surgery, hospitalization, lowered QOL. Personalized approach of Risk stratification and “treat to target” are emerging as best practices. Therapeutic drug monitoring and optimization of therapy are critically important goals in the biologic era. Treatment of the whole patient will result in best overall outcomes.

32. Backup Slides

33. RISK Study: The Microbiome shifts in pediatric Crohn’s disease: Decreased diversity, losses and gains Microbiome was profiled in 800 RISK subjects enrolled at 28 pediatric centers in US/CAN 500 cases + 300 controls Gevers et al. Cell Host Micro 2014;15:382

34. The relative goodness of fit of the models, P <0.0043 Clinical variables onlyClinical, expression and microbial C statistics (AUC)0.7050.760 A multi’omic model is superior in predicting surgery and steroid free remission in comparison to clinical factors alone. Multiple regression analysis including clinical, gene expression, and microbial variables. p-valueORCI Age≥10 vs. <10 0.88680.9440.430, 2.075 Ileal DU vs. no DU PCDAI>300.62440.7710.271, 2.188 PCDAI≤300.00294.7131.701, 13.057 Anti-TNF therapy 0.00205.1811.828, 14.706 APOA1 expression level > 80 th percentile0.01523.0581.241, 7.576 Blautia Abundant (>70 th percentile) vs non-abundant Veillonella abundant0.51831.6340.368, 7.25 Veillonella non- abundant 0.00280.2310.089,0.604 Haberman et al JCI 2014 PRO-KIIDS RISK Study

35. 0 20 40 60 80 100 Percent of patients (%) AZA + placeboIFX + placeboIFX+ AZA p<0.001 p=0.025p=0.002 SONIC: Steroid Free Remission 48/17067/16994/169 28.2 39.6 55.6 All Randomized Patients (N=508)* Colombel JF, et al. N Engl J Med 2010; 362:1383

36. Vedolizumab: Primary Maintenance Endpoint For Adult Crohn’s Disease VDZ / VDZ Q8w (n=154) VDZ / VDZ Q4w (n=154) VDZ / Placebo (n=153) p<0.01  =17%  =15% Patients % (95% CI) p<0.001

37. Predictors of Disabling Crohn’s Initial requirement for steroids OR: 3.1 [95% CI: 2.2 – 4.4] Age at diagnosis below 40 OR: 2.1[95% CI: 1.3 – 3.6] Perianal disease at diagnosis OR: 1.8[95% CI: 1.2 – 2.8] Referred cohort of 1128 CD patients 3 factors independently predictive disabling CD course within 5-year Beaugerie L et al. Gastroenterology 2006;130:650-6

38. Progressive Bowel Damage in CD Pariente et al. Inflamm Bowel Dis 2011 Proactive Effective Medical Therapy Reactive Maximal Medical Therapy Early Surgery Physical & Psychosocial Growth & Development What you see on the outside does not always indicate what is going on inside

39. Months No loss of response 100 80 60 40 20 0 0 12 24 36 48 Loss of Response After Immunomodulator Withdrawal TL=trough levels Drobne D et al. DDW 2011; Abstract 279 Loss of Response after Immunomodulator Withdrawal TL detectable & CRP <5 mg/L TL detectable & CRP >5 mg/L TL undetectable & CRP >5 mg/L Slide Courtesy of the GI Health Foundation

40. IS MUCOSAL HEALING ACHIEVABLE? HR 2.35 (95%CI 1.15-4.97) HR 4.28 (95%CI 1.9-11.5) Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.

41. SUGGESTED ALGORITHM Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054

42. IBD: Management Goals Relieve symptoms Treat inflammation Treat complications Address psychosocial issues Identify dysplasia and detect cancer Improve daily functioning Replenish nutritional deficits Minimize treatment toxicity Maintain remission Establish Diagnosis