Vedolizumab in Pediatric IBD: We are Ready to Use It Ted Denson, MD Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine

Disclosures: Avaxia Biologics: Advisory Board

Focus Questions Do we need additional biologics? Is Vedolizumab safe? Is Vedolizumab effective? Are we ready to use Vedolizumab in pediatric patients?

IBD Therapeutic Targets 1: Maladaptive response to intestinal injury & the enteric flora CD: defective innate antimicrobial response UC: defective epithelial response 2: T-cell activation including enteric flora antigens TCR CD4 CD28 CTLA4 MHC Class II B7 FUT2 Resting Mo Naive T cell GM-CSF auto-antibodies Anti-flagellin antibodies 3:Cytokines & chemokines B cell CD4+ T cell IL27 Selectins Activated Mo TNF IL-10 PMN Treg TGFb IL-12 IL-4 IL-8 Integrins IL-23 ICAM-1 Monocyte 4: Leukocyte adhesion & recruitment MAdCAM-1 IFNg Th1 Th2 IL-5 IL-13 Lymphocyte IL-17 Th17

Accelerated Step-up Therapy for IBD Surgery Disease Severity Anti-TNF Methotrexate Thiopurines Thiopurines Corticosteroids Corticosteroids Mesalamine Enteral Nutrition

REACH: Response and Remission † * p = 0.002 p < 0.001 % of Patients n = 99 n = 66 n = 33 n = 29 n = 17 n = 12 *Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30. †PCDAI score ≤ 10. Hyams et al. Gastroenterology 2007;132:863-873

12 Month Outcomes For The Three Early Therapy Approaches: PCDAI≤10 Without Resection (n=204 for 68 propensity score matched triads) CS-free, Surgery free Treatment Yes (n=136) No (n=68) Early anti-TNFα only (n=68) 58 (85%) 10 (15%) Early IM only (n=68) 41 (60%) 27 (40%) No early immunotherapy (n=68) 37 (54%) 31 (46%) (p=0.0003) No difference between early IM and no early IM Hyams et al. Gastroenterology 2014

Pooled Adverse Events for Pediatric IFX and ADA Dubinsky et al IBD 2013

Approx 60% CS-free inactive disease Kaplan-Meier Plot of Likelihood of Continuing Infliximab: Real World Experience Months on Infliximab Approx 60% CS-free inactive disease 1 year: 93% ± 2% 2 years: 78% ± 4% 3 years: 67% ± 5% Approx 50% require dose escalation Hyams et al. IBD 2009;15:816

Approach to anti-TNF Loss of Response 1 year: 93% ± 2% 2 years: 78% ± 4% 3 years: 67% ± 5% Loftus et al

IBD Therapeutic Targets 1: Maladaptive response to intestinal injury & the enteric flora CD: defective innate antimicrobial response UC: defective epithelial response 2: T-cell activation including enteric flora antigens TCR CD4 CD28 CTLA4 MHC Class II B7 FUT2 Resting Mo Naive T cell GM-CSF auto-antibodies Anti-flagellin antibodies 3:Cytokines & chemokines B cell CD4+ T cell IL27 Selectins Activated Mo TNF IL-10 PMN Treg TGFb IL-12 IL-4 IL-8 Integrins IL-23 ICAM-1 Monocyte 4: Leukocyte adhesion & recruitment MAdCAM-1 IFNg Th1 Th2 IL-5 IL-13 Lymphocyte IL-17 Th17

Sandborn WJ et al. N Engl J Med 2013;369:711-721. Primary End Points in the Vedolizumab Trial of CD Induction Therapy. Sandborn WJ et al. N Engl J Med 2013;369:711-721.

Sandborn WJ et al. N Engl J Med 2013;369:711-721. End Points in the Vedolizumab Trial of CD Maintenance Therapy. Sandborn WJ et al. N Engl J Med 2013;369:711-721.

Sandborn WJ et al. N Engl J Med 2013;369:711-721. Adverse Events Affecting at Least 5% of Patients Who Received Vedolizumab. Sandborn WJ et al. N Engl J Med 2013;369:711-721.

Outcome Measures at Week 6 in the Vedolizumab Trial of UC Induction Therapy. Feagan BG et al. N Engl J Med 2013;369:699-710

Outcome Measures in the Vedolizumab Trial of UC Maintenance Therapy. Feagan BG et al. N Engl J Med 2013;369:699-710

Adverse Events Affecting at Least 5% of Patients Receiving Vedolizumab in the Safety Population. Feagan BG et al. N Engl J Med 2013;369:699-710

Effects of Vedolizumab Induction Therapy for Patients With Crohn’s Disease in Whom Tumor Necrosis Factor Antagonist Treatment Failed Sands et al, Gastroenterology, Volume 147, Issue 3, 2014, 618 - 627.e3

Accelerated Step-up Therapy for IBD Surgery Vedolizumab: Therapeutic anti-TNF level Alternate mechanism Slow onset of action Disease Severity Anti-TNF Methotrexate Thiopurines Thiopurines Corticosteroids Corticosteroids Mesalamine Enteral Nutrition