DEBATE: Role of Vedolizumab in Pediatric IBD Con: We Are Not Yet Ready to Use Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children’s Hospital/Atlantic Health Professor of Pediatrics Icahn School of Medicine, Mount Sinai School of Medicine

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

It is great to be on the cutting Edge:

It is great to be on the cutting Edge: until you get cut….

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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

Imagine Trial P=0.065 P=0.8 28% 45% EXP= IFX experienced, N=IFX naïve Hyams et al. Gastroenterology 2012;143:365

Double-Blind Maintenance Study Design - IMAgINE 1 Open-label induction Double-Blind Maintenance Baseline/Week 2 ≥40 kg: 160/80 <40 kg: 80/40 Higher-Dose ≥40 kg: 40 mg eow <40 kg: 20 mg eow Primary Endpoint * Week 26 Week 52 Screening Baseline Week 2 Week 4 Lower-Dose ≥40 kg: 20 mg eow <40 kg: 10 mg eow Randomization stratified by: Week 4 body weight Week 4 responder status Prior infliximab use Dose escalation for flare or non-response beginning at Week 12 * Potential dose adjustment by body weight

Vedolizumab UC Trial Design VDZ (n=125) VDZ Q4 week (n =125) VDZ Q 8w (n=122) Open label VDZ Q 4w (non- ITT) VDZ (n =521) Feagan BG, et al. N Engl J Med. 2013;369:699-710

“Response Enriched” Maintenance Cohort Vedolizumab UC Trial Design VDZ (n=125) VDZ Q4 week (n =125) VDZ Q 8w (n=122) Open label VDZ Q 4w (non- ITT) VDZ (n =521) “Response Enriched” Maintenance Cohort Feagan BG, et al. N Engl J Med. 2013;369:699-710

Pediatric Vedolizumab Data

Pediatric Vedolizumab Data

Pediatric Vedolizumab Data

Pediatric Vedolizumab Data

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

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

Additional Factors Influencing Anti-TNF Clearance Evidence Body weight High body mass may increase clearance Gender Increased clearance in men High baseline TNFα, CRP Increased clearance Low albumin Age Older age with slower clearance Methotrexate Decreases clearance; may downregulate Fc-γ receptor expression on monocytes; reduce antibody formation Thiopurines Reduce antibody formation Corticosteroids May reduce antibody formation Colombel et al. IBD, 2012;18:349; Ordas et al. Clin Pharmacol Ther 2012;91:635

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

Proactive Testing in Pediatric IBD: Week 14 IFX Levels and Outcomes Week 54 Outcome (Yes v. No) Median IFX Level (ug/mL) Persistent Remission 4.7 versus 2.6* Clinical Remission 3.2 versus 2.2 Clinical & Laboratory Remission 4.2 versus 3.0 Sustained Durable Remission Week 14 to 54 5.5 versus 3.1* Week 22 to 54 5.1 versus 3.0* * p<0.05 Singh et al. Inflamm Bowl Disease 2014;20:1708

“Take Home” on Anti-TNF in Pediatrics Clinical Trial Data: about 50% remission at one year (relatively fixed dosing) Potential mechanisms for improvement: TDM Dose optimization “Timing”/Risk stratification

No early immunotherapy 2008-2012: 552 children Newly Diagnosed with Crohn’s Disease Enrolled in CCFA RISK Study Crohn’s disease: 552 children with complete data and 1 yr f/u No early immunotherapy n = 236 Anti-TNFα only n = 68 Early IM only n=248 Propensity Score Matching Anti-TNFα only n = 68 IM only n = 68 No early immunotherapy n = 68

No early immunotherapy 2008-2012: 552 children Newly Diagnosed with Crohn’s Disease Enrolled in CCFA RISK Study Crohn’s disease: 552 children with complete data and 1 yr f/u No early immunotherapy n = 236 Anti-TNFα only n = 68 Early IM only n=248 Propensity Score Matching Anti-TNFα only n = 68 IM only n = 68 No early immunotherapy n = 68

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

Conclusions Changing biologics burns bridges Anti-TNF era now 15 years old and we are just learning how to optimize Risk stratification—picking right patient early TDM/Dose optimization