1. 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

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

3. It is great to be on the cutting Edge:

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

6. X

7. 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:

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

9. 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

10. 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:

11. “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:

12. Pediatric Vedolizumab Data

13. Pediatric Vedolizumab Data

14. Pediatric Vedolizumab Data

15. Pediatric Vedolizumab Data

16. 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

17. 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

18. 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

19. 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:

20. 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

21. “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

22. No early immunotherapy
: 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

23. No early immunotherapy
: 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

24. 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

25. 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