1. 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

2. Disclosures:
Avaxia Biologics: Advisory Board

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

4. 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

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

6. 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:

7. 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

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

9. 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

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

11. 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

12. 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:

13. 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:

14. 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:

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

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

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

18. 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, e3

19. 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