Upload
jocelyn-bond
View
220
Download
0
Tags:
Embed Size (px)
Citation preview
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?
1: Maladaptive response to intestinal injury & the enteric floraCD: defective innate antimicrobial responseUC: defective epithelial response
2: T-cellactivation including enteric flora antigens
3:Cytokines & chemokines
RestingMo
ActivatedMo
Selectins
PMN
Integrins
Monocyte
MAdCAM-1
Lymphocyte
ICAM-1
4: Leukocyte adhesion & recruitment
IL-8 IL-23IL-12
IFN
TNF
Th1 Th2 IL-5
IL-4
CD4+
T cell
NaiveT cell
B cell
MHCClass II
B7
TCR
CD4CD28
CTLA4
IL-17 Th17
IL-13
GM-CSF auto-antibodiesAnti-flagellin antibodies
Treg IL-10
TGF
FUT2
IL27
IBD Therapeutic Targets
Accelerated Step-up Therapy for IBD
Dis
ease
Sev
erit
y
Thiopurines ThiopurinesCorticosteroids CorticosteroidsMesalamine Enteral Nutrition
Methotrexate
Anti-TNF
Surgery
REACH: Response and Remission
88
64
33
59 56
24
0102030405060708090
100
Week 10 Week 54 q8 Week 54 q12
Response Remission
*Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30.†PCDAI score ≤ 10.
% o
f Pa
tien
ts
n = 99 n = 66 n = 29n = 33 n = 17 n = 12
p = 0.002
p < 0.001
* †
Hyams et al. Gastroenterology 2007;132:863-873
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%)
CS-free, Surgery free
(p=0.0003)
12 Month Outcomes For The Three Early Therapy Approaches: PCDAI≤10
Without Resection (n=204 for 68 propensity score matched triads)
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
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%
Hyams et al. IBD 2009;15:816 Approx 50% require dose escalation
Approach to anti-TNF Loss of Response
1 year: 93% ± 2%2 years: 78% ± 4%3 years: 67% ± 5%
Loftus et al
1: Maladaptive response to intestinal injury & the enteric floraCD: defective innate antimicrobial responseUC: defective epithelial response
2: T-cellactivation including enteric flora antigens
3:Cytokines & chemokines
RestingMo
ActivatedMo
Selectins
PMN
Integrins
Monocyte
MAdCAM-1
Lymphocyte
ICAM-1
4: Leukocyte adhesion & recruitment
IL-8 IL-23IL-12
IFN
TNF
Th1 Th2 IL-5
IL-4
CD4+
T cell
NaiveT cell
B cell
MHCClass II
B7
TCR
CD4CD28
CTLA4
IL-17 Th17
IL-13
GM-CSF auto-antibodiesAnti-flagellin antibodies
Treg IL-10
TGF
FUT2
IL27
IBD Therapeutic Targets
Primary End Points in the Vedolizumab Trial of CD Induction Therapy.
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.
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
Dis
ease
Sev
erit
y
Thiopurines ThiopurinesCorticosteroids CorticosteroidsMesalamine Enteral Nutrition
Methotrexate
Anti-TNF
Surgery
Vedolizumab:Therapeutic anti-TNF levelAlternate mechanismSlow onset of action