DEBATE: Role of Vedolizumab in Pediatric IBDCon: We Are Not Yet Ready to Use
Joel R. Rosh, MDDirector, Pediatric Gastroenterology
Goryeb Children’s Hospital/Atlantic HealthProfessor of Pediatrics
Icahn School of Medicine, Mount Sinai School of Medicine
Disclosures
• Grant Support: – Abbvie, Astra-Zeneca, Janssen
• Consultant:– Abbvie, Given, Janssen, Soligenix
• Honoraria/Speakers’ Bureau– Abbott Nutrition, Abbvie, Prometheus
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
Imagine Trial
ADA-EXP LD ADA-EXP HD ADA -N LD ADA-N HD05
101520253035404550
52 Week Remission
Remission
17% 19% 28% 45%
P=0.8
P=0.065
Hyams et al. Gastroenterology 2012;143:365EXP= IFX experienced, N=IFX naïve
Screening
Baseline
Week 4
Week 26
Prim
ary Endpoint *
Week 52
Open-labelinduction
Baseline/Week 2≥40 kg: 160/80<40 kg: 80/40
Randomization stratified by:•Week 4 body weight•Week 4 responder status•Prior infliximab use
Higher-D
oseLow
er-D
ose
≥40 kg:40 mg eow
<40 kg:20 mg eow
≥40 kg:20 mg eow
<40 kg:10 mg eow
Double-Blind Maintenance
Dose escalation for flare or non-response beginning at Week 12
Study Design - IMAgINE 1
Week 2
* Potential dose adjustment by body weight
Vedolizumab UC Trial Design
VDZ (n =521)
VDZ Q4 week (n =125)
VDZ Q 8w (n=122)
VDZ (n=125)
Open label VDZ Q 4w(non- ITT)
Feagan BG, et al. N Engl J Med. 2013;369:699-710
Vedolizumab UC Trial Design
“Response Enriched” Maintenance Cohort
VDZ (n =521)
VDZ Q4 week (n =125)
VDZ Q 8w (n=122)
VDZ (n=125)
Open label VDZ Q 4w(non- ITT)
Feagan BG, et al. N Engl J Med. 2013;369:699-710
Pediatric Vedolizumab Data
Pediatric Vedolizumab Data
Pediatric Vedolizumab Data
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;15:816Approx 50% require dose escalation
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%
Hyams et al. IBD 2009;15:816Approx 50% require dose escalation
Additional Factors Influencing Anti-TNF Clearance
Factor EvidenceBody weight High body mass may increase clearance
Gender Increased clearance in men
High baseline TNFα, CRP Increased clearance
Low albumin Increased clearance
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
Trough serum infliximab
Detectable Undetectable
Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54
Patients in clinical remission (%) Patients with endoscopic improvement >75% (%)
Patients with complete endoscopic remission (%)Patients with CRP <5 mg/dL (%)
100 100
100 100
0 0
0 0
82
6
88
33
76
32 47
19
p<0.001
p=0.03
p<0.001
p<0.001
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 RemissionWeek 14 to 54
5.5 versus 3.1*
Sustained Durable RemissionWeek 22 to 54
5.1 versus 3.0*
(n=58)
* 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
2008-2012: 552 childrenNewly Diagnosed with Crohn’s Disease Enrolled in CCFA RISK
Study
Crohn’s disease: 552 children with complete data and 1 yr f/u
Anti-TNFα onlyn = 68
No early immunotherapy
n = 236
Early IM onlyn=248
Propensity Score Matching
Anti-TNFα onlyn = 68
No early immunotherapy n = 68
IM onlyn = 68
2008-2012: 552 childrenNewly Diagnosed with Crohn’s Disease Enrolled in CCFA RISK
Study
Crohn’s disease: 552 children with complete data and 1 yr f/u
Anti-TNFα onlyn = 68
No early immunotherapy
n = 236
Early IM onlyn=248
Propensity Score Matching
Anti-TNFα onlyn = 68
No early immunotherapy n = 68
IM onlyn = 68
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