Transcript DEBATE: Role of Vedolizumab in Pediatric IBD Con: We Are

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:
– 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….
REACH: Response and Remission
% of Patients
Response *
100
90
80
70
60
50
40
30
20
10
0
Remission
†
p = 0.002
88
p < 0.001
59
64
56
33
24
n = 99 n = 66
n = 33 n = 29
n = 17 n = 12
Week 10
Week 54 q8
Week 54 q12
*Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30.
†PCDAI score ≤ 10.
Hyams et al. Gastroenterology 2007;132:863873
Imagine Trial
52 Week Remission
50
45
40
35
30
25
20
15
10
5
0
P=0.065
P=0.8
Remission
17%
ADA-EXP LD
19%
ADA-EXP HD
EXP= IFX experienced, N=IFX naïve
28%
ADA -N LD
45%
ADA-N HD
Hyams et al. Gastroenterology 2012;143:365
Study Design - IMAgINE 1
Open-label
induction
Double-Blind Maintenance
Randomization stratified by:
•Week 4 body weight
•Week 4 responder status
•Prior infliximab use
Week 52
≥40 kg:
20 mg eow
<40 kg:
20 mg eow
Week 26
Primary Endpoint *
≥40 kg:
40 mg eow
Lower-Dose
Week 4
Week 2
Baseline
Screening
Higher-Dose
Baseline/Week 2
≥40 kg: 160/80
<40 kg: 80/40
<40 kg:
10 mg eow
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 (n
=521)
VDZ Q4
week (n
=125)
VDZ Q 8w
(n=122)
Open label
VDZ Q 4w
(non- ITT)
Feagan BG, et al. N Engl J Med. 2013;369:699-710
Vedolizumab UC Trial Design
VDZ (n=125)
VDZ (n
=521)
VDZ Q4
week (n
=125)
VDZ Q 8w
(n=122)
Open label
VDZ Q 4w
(non- ITT)
“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
Kaplan-Meier Plot of Likelihood of Continuing
Infliximab: Real World Experience
1 year: 93% ± 2%
2 years: 78% ± 4%
3 years: 67% ± 5%
Months on Infliximab
Approx 60% CS-free inactive disease
Approx 50% require dose escalation
Hyams et al. IBD 2009;15:816
Kaplan-Meier Plot of Likelihood of Continuing
Infliximab: Real World Experience
1 year: 93% ± 2%
2 years: 78% ± 4%
3 years: 67% ± 5%
Months on Infliximab
Approx 50% require dose escalation
Hyams et al. IBD 2009;15:816
Additional Factors Influencing Anti-TNF
Clearance
Factor
Evidence
Body 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
100
Undetectable
Patients with endoscopic improvement >75% (%)
Patients in clinical remission (%)
100
82
88
p<0.001
33
p<0.001
6
0
0
Patients with CRP <5 mg/dL (%)
100
100 Patients with complete endoscopic remission (%)
76
p<0.001
47
32
p=0.03
19
0
Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54
0
Proactive Testing in Pediatric IBD:
Week 14 IFX Levels and Outcomes
(n=58)
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*
Sustained Durable Remission
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
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
Anti-TNFα only
n = 68
Early IM only
n=248
No early
immunotherapy
n = 236
Propensity Score Matching
Anti-TNFα only
n = 68
IM only
n = 68
No early immunotherapy
n = 68
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
Anti-TNFα only
n = 68
Early IM only
n=248
No early
immunotherapy
n = 236
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