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.

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

IT IS GREAT TO BE ON THE CUTTING EDGE:

IT IS GREAT TO BE ON THE CUTTING EDGE: UNTIL YOU GET CUT….

X

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

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

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