EFFICACY AND SAFETY OF HIGHER vs LOWER DOSE ADALIMUMAB MAINTENANCE THERAPY AS A FUNCTION OF DISEASE SEVERITY IN PEDIATRIC PATIENTS WITH CROHN’S DISEASE: SUBANALYSIS OF IMAgINE 1

Jeffrey Hyams1, Wallace Crandall2, Joel Rosh3, Frank Ruemmele4, Johanna Escher5, Andreas Lazar6, Yaqin Wang7, Roopal Thakkar7

1Connecticut Children’s Medical Center, Hartford, CT, USA; 2Nationwide Children’s Hospital, Columbus, OH, USA; 3Goryeb Children’s Hospital/Atlantic Health, Morristown, NJ, USA; 4Université Sorbonne Paris-Cité, Hôpital Necker Enfants Malades, Paris, France; 5Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; 6AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany; 7AbbVie Inc, North Chicago, IL, USA

Advances in Inflammatory Bowel Diseases: Crohn’s & Colitis Foundation’s Clinical and Research Conference

Hollywood, FL, December 12-14, 2013

F. Ruemmele: Speaker fees: Schering-Plough, Nestlé, MSD, Johnson & Johnson, Centocor; Board membership: Scientific advisory committee of DEVELOP study (Johnson & Johnson), invited to MSD France, Nestlé Nutrition Institute, Nestlé Health Science, Danone, and MeadJohnson, Biocodex

W. Crandall: Consultant: AbbVie, Boehringer Ingelheim Pharma GmbH & Co KG; Financial support for research: AbbVie

J Rosh: Consultant: AbbVie, Janssen, Soligenex; Speaker fees: Abbott Nutrition, Prometheus; Board Membership: GI Health Foundation; Financial support for research: AstraZeneca, AbbVie, Janssen, UCB

J Escher: Consultant: Janssen Biologics; Speaker fees: MSD; Board membership: scientific advisory committee of DEVELOP study (Janssen Biologics); Financial support for research: MSD

J Hyams: Consultant: Janssen Orthobiotech, AbbVie; Speaker fees and expert testimony: Janssen Orthobiotech; Financial support for research: AbbVie

A Lazar, Y Wang, R Thakkar: Employees: AbbVie, may own AbbVie stock

The authors and AbbVie scientists designed the study, and analyzed and interpreted the data. AbbVie funded the research. All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the presentation. The authors maintained control over the final content.

The authors thank Kristina Kligys, PhD, of AbbVie who prepared the first draft and assisted in production of the slides

Disclosures

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• The treatment goal of Crohn’s disease (CD) in the pediatric population is to induce and maintain clinical remission and preserve and/or restore normal growth and pubertal development

• Adalimumab (ADA) has been shown to be an effective treatment for inducing and maintaining clinical remission and response in

children with moderately to severely active CD1

• ADA has recently been approved in the EU for the treatment of severely active CD in pediatric patients (6 to 17 yrs old) who are refractory or intolerant to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulator

Introduction

3

1Hyams, et al. 2012. Gastroenterology. 143: 365-74

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• IMAgINE 1: 52-wk randomized double-blind trial

• Children 6-17 years old (N=192) with a diagnosis of CD for at least 12 weeks, with a Pediatric Crohn’s Disease Activity Index (PCDAI) > 30 at Baseline– All patients had active disease despite concurrent therapy with

stable dose of oral corticosteroid (for ≥ 2 weeks) and/or IMM for ≥ 8 weeks, with stable dose ≥ 4 weeks

– Approximately 44% of patients received prior anti-TNF therapy

Introduction

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• At Weeks 26 and 52, a numerically higher proportion of patients receiving higher-dose (HD) ADA than lower-dose (LD) ADA achieved clinical remission, but the differences were not statistically significant at each timepoint1

– Remission Week 26: 38.7% HD vs 28.4% LD, p = 0.075– Remission Week 52: 33.3% HD vs 23.2% LD, p = 0.100

• In subgroup analyses at Week 52, a significantly higher remission rate was achieved in infliximab-naïve than infliximab-experienced patients with HD ADA1

Introduction

5

1Hyams, et al. 2012. Gastroenterology. 143: 365-74

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

Week 2

* Potential dose adjustment by body weight

Study Design-IMAgINE 1

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Aim

• To evaluate the efficacy and safety of the two maintenance ADA dosing regimens based on Baseline disease severity in children with moderately to severely active CD

• Disease severity was classified based on the median of Basline PCDAI observed for the study population– Moderate CD = BL PCDAI < 40– Severe CD = BL PCDAI ≥ 40

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Endpoints

• Clinical remission (PCDAI ≤ 10) at Week 52

• Clinical response (PCDAI decrease ≥ 15 points from Baseline) at Week 52

• Clinical remission and response at Week 52 by prior infliximab use

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• Chi-square test to compare treatment groups including subgroup analysis by prior infliximab use

• Non-responder imputation (NRI) was applied, whereby patients were considered as non-responders for: Missing data Premature discontinuation Switch to weekly therapy

Data Analysis

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% P

atie

nts

in R

emis

sio

n

0

20

40

60

80

100LD ADAHD ADA

Moderate CD Severe CD

36.6 35.9

13.0

31.5

15/41 14/39 7/54 17/54

p< 0.05

35.0median BL PCDAI 35.0 43.8 45.0

Clinical Remission = PCDAI ≤ 10

Clinical Remission - Week 52

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Clinical Response = decrease in PCDAI ≥ 15 points from BL

% P

atie

nts

wit

h R

esp

on

se

0

20

40

60

80

100LD ADAHD ADA

41.546.2

18.5

38.9

17/41 18/39 10/54 21/54

Moderate CD Severe CD

p=0.02

35.0 35.0 43.8 45.0median BL PCDAI

Clinical Response - Week 52

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% P

atie

nts

in R

emis

sio

n0

20

40

60

80

100

Moderate CD Severe CD

26.3

15.49.1

20.7

5/19 2/13 2/22 6/29

35.0 35.0 45.0 42.5

By Prior Infliximab use

Infliximab-experiencedInfliximab-naive

LD ADA HD ADA

% P

atie

nts

in R

emis

sio

n

0

20

40

60

80

100

45.5 46.2

10/22 12/26

15.6

44.0

5/32 11/25

Moderate CD Severe CD

p=0.02

45.042.535.035.0Median BLPCDAI

Clinical Remission - Week 52

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By Prior Infliximab use

Infliximab-experiencedInfliximab-naive

% P

atie

nts

wit

h R

esp

on

se

0

20

40

60

80

100

Moderate CD Severe CD

50.053.8

21.9

56.0

11/22 14/26 7/32 14/25

p < 0.01

35.0 35.035.0 42.5 45.0

LD ADA HD ADA

Median BLPCDAI

Clinical Response - Week 52

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SafetyBL PCDAI < 40 BL PCDAI ≥ 40

Lower-DoseADA 20/10mgN=41, 22.7 PY

Events (E/100PY)

Higher-DoseADA 40/20mgN=39, 25 PY

Events (E/100PY)

Lower-DoseADA 20/10mgN=54, 24.8 PY

Events (E/100PY)

Higher-DoseADA 40/20mgN=54, 29.2 PY

Events (E/100PY)

Any AE 223 (982.4) 235 (940.0) 241 (971.8) 272 (931.5)

Serious AE 4 (17.6) 8 (32.0) 16 (64.5) 16 (54.8)

AE leading to discontinuation

2 (8.8) 3 (12.0) 11 (44.4) 17 (58.2)

Serious infections 1 (4.4) 1 (4.0) 2 (8.1) 4 (13.7)

Malignancy 0 0 0 0

Opportunistic infection (excl TB)

0 0 1 (4.0) 1 (3.4)

Injection site rxn 6 (26.4) 9 (36.0) 18 (72.6) 16 (54.8)

Hematologic AE 4 (17.6) 4 (16.0) 1 (4.0) 7 (24.0)

Deaths 0 0 0 0

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Conclusions

• At Week 52, higher-dose maintenance ADA was a more effective therapy than lower-dose ADA for children with severe CD; patients with moderate CD benefitted equally from either dose

• Infliximab-naïve patients achieved the greatest remission and response rates

• SAEs were slightly more frequent in patients with moderate CD receiving higher-dose than lower-dose ADA. The overall safety profile was similar for higher-dose and lower-dose ADA treatment

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BACK-UP SLIDES

% P

atie

nts

in R

emis

sio

n

0

20

40

60

80

100

BL PCDAI < 40 BL PCDAI 40

LD ADAHD ADA

29.3

51.3

29.627.8

12/41 20/39 16/5415/54

p< 0.05

Clinical Remission = PCDAI ≤ 10

Clinical Remission - Week 26

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% P

ati

en

ts w

ith

Resp

on

se

0

20

40

60

80

100 LD ADAHD ADA

BL PCDAI < 40 BL PCDAI 40

51.2

66.7

46.353.7

21/41 26/39 25/54 29/54

Clinical Response = decrease in PCDAI ≥ 15 points from BL

Clinical Response - Week 26

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