Transcript Rosh - 2013 Advances in Inflammatory Bowel Diseases

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
Disclosures
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
CCFA 2013| Date 12-13-13
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Introduction
•
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
1Hyams,
et al. 2012. Gastroenterology. 143: 365-74
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Introduction
• 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
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Introduction
• 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
1Hyams,
et al. 2012. Gastroenterology. 143: 365-74
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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
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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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Data Analysis
• 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
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Clinical Remission - Week 52
Clinical Remission = PCDAI ≤ 10
% Patients in Remission
100
LD ADA
HD ADA
80
p< 0.05
60
40
36.6
35.9
20
0
median BL PCDAI
31.5
13.0
15/41
14/39
7/54
17/54
35.0
35.0
43.8
45.0
Moderate CD
Severe CD
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Clinical Response - Week 52
Clinical Response = decrease in PCDAI ≥ 15 points from BL
% Patients with Response
100
LD ADA
HD ADA
80
p=0.02
60
40
41.5
46.2
38.9
18.5
20
0
median BL PCDAI
17/41
18/39
10/54
21/54
35.0
35.0
43.8
45.0
Moderate CD
Severe CD
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Clinical Remission - Week 52
By Prior Infliximab use
Infliximab-naive
Infliximab-experienced
100
80
p=0.02
60
45.5
46.2
44.0
40
20
0
Median BL
PCDAI
15.6
10/22
12/26
5/32
11/25
35.0
35.0
42.5
45.0
Moderate CD
Severe CD
LD ADA
% Patients in Remission
% Patients in Remission
100
80
60
40
26.3
20
20.7
15.4
9.1
0
5/19
2/13
2/22
6/29
35.0
35.0
45.0
42.5
Moderate CD
Severe CD
HD ADA
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Clinical Response - Week 52
By Prior Infliximab use
Infliximab-naive
Infliximab-experienced
% Patients with Response
p < 0.01
80
60
50.0
56.0
53.8
40
21.9
20
0
Median BL
PCDAI
11/22
14/26
7/32
14/25
35.0
35.0
42.5
45.0
Moderate CD
Severe CD
LD ADA
% Patients with Response
100
100
80
60
40
31.6
30.8
24.1
20
0
13.6
6/19
4/13
3/22
7/29
35.0
35.0
45.0
42.5
Moderate CD
Severe CD
HD ADA
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Safety
BL PCDAI < 40
BL PCDAI ≥ 40
Lower-Dose
ADA 20/10mg
N=41, 22.7 PY
Events
(E/100PY)
Higher-Dose
ADA 40/20mg
N=39, 25 PY
Events
(E/100PY)
Lower-Dose
ADA 20/10mg
N=54, 24.8 PY
Events
(E/100PY)
Higher-Dose
ADA 40/20mg
N=54, 29.2 PY
Events
(E/100PY)
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)
0
0
0
0
Any AE
Deaths
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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
Clinical Remission - Week 26
Clinical Remission = PCDAI ≤ 10
% Patients in Remission
100
80
LD ADA
HD ADA
p< 0.05
60
51.3
40
29.3
27.8
29.6
15/54
16/54
20
0
12/41
20/39
BL PCDAI < 40
BL PCDAI  40
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Clinical Response - Week 26
Clinical Response = decrease in PCDAI ≥ 15 points from BL
LD ADA
HD ADA
% Patients with Response
100
80
66.7
60
53.7
51.2
46.3
40
20
0
21/41
26/39
BL PCDAI < 40
25/54
29/54
BL PCDAI  40
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