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For Advisors Only
BIOLOGIC THERAPY IN CROHN’S DISEASE
BIOLOGIC THERAPY IN CROHN’S DISEASE
ATILLA ERTAN, FACP, AGAF, MACGATILLA ERTAN, FACP, AGAF, MACG
Disclamer
• Grant/research support from Centocor, UCB Inc, Abbott Labs, Elan-Biogen Pharmaceuticals, Sucampo Pharmaceuticals, Genentech, Axcan, Barrx Inc & Salix Pharmaceuticals.
• Scientific advisory board member for Centocor, UCB Inc, Abbott Laboratories & Prometheus Labs.
THERAPEUTIC GOALS IN IBD
• Clinical improvement
• Clinical remission
• Corticosteroid weaning
• Maintenance of remission
• Maintained tissue healing
• Decrease in hospitalization & surgical interventions
• Prevention of complications
• Change natural course of the disease
© UCB 2006. All rights reserved.
Monoclonal Antibodies, Fusion Proteins and Fab' fragments against TNF
Humanized Fab' fragment
Certolizumab pegolFab'
Chimeric monoclonal
antibody
InfliximabmAb
Human monoclonal
antibody
AdalimumabmAb
Human recombinant receptor/Fc fusion
protein
Fc
Receptor
Constant 2
Constant 3
Etanercept
FcIgG1
Adapted with permission from: Hanauer. Rev Gastroenterol Disord 2004; 4 (supp 3): S18-24
PEGPEG
VL VH
CH1C
Certolizumab pegol
• Humanized PEGylated Fab' fragment of an anti-TNF-α monoclonal antibody
• Single Fab' fragment
– engineered for production in E.coli
– no need for glycosylation of Fc portion
• 2 x 20 kD PEG
– to extend half life of the Fab' to a value comparable with a whole antibody product (approx. 2 weeks)
– compatible with SC administration
• Site specific PEGylation
– to hinge thiol
– using proprietary linkage technology
• No monocyte or lymphocyte apoptosis, no complement activation, no ADCC
Chapman A et al., Nature Biotech 1999; 17: 780-3Nesbitt and Henry, Abstract , ACG, Orlando FL, 2004
Molecular structure of certolizumab pegol. The chains of the Fab' fragments are shown in
green/blue; the PEG is in yellow
• Fully human monoclonal antibody (IgG1) that specifically neutralizes TNF-
• Half-life of 12 to 14 days
• Patient self-administered sc pen injection
• RA, PsA, and AS dose: single 40 mg injection every other week (eow)
• CD: starting dose 160/80 mg week 0, week 2– Maintenance dose 40 mg eow week 4
• Approved for RA, PsA, AS, CD with>190,000 patients currently being treated worldwide
HUMIRA® (adalimumab)
For Advisors Only
Phase III Study of HUMIRA Induction of Remission in Anti-TNF Naïve Patients
CLASSIC I (M02-403)CLASSIC I (M02-403)
Hanauer S, et al. Gastroenterol 2006;130:323–33
CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease
Results at Week 4
* p<0.05; † p=0.003; ‡ p=0.002Clinical remission=CDAI<150Clinical response 70 or 100=CDAI decrease from baseline ≥70 or ≥100
18%
24%
36%
12%
53%55%
34% 32%
37%
49%
Su
bje
cts
(%)
*
‡
24%
0
10
20
30
40
50
60
70
Placebo/placebo HUMIRA 40/20
HUMIRA 80/40 HUMIRA 160/80
58%
Clinical Remission
Response, 70
Response, 100
*†*
Humira Prescribing Information Feb 2007;
Based on Hanauer, S. et al. Gastroenterol. 2006;130:323–33
CLASSIC I
For Advisors Only
Phase III Study of HUMIRA Maintenance of Remission in Anti-TNF Naïve Patients
CLASSIC II (M02-433)CLASSIC II (M02-433)
Sandborn WJ, et al. Gut Published Online First: 13 February 2007
Randomized Cohort:Clinical Remission (CDAI<150)
5044
79
84*
83*
94*
0102030405060708090
100
0 10 20 30 40 50 60
Weeks
Pa
tie
nts
ma
inta
inin
g r
em
iss
ion
(%
)
Placebo (n=18) 40 mg EOW (n=19) 40 mg wkly (n=18)
LOCF; ITT population, n=55*p<0.05 versus placebo
*
CLASSIC II
Sandborn WJ, et al. Gut Published Online First: 13 February 2007
Open-label Cohort:Clinical Remission and Response
62%65%
71% 72%
46%40%
0%
25%
50%
75%
Week 24 Week 56
Pa
tie
nts
(%
)
LOCF (n=204)
Remission
CDAI 100
CDAI 70
Based on Sandborn, W. et al. 520, ACG 2005;
CLASSIC II
Sandborn WJ, et al. Gut Published Online First: 13 February 2007
Open-label Cohort: Conclusions
• HUMIRA administration led to long-lasting improvements in clinical response and remission
– 60% of patients achieved remission at week 56 with HUMIRA 40 mg EOW
• 64% of patients completed 56 weeks of therapy– 54% of those patients maintained on 40 mg EOW
• Long-term administration of HUMIRA was well-tolerated in patients with Crohn’s disease
– No new safety concerns
CLASSIC II
Sandborn WJ, et al. Gut Published Online First: 13 February 2007; Data on file.
For Advisors Only
CHARMFistula Outcomes
CHARMFistula Outcomes
Complete Healing of Draining Fistulas at Last 2 Visits,
Total Randomized Patients
Healing = no draining fistulas for at least their last 2 post-baseline evaluations Patients with fistulas: draining fistulas at both screening and baseline
NR
RNR RR
13
37
3033
0
10
20
30
40
50
PBO 40 mg EOW 40 mg weekly both HUMIRA groups
6/47 11/30 12/40 23/70
Pa
tient
s C
omp
lete
ly H
ea
led
(%
)
p= 0.016, combined HUMIRA groups vs placebo
Colombel JF et al. T686d, DDW 2006
CHARM
Maintenance of Healing of Draining Fistulas: Weeks 26 and 56;
All Randomized Patients
NR
RNR RR
Healing = no draining fistulasPatients with fistulas: draining fistulas at both screening and baseline
13 13
33 3328 28 3030
0
10
20
30
40
50
Week 26 Week 26 and 56
PBO 40 mg EOW 40 mg weekly both HUMIRA groups
Pa
tient
s C
omp
lete
ly H
ea
led
(%
)
6/47 10/30 11/40 21/70 6/47 10/30 11/40 21/70
p= 0.043 p= 0.043
Colombel JF, et al. Gastroenterol. 2007;132 (1):52-65
CHARM
Conclusions
• HUMIRA maintained remission in patients with moderately to severely active Crohn’s disease
– There was no significant difference between the 40mg eow and 40mg weekly maintenance doses
– HUMIRA was effective regardless of previous anti-TNF exposure
• Patients treated with HUMIRA discontinued steroids and remained in remission more frequently than patients receiving placebo
• HUMIRA treatment significantly increased the proportion of patients with complete healing of draining fistulas
• HUMIRA was well tolerated
– Significantly lower rate of SAEs with HUMIRA maintenance compared to placebo
– No new safety concerns compared to experience in RA and previous Crohn’s studies
Colombel JF, et al. Gastroenterol. 2007;132 (1):52-65
CHARM
For Advisors Only
Gauging Adalimumab Efficacy in Infliximab Non-Responders
Phase III Study of HUMIRA Induction in Infliximab Failure Patients
GAIN (M04-691)GAIN (M04-691)
Sandborn WJ, et al. Ann Intern Med 2007;146(12):829-38
Response Rate 70-Point CDAI Decrease (CR-70)
*p<0.005, †p<0.001, both vs. placebo.
*
†
Week
0
10
20
30
40
50
60
0 1 2 3 4
Placebo 160/80 mg
†
21
35
52 52
33 34% of Patients
Sandborn WJ, et al. Ann Intern Med 2007;146(12):829-38
GAIN
Conclusions
• HUMIRA was effective in inducing clinical remission and response in subjects with moderate to severe Crohn’s disease who had lost response or had adverse reactions to infliximab
– Effect was observed as early as Week 1 (CR-70)
• HUMIRA was well-tolerated with overall lower incidence of adverse events compared to placebo and with an AE profile similar to previous studies in Crohn’s and RA
Sandborn WJ, et al. Ann Intern Med. 2007;146(12): 829-38
GAIN
Summary: HUMIRA in Crohn’s Disease
• HUMIRA rapidly induces remission and response in patients with moderately to severely active disease
• HUMIRA is effective as a maintenance therapy
– Remission and response
– Steroid discontinuation
– Healing of draining fistulas
• HUMIRA is effective in a broad patient population
– Anti-TNF naïve
– Anti-TNF experienced
• Across clinical studies, HUMIRA was well tolerated, with a safety profile consistent with RA
• Recommended dose: – Starting Dose: 160 mg week 0, 80 mg week 2
– Maintenance Dose: 40 mg EOW beginning week 4
For Advisors Only
CLASSIC IICLASSIC II
Immunogenicity dataImmunogenicity data
Immunogenicity
• 7/269 patients (2.6%) were positive for AAAs
% AAA+ + Immunosuppressants 0% - Immunosuppressants 3.8%
CLASSIC II
• 3/7 AAA+ patients (43%) in remission at Week 24
• 2/7 AAA+ patients (29%) in remission at Week 56
Sandborn WJ, et al. Gut Published Online First: 13 February 2007
THERAPEUTIC GOALS IN IBD
• Clinical improvement
• Clinical remission
• Corticosteroid weaning
• Maintenance of remission
• Maintained tissue healing
• Decrease in hospitalization & surgical interventions
• Prevention of complications
• Change natural course of the disease
For Advisors Only
CHARMSafety Data
CHARMSafety Data
Adverse Events of Interest: All Exposure
Adverse events (AE), n=1459 E (E/100-PYs)
Any AE 12,124 (805.0)
Any serious AE 487 (32.3)
Any AE leading to discontinuation 326 (21.6)
Infectious AE 2,146 (142.5)
Serious infections 90 (6.0)
Malignant neoplasms 17 (1.1)
Injection-site related AE 552 (36.7)
Opportunistic infections 32 (2.1)
Congestive heart failure (CHF) 1 (<0.1)
Demyelinating disease 2 (0.1)
Any fatal AE 1 (<0.1)
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Overview of Opportunistic Infections: All Exposure
System organ class, n (%)Any HUMIRA
n=1459
Any AE 29 (2.0)
Oral Candidiasis 22 (1.5)
Esophageal Candidiasis 4 (0.3)
Coccidioidomycosis 1 (<0.1)
Nocardiosis 1 (<0.1)
Tuberculosis 3 (0.2)
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Conclusions
• HUMIRA was generally safe and well-tolerated in the treatment of patients with moderately to severely active Crohn’s disease
• No clinically meaningful differences during the induction period in patients treated with HUMIRA vs placebo
• When normalized for exposure, patients who received placebo experienced generally higher rates of adverse events than patients treated with maintenance HUMIRA
• The safety profile of HUMIRA is consistent over more than 10 years of clinical experience
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
THERAPEUTIC GOALS IN IBD
• Clinical improvement
• Clinical remission
• Corticosteroid weaning
• Maintenance of remission
• Maintained tissue healing
• Decrease in hospitalization & surgical interventions
• Prevention of complications
• Change natural course of the disease
For Advisors Only
DDW 2007HUMIRA Data Update
DDW 2007HUMIRA Data Update
For Advisors Only
An Evaluation of Adalimumab on the Risk of Hospitalization in Patients With Crohn’s Disease,
Data from CHARM
An Evaluation of Adalimumab on the Risk of Hospitalization in Patients With Crohn’s Disease,
Data from CHARM
BG Feagan1, R Panaccione2, WJ Sandborn3, GR D’Haens4, S Schreiber5, PJ Rutgeerts6, EV Loftus3,
KG Lomax7, EQ Wu8, PM Mulani9
1Department of Medicine, Epidemiology and Biostatistics, University of Western Ontario, London Health Sciences Centre, London, ON, Canada; 2Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, AB, Canada;
3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 4Department of Gastroenterology, Imelda GI Clinical Research Center, Bonheiden, Belgium; 5Department of Medicine, Christian-Albrechts University,
Kiel, Germany; 6Gastro-Enterologie, University Hospital of Gasthuisberg, Leuven, Belgium; 7Immunology Development, Abbott, Parsippany, NJ, USA; 8Analysis Group Inc., Boston, MA, USA;
9Global Health Economics & Outcomes Research, Abbott, Abbott Park, IL, USA
BG Feagan1, R Panaccione2, WJ Sandborn3, GR D’Haens4, S Schreiber5, PJ Rutgeerts6, EV Loftus3,
KG Lomax7, EQ Wu8, PM Mulani9
1Department of Medicine, Epidemiology and Biostatistics, University of Western Ontario, London Health Sciences Centre, London, ON, Canada; 2Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, AB, Canada;
3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 4Department of Gastroenterology, Imelda GI Clinical Research Center, Bonheiden, Belgium; 5Department of Medicine, Christian-Albrechts University,
Kiel, Germany; 6Gastro-Enterologie, University Hospital of Gasthuisberg, Leuven, Belgium; 7Immunology Development, Abbott, Parsippany, NJ, USA; 8Analysis Group Inc., Boston, MA, USA;
9Global Health Economics & Outcomes Research, Abbott, Abbott Park, IL, USA
Feagan BG, et al. Gastroenterology 2007;132(4 Suppl 2):A-513.
Cox Regression: CD-Related Hospitalization All Randomized Patients (n=778)
*The hospitalization risk for HUMIRA patients is calculated using the Kaplan-Meier estimate of the hospitalization risk for placebo patients and the hazards ratio from the Cox regression model. The following formula was used: 4.1% = 1–(1–9.5%)0.421.
Treatment GroupParameterEstimates
Hazards Ratio (95% CI) P-value
HUMIRA –0.8640.421
(0.244–0.727)0.0019
Placebo (reference group)
0.000 1.000 –
All Randomized Patients
• Multivariate Cox regression results: Given a 3-month CD-related hospitalization risk of 9.5% for a patient on placebo, the hospitalization risk would reduce to 4.1% if the patient was treated with HUMIRA*
RNR RR
CHARM
Conclusions• HUMIRA treatment resulted in statistically significant
reductions of both all-cause and CD-related hospitalization risks in patients with moderate-to severe Crohn’s disease
– For randomized responders, the relative risk reductions of CD-related hospitalization for HUMIRA compared to placebo were 78% and 57% at 3 months and 1 year, respectively
– Even after controlling for potential confounding variables, HUMIRA had a statistically significant impact on reduction of all-cause and CD-related hospitalization risk compared to placebo
• This risk reduction associated with HUMIRA implies significant benefits to patients in terms of absenteeism and improving patient quality of life
• The lowering of hospitalization risk with HUMIRA could also reflect in significant costs savings to payers
CHARM
Feagan BG, et al. Gastroenterology 2007;132(4 Suppl 2):A-513.
For Advisors Only
Early Crohn’s Disease Shows High Levels of Remission to Therapy With Adalimumab:
Sub-analysis of CHARM
Early Crohn’s Disease Shows High Levels of Remission to Therapy With Adalimumab:
Sub-analysis of CHARM
S Schreiber1*, W Reinisch2*, JF Colombel3,
WJ Sandborn4, DW Hommes5, J Li6, JD Kent7, PF Pollack6
1Medicine, Christian Albrechts University, Kiel, Germany; 2Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 3Hepatogastroenterology, CHU Lille, Lille, France; 4Gastroenterology and Hepatology, Mayo
Clinic, Rochester, MN, USA; 5Gastroenterology and Hepatology, Leiden Medical Center, Leiden, Netherlands; 6Abbott, Parsippany, NJ, USA; 7Abbott,
Abbott Park, IL, USA; *Co-lead authors
S Schreiber1*, W Reinisch2*, JF Colombel3,
WJ Sandborn4, DW Hommes5, J Li6, JD Kent7, PF Pollack6
1Medicine, Christian Albrechts University, Kiel, Germany; 2Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 3Hepatogastroenterology, CHU Lille, Lille, France; 4Gastroenterology and Hepatology, Mayo
Clinic, Rochester, MN, USA; 5Gastroenterology and Hepatology, Leiden Medical Center, Leiden, Netherlands; 6Abbott, Parsippany, NJ, USA; 7Abbott,
Abbott Park, IL, USA; *Co-lead authors
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
*p=0.002, **p<0.001, †p=0.014, ‡p=0.001 all vs placebo
Clinical Remission at Weeks 26 and 56 by Disease Duration: RR
Week 26 Week 56
Placebo All HUMIRA
14
25
17
59*
40 41**
0
10
20
30
40
50
60
70
% o
f p
atie
nts
111117
35**
4451
0
10
20
30
40
50
60
70
% o
f p
atie
nts
†
‡
<2 years: PBO n=23 HUMIRA n=39; 2 to <5 years: PBO n=36, HUMIRA n=57; 5 years: PBO n=111, HUMIRA n=233
<2 years 2 to <5 years 5 years <2 years 2 to <5 years 5 years
CHARM
RR
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
*p=0.008, **p<0.001, †p=0.017, ‡p=0.002 vs placebo
Clinical Response (CR-100) at Weeks 26 and 56 by Disease Duration: RR
Placebo All HUMIRA
30 3124
50**51
67*
010
2030
4050
6070
80
% o
f p
atie
nts
151722
42**49
54
0
10
20
30
40
50
60
70
% o
f p
atie
nts
†
‡
<2 years: PBO n=23 HUMIRA n=39; 2 to <5 years: PBO n=36, HUMIRA n=57; 5 years: PBO n=111, HUMIRA n=233
<2 years 2 to <5 years 5 years <2 years 2 to <5 years 5 years
CHARM
Week 26 Week 56
RR
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
*p<0.001, **p=0.017, †p=0.004 vs placebo
Clinical Response (CR-70) at Weeks 26 and 56 by Disease Duration: RR
Placebo All HUMIRA
24
3339
67
54 53*
010
2030
4050
6070
80
% o
f p
atie
nts
161922
43**
5154*
0
10
20
30
40
50
60
70
% o
f p
atie
nts
†
<2 years: PBO n=23 HUMIRA n=39; 2 to <5 years: PBO n=36, HUMIRA n=57; 5 years: PBO n=111, HUMIRA n=233
<2 years 2 to <5 years 5 years <2 years 2 to <5 years 5 years
CHARM
Week 26 Week 56
RR
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
Disease Duration <2 years
Disease Duration 2–5 years
Disease Duration 5 years
Adverse Event, %PBON=23
All HUMIRA N=39
PBON=36
All HUMIRA N=57
PBON=111
All HUMIRA N=233
Any AE 78 87 75 86 88 90
AEs leading to discontinuation of drug
13 8 11 5 17 6*
Infectious AE 39 44 42 53 32 49*
Any SAE 9 3 11 5 18 9*
Infectious SAE 0 0 6 4 5 2
Injection-site reaction 4 23 3 11 5 17*
Deaths 0 0 0 0 0 0
*p<0.05 vs placebo
Adverse Events by Disease Duration:All HUMIRA-Treated Patients
CHARM
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
Conclusions
• HUMIRA maintained remission through Week 56 in patients with active CD, regardless of disease duration– Maintenance of clinical remission and response through
Week 56 was greater in HUMIRA-treated patients with early Crohn’s disease (<2 years)
• Long-term maintenance of remission rates suggest that early disease modification with HUMIRA would be beneficial to early CD patients
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
CHARM
For Advisors Only
GAINRapid Response to Adalimumab in Crohn’s
Disease Patients who Have Failed Infliximab
GAINRapid Response to Adalimumab in Crohn’s
Disease Patients who Have Failed Infliximab
GR D’Haens1, RA Enns2, G Van Assche3, JD Kent4, J Li5, PF Pollack5, DT Rubin6
1Gastroenterology, Imelda GI Clinical Research Center, Bonheiden, Belgium; 2Gastroenterology, University of British Columbia, Vancouver, BC, Canada;
3Gastroenterology, University of Leuven, Leuven, Belgium; 4Abbott, Abbott Park, IL, USA; 5Abbott, Parsippany, NJ, USA; 6Gastroenterology, University of Chicago, Chicago, IL, USA
GR D’Haens1, RA Enns2, G Van Assche3, JD Kent4, J Li5, PF Pollack5, DT Rubin6
1Gastroenterology, Imelda GI Clinical Research Center, Bonheiden, Belgium; 2Gastroenterology, University of British Columbia, Vancouver, BC, Canada;
3Gastroenterology, University of Leuven, Leuven, Belgium; 4Abbott, Abbott Park, IL, USA; 5Abbott, Parsippany, NJ, USA; 6Gastroenterology, University of Chicago, Chicago, IL, USA
D’Haens GR, et al. Gastroenterology 2007;132(4 Suppl 2):A-502.
Rationale
• Significant responses to HUMIRA in rheumatoid arthritis have been observed as early as one day after the first injection1
• A previous multicenter study in CD patients found significant correlation with 3 patient-reported diary components of the Crohn’s disease activity index [CDAI] (number of stools, abdominal pain, and general well-being) and the overall CDAI score (r=0.87, p<0.001)2
1. Wolfe F, et al. Arthiritis Rheum 2006;54(9) (Suppl):S424; 2. Sandler RS, et al. J Clin Epi 1988;41:451–58
GAIN
D’Haens GR, et al. Gastroenterology 2007;132(4 Suppl 2):A-502.
Objective and Methods
• To assess the time to symptomatic response to HUMIRA in CD patients who have failed prior treatment with infliximab
• Endpoints: CDAI diaries– Summation of 3 patient-reported components extracted from
7-day CDAI diaries collected at baseline, Weeks 1, 2, and 4 Abdominal pain—sum of 7 daily ratings (0=none, 1=mild,
2=moderate, 3=severe) Frequency of loose stools—number of liquid or very soft stools in 1
week General well-being—sum of 7 daily ratings (0=generally well,
1=slightly under par, 2=poor, 3=very poor, 4=terrible)
– Days 1–7 summed; 9–15; 23–29
GAIN
D’Haens GR, et al. Gastroenterology 2007;132(4 Suppl 2):A-502.
Conclusions
• HUMIRA led to statistically significant rapid improvements in patient-reported CDAI measures as early as Day 4. Statistically significant differences between HUMIRA and placebo groups were maintained for the remainder of the study
GAIN
D’Haens GR, et al. Gastroenterology 2007;132(4 Suppl 2):A-502.
For Advisors Only
Adalimumab Safety in Crohn’s Disease Clinical Trials
Adalimumab Safety in Crohn’s Disease Clinical Trials
JF Colombel1, WJ Sandborn2, W Reinisch3, SB Hanauer4, PJ Rutgeerts5, BE Sands6, W Lau7, JD Kent8, PF Pollack9
1Hepatogastroenterology, CHU Lille, Lille, Nord, France; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 3Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 4Section of
Gastroenterology, University of Chicago, Chicago, IL, USA; 5Gastro-Enterologie, University Hospital of Gasthuisberg, Leuven, Belgium; 6MGH Crohn’s and Colitis Center, Massachusetts General Hospital, Boston, MA, USA; 7Biostatistics, Abbott, Parsippany, NJ, USA; 8Immunology Development, Abbott, Abbott Park, IL, USA; 9Immunology Development, Abbott,
Parsippany, NJ, USA
JF Colombel1, WJ Sandborn2, W Reinisch3, SB Hanauer4, PJ Rutgeerts5, BE Sands6, W Lau7, JD Kent8, PF Pollack9
1Hepatogastroenterology, CHU Lille, Lille, Nord, France; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 3Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 4Section of
Gastroenterology, University of Chicago, Chicago, IL, USA; 5Gastro-Enterologie, University Hospital of Gasthuisberg, Leuven, Belgium; 6MGH Crohn’s and Colitis Center, Massachusetts General Hospital, Boston, MA, USA; 7Biostatistics, Abbott, Parsippany, NJ, USA; 8Immunology Development, Abbott, Abbott Park, IL, USA; 9Immunology Development, Abbott,
Parsippany, NJ, USA
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Objectives and Methods
• To assess overall HUMIRA safety across induction and maintenance datasets in Crohn’s disease clinical trials
• Clinical trial safety data of patients who received at least 1 open-label (OL) or randomized double-blind (DB) injection of HUMIRA were evaluated in 3 analysis sets:
– Induction trials CLASSIC I
GAIN
The OL 4-week induction phase of CHARM
– DB Maintenance trials CLASSIC II
CHARM
• Safety data collected through February 14, 2006, were included in this summary analysis
– All Exposure
CLASSIC I
CLASSIC II
CHARM
GAIN
OL extension trial following CHARM and GAIN
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Patient Exposure to HUMIRA in Crohn’s Clinical Trials
• The Crohn’s disease clinical trial database represents 1,506-PYs of exposure to HUMIRA
*Includes induction and extension trials through February 14, 2006
Exposure Patients*
Any 1,459
>6 months 883
>1 year 661
>2 years 240
>3 years 69
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Adverse Events of Interest: Induction Period
*Statistically significant difference vs placebo (p<0.05) using Fisher’s Exact test Statistical testing was only performed for the pooled HUMIRA 160/80 mg and placebo groupsNo malignant neoplasm or congestive heart failure (CHF) occurred
Adverse events (AE), n (%)Placebon=240
HUMIRA80/40 mg DB
n=75
HUMIRA 80/40 mg OL
n=854
HUMIRA 160/80 mg DB
n=235
Any AE 176 (73) 51 (68) 508 (60) 148 (63)*
Any serious AE 11 (5) 1 (1) 45 (5) 5 (2)
Any AE leading to discontinuation 6 (3) 1 (1) 54 (6) 2 (1)
Infectious AE 51 (21) 12 (16) 130 (15) 38 (16)
Serious infections 4 (2) 0 10 (1) 2 (1)
Injection-site related AE 29 (12) 16 (21) 109 (13) 41 (17)
Opportunistic infections 0 0 1 (0.1) 1 (0.4)
Demyelinating disease 0 0 1 (0.1) 0
Any fatal AE 0 0 1 (0.1) 0
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Adverse Events of Interest: Double-Blind Maintenance Period (E/100-PYs)
EOW = every other week; W = weekly; E = Events; E/100-PYs = Events/100-patient-yearsNo congestive heart failure (CHF), Lupus-like illness, demyelinating disease, or fatal AE occurred
Adverse events (AE)Placebo
n=279, 101.6-PYs
HUMIRA 40 mg eow
n=279, 156.6-PYs
HUMIRA 40 mg weekly
n=275, 162.3-PYs
Any AE 990 770 768
Any serious AE 48 19 20
Any AE leading to discontinuation
36 17 12
Infectious AE 168 147 136
Serious infections 9 5 4
Malignant neoplasm 2 0 0
Injection-site related AE 21 42 30
Opportunistic infections 2 1 3
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Adverse Events of Interest: All Exposure
Adverse events (AE), n=1459 E (E/100-PYs)
Any AE 12,124 (805.0)
Any serious AE 487 (32.3)
Any AE leading to discontinuation 326 (21.6)
Infectious AE 2,146 (142.5)
Serious infections 90 (6.0)
Malignant neoplasms 17 (1.1)
Injection-site related AE 552 (36.7)
Opportunistic infections 32 (2.1)
Congestive heart failure (CHF) 1 (<0.1)
Demyelinating disease 2 (0.1)
Any fatal AE 1 (<0.1)
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Overview of Malignant Neoplasms: All Exposure
Three events were coded as neoplasms but were not confirmed as malignant: 1Lung nodule, 2Lymphoid tissue regrowth, 3Bowen’s keratosis
System organ class, n (%) Patients (n=1,459)Any AE 16 (1.1)
Acute Myeloid Leukemia 1 (<0.1)
Basal Cell Carcinoma 3 (0.2)
Bladder 1 (<0.1)
Breast 1 (<0.1)
Lung Neoplasm1 1 (<0.1)
Neoplasm2 1 (<0.1)
Neoplasm Skin3 1 (<0.1)
Non-Hodgkin’s Lymphoma 1 (<0.1)
Ovarian 1 (<0.1)
Thyroid 2 (0.1)
Prostate 1 (<0.1)
Skin 1 (<0.1)
Squamous Cell Carcinoma 2 (0.1)
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Overview of Opportunistic Infections: All Exposure
System organ class, n (%)Any HUMIRA
n=1459
Any AE 29 (2.0)
Oral Candidiasis 22 (1.5)
Esophageal Candidiasis 4 (0.3)
Coccidioidomycosis 1 (<0.1)
Nocardiosis 1 (<0.1)
Tuberculosis 3 (0.2)
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
Conclusions
• HUMIRA was generally safe and well-tolerated in the treatment of patients with moderately to severely active Crohn’s disease
• No clinically meaningful differences during the induction period in patients treated with HUMIRA vs placebo
• When normalized for exposure, patients who received placebo experienced generally higher rates of adverse events than patients treated with maintenance HUMIRA
• The safety profile of HUMIRA is consistent over more than 10 years of clinical experience
Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.
For Advisors Only
HUMIRA Safety DataAcross Indications
HUMIRA Safety DataAcross Indications
Rates of AEs of Interest (E/100-PYs) in HUMIRA Global Clinical Trials
Indication RA PsA AS Ps JIA CDExposure (PYs) 12,506 484 423 135 99 1,506Patients 10,050 395 393 142 171 1,459Serious Infections 5.05 2.07 0.95 0.74 4.04 5.98Tuberculosis 0.27 0 0 0 0 0.20Lymphomas 0.12 0.41 0.24 0 0 0.07Demyelinating disease 0.08 0 0 0 0 0.13
SLE/Lupus-like syndrome 0.10 0 0 0 0 0.07
CHF 0.28 0 0 0 0 0
Schiff MH, et al. Ann Rheum Dis. 2006;65:889-894. Burmester G, et al. EULAR 2006, Amsterdam. #THU0214.Burmester GR, et al. ACR, Washington DC, 2006, #467.Colombel JF, et al. Gastroenterology 2007;132(4 Suppl 2):A-504.