for advisors only biologic therapy in crohn’s disease atilla ertan, facp, agaf, macg

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


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


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


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)


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


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


*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

†

‡



CHARM

Week 26 Week 56

RR


*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

†



CHARM

Week 26 Week 56

RR


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


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


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


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


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


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


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


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


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


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


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)


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)


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)


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


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.

for advisors only biologic therapy in crohn’s disease atilla ertan, facp, agaf, macg

Documents

macg slide

yellow slide

crohns disease slide

eow week

week eow cd

maintenance of remission

maintenance dose

fab fragments