BIOLOGIC THERAPY BIOLOGIC THERAPY IN CROHN’S DISEASEIN CROHN’S DISEASE

ATILLA ERTAN, M.D. ATILLA ERTAN, M.D.

THERAPEUTIC GOALS IN IBDTHERAPEUTIC GOALS IN IBD

Clinical improvementClinical improvement Clinical remissionClinical remission Corticosteroid weaningCorticosteroid weaning Maintenance of remissionMaintenance of remission Maintained tissue healingMaintained tissue healing Decrease in hospitalization & surgical Decrease in hospitalization & surgical

interventionsinterventions Prevention of complicationsPrevention of complications Change natural course of the diseaseChange natural course of the disease

HISTORY OF CROHN’S DISEASE TREATMENT

1979 Sulfasalazine, steroids1979 Sulfasalazine, steroids

19801980 Antibiotics, Azathioprine, 6-MPAntibiotics, Azathioprine, 6-MP

19931993 5-ASA5-ASA

19941994 BudesonideBudesonide

19951995 MtxMtx

19981998 InfliximabInfliximab

20042004 Second generation biologicsSecond generation biologics

TNF Biophysiology Most TNF is produced by monocytes, Most TNF is produced by monocytes, macrophages and lymphocytes. TNF also macrophages and lymphocytes. TNF also produced by intestinal epithelial cell in produced by intestinal epithelial cell in response response to bacterial invasion.to bacterial invasion.

TNF increases secretion of chemokines, TNF increases secretion of chemokines, cytokines and activates adoptosis from the cytokines and activates adoptosis from the epithelial cells.epithelial cells.

TNF activates adhesion molecules, such as TNF activates adhesion molecules, such as ICAM-I.ICAM-I.

Key Actions Attributed to TNFKey Actions Attributed to TNF

Synthesis and Actions of TNFSynthesis and Actions of TNF

Mechanism for Antibody Mechanism for Antibody Neutralization of TNFNeutralization of TNF

van Deventer S. van Deventer S. GutGut. 1997; 40:443-48.. 1997; 40:443-48.

Scallon BJ. Scallon BJ. CytokineCytokine. 1995; 7:251-59.. 1995; 7:251-59.

Feldman M, et al. Feldman M, et al. Adv Immunol.Adv Immunol. 1997; 64:283-350. 1997; 64:283-350.

© 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

Chimeric A2 (cA2) Monoclonal Chimeric A2 (cA2) Monoclonal AntibodyAntibody

InfliximabInfliximab

Chimeric (mouse/human) Chimeric (mouse/human) IgGIgG11 monoclonal antibody monoclonal antibody

Binds to TNFBinds to TNF with high specificity, high with high specificity, high affinity, and high avidityaffinity, and high avidity

Human (IgG1)

Mouse(Binding Sites for TNF)

Infliximab in Patients with Crohn’sInfliximab in Patients with Crohn’sDiseaseDisease

Clinical Response defined as at least a 70-point reduction in CDAI.Clinical Remission defined as a decline of the CDAI below 150.

Targan S, et al. Targan S, et al. New Engl J MedNew Engl J Med. . 1997;337:1029-35.1997;337:1029-35.

Infliximab in PatientsInfliximab in Patientswith Fistulizing Crohn’s Diseasewith Fistulizing Crohn’s Disease

Present D, et al. Present D, et al. New Engl J MedNew Engl J Med. 1999; 340:1398-. 1999; 340:1398-405.405.

Clinical Response at Week 8, 30 Clinical Response at Week 8, 30 and 54and 54

ACT 1

3730

19.8

69

5245.5

62

5144.3

0

20

40

60

80

100

Week 8 Week 30 Week 54

Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab

Pro

po

rtio

n o

f P

ati

ents

(%

)

*p<0.001**p=0.002

**

* ** * *

Rutgeerts P et al. Rutgeerts P et al. NEJMNEJM. 2005;353(23):30-44.. 2005;353(23):30-44.

Clinical Remission at Week 8, 30 Clinical Remission at Week 8, 30 and 54and 54

ACT 1

Rutgeerts P et al. Rutgeerts P et al. NEJMNEJM. 2005;353(23):30-44.. 2005;353(23):30-44.

Pro

po

rtio

n o

f P

ati

ents

(%

)

14.9 15.7 16.5

38.833.9 34.732

36.9 34.4

0

20

40

60

80

100

Week 8 Week 30 Week 54

Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab

*p<0.001**p=0.002†p=0.001

* *** †

††

Patients in Clinical Remission at Patients in Clinical Remission at Week 54Week 54

Week 2 RespondersWeek 2 Responders

Week 2 Responders Receiving Steroids at BaselineWeek 2 Responders Receiving Steroids at Baseline

Clinical Remission with Steroid Clinical Remission with Steroid Withdrawal at Week 54Withdrawal at Week 54

082201.1 Lindenbaum (on screen) 15

Maintenance Therapy was Maintenance Therapy was Associated with Greater Associated with Greater

Mucosal HealingMucosal Healing

Rutgeerts, et al. Gastroenterology 2004;126:402-413.

Number of Crohn’s-related Number of Crohn’s-related Hospitalizations per 100 PatientsHospitalizations per 100 PatientsAll Randomized PatientsAll Randomized Patients

Rutgeerts, et al. Gastroenterology 2004;126:402-413.

Maintenance Therapy Is Maintenance Therapy Is Associated with Fewer CD Associated with Fewer CD

SurgeriesSurgeries

Rutgeerts, et al. Gastroenterology 2004;126:402-413.

Conclusions Conclusions

The ACCENT I trial proves that when The ACCENT I trial proves that when REMICADEREMICADE®® (infliximab) is dosed every 8 (infliximab) is dosed every 8 weeks, patients are more likely toweeks, patients are more likely to Maintain clinical remissionMaintain clinical remission Discontinue steroidsDiscontinue steroids Maintain clinical responseMaintain clinical response Achieve mucosal healingAchieve mucosal healing

REMICADE maintenance is safeREMICADE maintenance is safe Results consistent with earlier experienceResults consistent with earlier experience

Rutgeerts, et al. Gastroenterology 2004;126:402-413.

Conclusions cont.Conclusions cont.

Regular maintenance treatment with 5 or Regular maintenance treatment with 5 or 10 mg/kg REMICADE10 mg/kg REMICADE®® (infliximab) (infliximab) substantially reduces the rate and substantially reduces the rate and duration of hospitalization in Crohn’s duration of hospitalization in Crohn’s disease patients, compared with single disease patients, compared with single infusion plus episodic retreatment with 5 infusion plus episodic retreatment with 5 mg/kgmg/kg

Rutgeerts, et al. Gastroenterology 2004;126:402-413.

Conclusions cont.Conclusions cont.

Regular maintenance treatment with 5 or Regular maintenance treatment with 5 or 10 mg/kg REMICADE may reduce the 10 mg/kg REMICADE may reduce the number of all surgeries/procedures in number of all surgeries/procedures in Crohn’s disease patients, compared with Crohn’s disease patients, compared with single infusion plus episodic retreatment single infusion plus episodic retreatment with 5 mg/kgwith 5 mg/kg

Infusion ReactionsInfusion Reactions

Important Safety Information: Important Safety Information:

HypersensitivityHypersensitivity

Infliximab sInfliximab should not be administered to patients hould not be administered to patients with hypersensitivity to murine proteins or other with hypersensitivity to murine proteins or other components of the product. components of the product. Infliximab Infliximab has been has been associated with hypersensitivity reactions that associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in dyspnea, and hypotension have occurred in association with association with Infliximab Infliximab infusions. Serious infusions. Serious infusion reactions including anaphylaxis were infusion reactions including anaphylaxis were infrequent. Medications for the treatment of infrequent. Medications for the treatment of hypersensitivity reactions should be hypersensitivity reactions should be available.available.

Infusion ReactionsInfusion Reactions

Infliximab infusions:Infliximab infusions: 20,309 20,309Infusions with reactions:Infusions with reactions: 4.6% 4.6%Infusions with serious reactions: 0.12%Infusions with serious reactions: 0.12%

TREAT Registry

Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

InfectionsInfections

INFECTIONS DURING INFLIXIMAB THERAPY INFECTIONS DURING INFLIXIMAB THERAPY (n=170.000) (n=170.000)

INFECTIONINFECTION n nMyobacterium tbcMyobacterium tbc 8484Pneumocystis cariniiPneumocystis carinii 1212Listeria monocytogenesListeria monocytogenes 1111HistoplasmosisHistoplasmosis 9 9Candidiasis Candidiasis 7 7Aspergillosis Aspergillosis 6 6Cryptococcosis Cryptococcosis 2 2Coccidioidomycosis Coccidioidomycosis 2 2

Tuberculosis: ContextTuberculosis: Context Patient ScreeningPatient Screening

Every patient being considered for an anti-TNF agent Every patient being considered for an anti-TNF agent requires screeningrequires screening

Thorough screening may reveal potential risks: Thorough screening may reveal potential risks: • Past exposurePast exposure• TB treatmentTB treatment• Place of birth and travel historyPlace of birth and travel history

Why is TB reactivation still occurring?Why is TB reactivation still occurring?• Many cases occur in patients who were not adequately Many cases occur in patients who were not adequately

screened and prophylaxedscreened and prophylaxed• Some cases occur in patients with false-negative screening Some cases occur in patients with false-negative screening

teststests TB should always be considered in all immunosuppressed TB should always be considered in all immunosuppressed

patients, even if their screening PPD was negativepatients, even if their screening PPD was negative

Monitoring for potential infections is always Monitoring for potential infections is always required when treating patients with required when treating patients with immunosuppressive drugsimmunosuppressive drugs

JAMA. 2004;292(14):1676-1678.

Serious Infections: ContextSerious Infections: ContextOther IBD Immunosuppressive Other IBD Immunosuppressive

AgentsAgents Annual rate of serious infections in infliximab-treated Annual rate of serious infections in infliximab-treated

patients 6.4%patients 6.4% There is also an increased risk of serious infections with There is also an increased risk of serious infections with

other IBD immunosuppressive agentsother IBD immunosuppressive agents Many conventional therapies for Crohn’s disease have Many conventional therapies for Crohn’s disease have

not been well studied in clinical trialsnot been well studied in clinical trials

Malignancy & Malignancy & LymphomaLymphoma

Lymphoma in CD PatientsLymphoma in CD Patients

CD PublicationCD PublicationRelative incidence of Relative incidence of lymphoma lymphoma

Greenstein, 1985Greenstein, 1985 4.7- fold increase4.7- fold increase

Mellemkjaer, 2000Mellemkjaer, 2000 1.5- fold increase1.5- fold increase

Lewis, 2001Lewis, 2001 1.4- fold increase1.4- fold increase

Bernstein, 2001Bernstein, 2001 2.4- fold increase2.4- fold increase

Malignancies and Lymphomas: Malignancies and Lymphomas: Other TreatmentsOther Treatments

TreatmentTreatment

Cancer Cancer (% of (% of

patients)patients)AZAAZA11 4.1% 4.1% 6-MP6-MP22 6.3%*6.3%*6-MP6-MP33 3.1%3.1%

1Connell WR et al., Lancet. 1994;343:1249–52. 2Warman JI. J Clin Gastroenterology. 2003;37(3):220–225. 3Present D et al.,

Annals of Internal Medicine. 1989;111:641–9.

*Including 0.7% with lymphoma

Malignancies in Controlled Portions Malignancies in Controlled Portions of Clinical Trials Compared with of Clinical Trials Compared with

General Population General Population

**Excludes non-melanoma skin cancers because also excluded in SEER database

32

Patient-Patient-years of F/Uyears of F/U

Expected # Expected # From SEER From SEER Database** Database**

General U.S. General U.S. PopulationPopulation

Observed Observed Number in Number in

Infliximab TrialsInfliximab Trials

PlaceboPlacebo 892892 5.655.65 11

InfliximabInfliximab 49904990 29.0429.04 2929

Data on file, Centocor, Inc.

Clinical TrialsClinical Trials

Malignancy: ContextMalignancy: Context

At the present time, it is not possible to be certain At the present time, it is not possible to be certain whether the use of anti-TNF agents increases a whether the use of anti-TNF agents increases a patient’s chance of developing a malignancypatient’s chance of developing a malignancy

There is also concern conventional There is also concern conventional immunomodulators may increase the risk of immunomodulators may increase the risk of malignancymalignancy

Risks must always be weighed against the risks of Risks must always be weighed against the risks of inadequate treatment of the underlying disease inadequate treatment of the underlying disease

Caution should be exercised when treating any Caution should be exercised when treating any patient with a current or past history of malignancypatient with a current or past history of malignancy

© UCB 2006. All rights reserved.

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 (ca. 2 weeks) to a

value compared with a whole antibody product

compatible with sc administration

Site specific PEGylation to hinge thiol

using proprietary linkage technology

In vitro no monocytes and lymphocytes apoptosis, no complement activation, no ADCC

Chapman A et al., Nature Biotech 1999; 17: 780-3Fossati G and Nesbitt AM. Am J Gastroenterol 2005;100 (Suppl 9):S299

Molecular structure of certolizumab pegolThe chains of the Fab' fragment are shown in

green and blue and the PEG is shown in yellow

© 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

© UCB 2006. All rights reserved.

Phase II: Clinical Response in Patients (ITT)

Adapted from: Schreiber et al. Gastroenterology. 2005;29(3):807-18

p=0.010 p=0.006p=0.005

p=0.010

0

20

40

60

80

100

0 2 4 6 8 10 12

Weeks

% o

f P

ati

en

ts

Placebo (N=73) Certolizumab pegol 400 mg (N=72)

© UCB 2006. All rights reserved.

Phase II: Clinical Response in Patients (Baseline CRP 10 mg/L)

p=0.002p<0.001

p=0.004 p<0.001p<0.001

p=0.005

0

20

40

60

80

100

0 2 4 6 8 10 12

Weeks

% o

f P

ati

en

ts

Placebo (N=28) Certolizumab pegol 400 mg (N=32)

Adapted from: Schreiber et al. Gastroenterology. 2005;29(3):807-18

PRECiSE 2: PRECiSE 2: Clinical Response Clinical Response at Week 26 (ITT)at Week 26 (ITT)

(n=210) (n=215) (n=101) (n=112)

p<0.001 p<0.001

3 inj. Certolizumab pegol + Placebo

36.2 33.7

62.8 61.6

0

20

40

60

80

100

All

% o

f P

atie

nts

Certolizumab pegol 400 mg sc

CRP 10 mg/L

Schreiber, et al. Gut 2005; 54 (Suppl VII) A82

PRECiSE 2: PRECiSE 2: Clinical Response at Clinical Response at Week 26 by Prior Anti-TNF Use Week 26 by Prior Anti-TNF Use

(n=159) (n=163) (n=51) (n=52)

P=0.018

p<0.001

© UCB 2006. All rights reserved

39.6

25.5

68.7

44.2

0

20

40

60

80

100

No prior Anti-TNF Prior Anti-TNF (IFX)

% o

f P

atie

nts

3 inj. Certolizumab pegol + Placebo

Certolizumab pegol 400 mg

UCB, Inc. Data on File

PRECiSE 2: ConclusionsPRECiSE 2: Conclusions

PRECiSE 2 demonstrated that in the PRECiSE 2 demonstrated that in the clinical trial clinical trial certolizumab certolizumab pegol pegol induced clinical response and induced clinical response and maintained clinical response and maintained clinical response and remission in patients with active remission in patients with active Crohn’s disease, regardless of Crohn’s disease, regardless of baseline CRP level. baseline CRP level.

PRECISE 2: Conclusions cont.PRECISE 2: Conclusions cont.

CertolizumabCertolizumab d demonstrated efficacy emonstrated efficacy across a broad patient population across a broad patient population and well tolerated safety profile.and well tolerated safety profile.

CertolizumabCertolizumab 400 mg q 4wk with an 400 mg q 4wk with an additional induction dose at wk 2, will be additional induction dose at wk 2, will be a valuable addition to the Crohn’s a valuable addition to the Crohn’s disease treatment armamentarium, disease treatment armamentarium, when approved.when approved.

PRECiSE Phase III studiesPRECiSE Phase III studies

((PPegylated antibody fegylated antibody fRRagment agment EEvaluation valuation

in in CCrohn’s drohn’s diisease sease SSafety and afety and EEfficacy)fficacy) PRECiSE 1 and 2 are large international, PRECiSE 1 and 2 are large international,

Phase III, placebo-controlled studies Phase III, placebo-controlled studies designed to demonstrate the safety and designed to demonstrate the safety and efficacy of certolizumab pegol in efficacy of certolizumab pegol in inducing and maintaining response and inducing and maintaining response and remission in patients with moderate to remission in patients with moderate to severe Crohn’s diseasesevere Crohn’s disease

BIOLOGICS (TNF-Abs) In CROHN'S DISEASE

Name Route

Humanized antibody % Efficacy Immunogenicity

INFLIXIMAB/REMICADE IV 75 Yes High

CERTOLIZUMAB/CIMZIA SC 100 Yes Low

ADALIMUMAB/HUMIRA SC 100 Yes Low

ETANERCEPT     No  

ONERCEPT     No  

CD571     No  

Infliximab Benefit:Risk in IBD:Infliximab Benefit:Risk in IBD:SummarySummary

The natural history of inflammatory bowel disease The natural history of inflammatory bowel disease results in a poor quality of life for many patientsresults in a poor quality of life for many patients

Infliximab has been a major advance in treating IBDInfliximab has been a major advance in treating IBD Infliximab therapy is associated with risks, but these Infliximab therapy is associated with risks, but these

risks must be placed in context:risks must be placed in context: Benefits patients derive from infliximabBenefits patients derive from infliximab Risks of under-treating IBDRisks of under-treating IBD Risks of surgeries, other immunosuppressive medications Risks of surgeries, other immunosuppressive medications

and corticosteroids used for IBDand corticosteroids used for IBD For most patients, the benefit of infliximab will For most patients, the benefit of infliximab will

outweigh its risks, but treatment decisions need to be outweigh its risks, but treatment decisions need to be individualizedindividualized

PlaceboPlacebo InfliximabInfliximab

Patients treatedPatients treated 16001600 57065706Average wks follow-upAverage wks follow-up 29.029.0 45.545.5# infections per 100 pt-yrs# infections per 100 pt-yrs 115.6115.6 132.3132.3# infections requiring # infections requiring 54.854.8 61.261.2

treatment per 100 pt-yrstreatment per 100 pt-yrs

# serious infections per 100 pt-yrs# serious infections per 100 pt-yrs 5.65.6 6.46.4PneumoniaPneumonia 0.110.11 1.081.08AbscessAbscess 0.450.45 0.840.84CellulitisCellulitis 0.450.45 0.320.32SepsisSepsis 0.220.22 0.320.32TuberculosisTuberculosis 0.110.11 0.380.38

Infections in All Completed Clinical TrialsClinical TrialsClinical Trials

Data on file, Centocor, Inc.

Important Safety Information: Important Safety Information: Risk of InfectionRisk of Infection

Tuberculosis (tb) (frequently disseminated or Tuberculosis (tb) (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections, have been infections, and other opportunistic infections, have been observed in patients receiving infliximab. Some of these observed in patients receiving infliximab. Some of these infections have been fatal. Patients should be evaluated infections have been fatal. Patients should be evaluated for latent tb infection with a skin test.for latent tb infection with a skin test.11 treatment of latent treatment of latent tb infection should be initiated prior to therapy with tb infection should be initiated prior to therapy with infliximab. Active tb has developed in patients receiving infliximab. Active tb has developed in patients receiving infliximab who were tuberculin skin test–negative prior to infliximab who were tuberculin skin test–negative prior to receiving infliximab. Monitor patients receiving infliximab receiving infliximab. Monitor patients receiving infliximab for signs and symptoms of active tb, including those who for signs and symptoms of active tb, including those who are tuberculin skin test–negative. are tuberculin skin test–negative.

1American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection.Am J Respir Crit Care Med. 2000;161:S221–S247.

Lymphomas Observed Lymphomas Observed During Infliximab Clinical TrialsDuring Infliximab Clinical Trials

Pt Yrs Pt Yrs follow-follow-

upup

Observed Observed

LymphomasLymphomas

Expected Expected Lymphomas in Lymphomas in

Non-RA Non-RA Population*Population*

All All StudiesStudies 49964996 55 1.101.10

RA RA StudiesStudies 24282428 22 0.620.62

47

Data on file, Centocor, Inc.

Important Safety Information: Important Safety Information: ContraindicationsContraindications

Infliximab is contraindicated in patients with moderate Infliximab is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have of cardiovascular events at the 5 mg/kg dose have been observed in these patients. Infliximab should be been observed in these patients. Infliximab should be used with caution and only after consideration of used with caution and only after consideration of other treatment options. Patients should be other treatment options. Patients should be monitored closely. Discontinue infliximab if new or monitored closely. Discontinue infliximab if new or worsening CHF symptoms appear. Infliximab should worsening CHF symptoms appear. Infliximab should not be administered to patients with hypersensitivity not be administered to patients with hypersensitivity to murine proteins or other components of the to murine proteins or other components of the product. product.

Important Safety Information: Important Safety Information: HepatotoxicityHepatotoxicity

Severe hepatic reactions, including acute liver failure, Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving infliximab postmarketing. Some rarely in patients receiving infliximab postmarketing. Some cases were fatal or required liver transplant. cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., enzyme elevations (e.g., 5 times the upper limit of normal) 5 times the upper limit of normal) develop, infliximab should be discontinued, and a thorough develop, infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken. investigation of the abnormality should be undertaken. Infliximab has been associated with reactivation of hepatitis Infliximab has been associated with reactivation of hepatitis B. Chronic carriers of hepatitis B should be evaluated and B. Chronic carriers of hepatitis B should be evaluated and monitored prior to and during treatment. monitored prior to and during treatment.

Important Safety Information: Important Safety Information: Neurologic EventsNeurologic Events

TNF inhibitors, including infliximab, have been associated TNF inhibitors, including infliximab, have been associated with rare cases of new or exacerbated symptoms of with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, and demyelinating disorders including multiple sclerosis, and optic neuritis, seizure, and CNS manifestations of systemic optic neuritis, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering infliximab in vasculitis. Exercise caution when considering infliximab in all patients with these disorders. Consider discontinuation all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.for significant CNS adverse reactions.

Rationale for Protocol C87042Rationale for Protocol C87042 Infliximab (IFX), a chimeric monoclonal antibody against TNF-alpha, Infliximab (IFX), a chimeric monoclonal antibody against TNF-alpha,

is the only approved biological therapy for treatment of Crohn’s is the only approved biological therapy for treatment of Crohn’s disease. disease.

IFX contains substantial murine protein sequences in the variable IFX contains substantial murine protein sequences in the variable region. Thus, it is immunogenic and intermittent administration region. Thus, it is immunogenic and intermittent administration results in antibodies to IFX (ATIs).results in antibodies to IFX (ATIs).

Humanized monoclonal antibodies are relatively less immunogenic Humanized monoclonal antibodies are relatively less immunogenic than chimeric antibodies.than chimeric antibodies.

We hypothesize that the pegylated humanized We hypothesize that the pegylated humanized anti-TNF-alpha anti-TNF-alpha monoclonal antibodymonoclonal antibody Fab' Fab' fragment (certolizumab pegol) could be a fragment (certolizumab pegol) could be a valuable treatment alternative to IFX in patients previously treated valuable treatment alternative to IFX in patients previously treated successfully with IFX but who have lost response or who have successfully with IFX but who have lost response or who have developed intolerance to IFX.developed intolerance to IFX.

Baert F, et al. NEJM 2003; 348: 601-8; Farrell RJ, et al. Gastroenterology 2003; 124:917-24; Hanauer S, et al. Gastroenterology 1999; 116: A731; Breedveld FC, Lancet 2000; 355:735-740.