1. BIOLOGIC THERAPY IN CROHN’S DISEASE
ATILLA ERTAN, M.D.

2. 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

3. HISTORY OF CROHN’S DISEASE TREATMENT
Sulfasalazine, steroids
Antibiotics, Azathioprine, 6-MP
ASA
1994 Budesonide
1995 Mtx
1998 Infliximab
2004 Second generation biologics

4. TNF Biophysiology
Most TNF is produced by monocytes, macrophages and lymphocytes. TNF also produced by intestinal epithelial cell in response to bacterial invasion.
TNF increases secretion of chemokines, cytokines and activates adoptosis from the epithelial cells.
TNF activates adhesion molecules, such as ICAM-I.

5. Key Actions Attributed to TNF
The effects of TNF vary depending upon the target cell, but can generally be characterized as proinflammatory. TNF induces macrophages to produce proinflammatory cytokines, such as IL-1 and IL-12, and chemokines, such as IL-8, which cause increased inflammation. Endothelium responds to TNF with enhanced expression of adhesion molecules, including E-selectin, resulting in increased cell infiltration. Fibroblasts produce IL-6 in response to TNF, which activates the acute phase response and leads to increased C-reactive protein, or CRP, in the serum. Fibroblasts are also induced to increase metalloproteinase synthesis and decrease collagen production, leading to tissue remodeling. In addition, TNF alters the epithelium by increasing ion transport and permeability which results in compromised barrier function.

6. Synthesis and Actions of TNF

7. Mechanism for Antibody Neutralization of TNF
The chimeric A2 (cA2) antibody consists of 75% human IgG1 at the constant regions joined with 25% murine at the antigen-binding regions. It has been speculated that the chimeric antibodies are less immunogenic than totally murine antibodies. Antibodies with human constant domains of the IgG1 subtype may also be more efficient in Fc region-mediated effector functions such as complement fixation, antibody-dependent cellular cytotoxicity and Fc-mediated antibody clearance. A prolonged circulating half-life has been seen in chimeric antibodies – a desirable feature for a prolonged therapeutic effect in chronic inflammation.
van Deventer S. Gut. 1997; 40:
Scallon BJ. Cytokine. 1995; 7:
Feldman M, et al. Adv Immunol. 1997; 64:

9. Chimeric A2 (cA2) Monoclonal Antibody
Infliximab
Mouse
(Binding Sites for TNFa)
Human (IgG1) k
The chimeric A2 (cA2) antibody consists of 75% human IgG1 at the constant regions joined with 25% murine at the antigen-binding regions. It has been speculated that the chimeric antibodies are less immunogenic than totally murine antibodies. Antibodies with human constant domains of the IgG1 subtype may also be more efficient in Fc region-mediated effector functions such as complement fixation, antibody-dependent cellular cytotoxicity and Fc-mediated antibody clearance. A prolonged circulating half-life has been seen in chimeric antibodies – a desirable feature for a prolonged therapeutic effect in chronic inflammation. k
Chimeric (mouse/human) IgG1 monoclonal antibody
Binds to TNFa with high specificity, high affinity, and high avidity
Knight JM, et al. Mol Immunol. 1993; 16:

10. Infliximab in Patients with Crohn’s Disease
The clinical response rate to a single dose of infliximab for moderate-to-severe CD inadequately responding to conventional therapy is 65%.
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. New Engl J Med. 1997;337:

11. Infliximab in Patients with Fistulizing Crohn’s Disease
62% of patients with fistulizing CD achieved a clinical response in the Present study. The primary endpoint was defined as a reduction of 50% or more from base line in the number of open fistulas observed at two or more consecutive visits. In order for a patient to reach the primary endpoint, a minimum of 21 days between consecutive visits was required. A complete response was defined as the absence of any draining fistulas at two or more consecutive visits.
Present D, et al. New Engl J Med. 1999; 340:

12. Clinical Response at Week 8, 30 and 54
ACT 1
Clinical Response at Week 8, 30 and 54
Proportion of Patients (%)
*p<0.001
**p=0.002 * **
Rutgeerts P et al. NEJM. 2005;353(23):30-44.

13. Clinical Remission at Week 8, 30 and 54
ACT 1
Proportion of Patients (%)
*p<0.001
**p=0.002
†p=0.001 * ** †
Rutgeerts P et al. NEJM. 2005;353(23):30-44.

14. Patients in Clinical Remission at Week 54
Week 2 Responders

15. Clinical Remission with Steroid Withdrawal at Week 54
Week 2 Responders Receiving Steroids at Baseline
Lindenbaum (on screen) 15

16. Maintenance Therapy was Associated with Greater Mucosal Healing
Rutgeerts, et al. Gastroenterology 2004;126:

17. Number of Crohn’s-related Hospitalizations per 100 Patients
All Randomized Patients
Rutgeerts, et al. Gastroenterology 2004;126:

18. Maintenance Therapy Is Associated with Fewer CD Surgeries
Reference?
Rutgeerts, et al. Gastroenterology 2004;126:

19. Conclusions
The ACCENT I trial proves that when REMICADE® (infliximab) is dosed every 8 weeks, patients are more likely to
Maintain clinical remission
Discontinue steroids
Maintain clinical response
Achieve mucosal healing
REMICADE maintenance is safe
Results consistent with earlier experience
Rutgeerts, et al. Gastroenterology 2004;126:

20. Conclusions cont.
Regular maintenance treatment with 5 or 10 mg/kg REMICADE® (infliximab) substantially reduces the rate and duration of hospitalization in Crohn’s disease patients, compared with single infusion plus episodic retreatment with 5 mg/kg
Rutgeerts, et al. Gastroenterology 2004;126:

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

22. Infusion Reactions

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

24. Infusion Reactions Infliximab infusions: 20,309
TREAT Registry
Infusion Reactions
Infliximab infusions: ,309
Infusions with reactions: %
Infusions with serious reactions: 0.12%
The experience from the TREAT registry in CD parallels that of clinical trials with regard to infusion reactions. With over 20,000 infliximab infusions administered, the rate of infusion reactions is 4.6% of infusions, and the incidence of serious infusion reactions is approximately 1 per 1000 infusions.
Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.

25. Infections

26. INFECTIONS DURING INFLIXIMAB THERAPY (n=170.000)
INFECTION n
Myobacterium tbc
Pneumocystis carinii
Listeria monocytogenes 11
Histoplasmosis
Candidiasis
Aspergillosis
Cryptococcosis
Coccidioidomycosis

27. Tuberculosis: Context
Patient Screening
Every patient being considered for an anti-TNF agent requires screening
Thorough screening may reveal potential risks:
Past exposure
TB treatment
Place of birth and travel history
Why is TB reactivation still occurring?
Many cases occur in patients who were not adequately screened and prophylaxed
Some cases occur in patients with false-negative screening tests
TB should always be considered in all immunosuppressed patients, even if their screening PPD was negative
Monitoring for potential infections is always required when treating patients with immunosuppressive drugs
Tuberculosis is an important safety issue with infliximab, as it is with all anti-TNF biologic drugs. However, the risk of TB can be decreased by appropriate patient selection, screening and prophylaxis. Nonetheless, cases of TB still occur in infliximab-treated patients. In many cases, patients have not been appropriately screened and prophylaxed. However, cases also occur in patients who screen negative for TB. The PPD is a good screening test for TB, but like all medical tests it is not accurate in every case. At best it is 90% sensitive, even in patients with active pulmonary TB. Therefore, it is important that TB always be considered in an anti-TNF-treated patient who develops an otherwise unexplained febrile illness. In some cases, empiric coverage for TB may be appropriate until it can be ruled out.
JAMA. 2004;292(14):

28. Serious Infections: Context Other IBD Immunosuppressive Agents
Annual rate of serious infections in infliximab-treated patients 6.4%
There is also an increased risk of serious infections with other IBD immunosuppressive agents
Many conventional therapies for Crohn’s disease have not been well studied in clinical trials
As previously discussed, it is an unfortunate fact that most patients with moderate-to-severe CD require therapy with immunosuppressive drugs. Other immunosuppressive drugs, such as corticosteroids and immunomodulators are also associated with a risk of serious infections. Doctors should also take into account the extensiveness of available clinical data for each of these agents. REMICADE has been studied extensively in patients with CD, while the efficacy and safety of other products used in CD have not been well characterized in clinical trials.

29. Malignancy & Lymphoma

30. Lymphoma in CD Patients
CD Publication
Relative incidence of lymphoma
Greenstein, 1985
4.7- fold increase
Mellemkjaer, 2000
1.5- fold increase
Lewis, 2001
1.4- fold increase
Bernstein, 2001
2.4- fold increase
There is also evidence there is an increased risk of lymphoma in CD patients, especially those with more severe disease. Similar to RA, it is not clear whether this is due to the underlying disease itself or to the conventional immunomodulator medications these patients frequently take.
Greenstein et al: A retrospective review of the case records of 1227 Crohn’s disease patients admitted to The Mount Sinai Hospital between 1960 and 1982.
Mellemkjaer et al: A cohort study of 2645 patients who had been hospitalized with Crohn’s disease during who were identified from the Danish National Registry of Patients in comparison with the incidence in the general population of Denmark. Cancer incidence for up to 17 years was determined in the cohort and compared to an expected number derived from national cancer incidence rates.
Lewis et al:A population based retrospective study was conducted in IBD patients (n=6605, CD; n=10,391, UC; n=67,970, controls) to determine the risk of lymphoma within the United Kingdom. Patients were followed for an average of 3.7, 3.9, 4.4 years, respectively.
Bernstein et al: A population based matched cohort design of crohn’s disease patients with 21,340 person-years of observation for Site specific cancer incidence rates in a cohort of persons with IBD were compared with those of non-IBD cohort that matched (1:10) to the IBD cohort based on age, gender, and geographic location of residence. The population based data was gathered from the administration claims data of Manitoba universal provincial insurance plan.

31. Malignancies and Lymphomas: Other Treatments
Cancer (% of patients)
AZA1
4.1%
6-MP2
6.3%*
6-MP3
3.1%
As noted in previous slides, theoretical concern about an increased risk of malignancy also exists with conventional immunomodulators. One of the roles of the immune system is cancer surveillance. Furthermore, as noted, at least some data suggests an increased risk of lymphoma in patients treated with azathioprine or 6-MP. It is not clear whether there is also an increased risk of other malignancies with these agents. Malignancies have developed in azathioprine/6-MP-treated patients at the rates noted in this slide in the published series available with this information. However, it is not possible to know whether these rates are higher than would be expected because the average follow-up period is not supplied in these reports, and since the age, race and gender of these patients is not known, it is not possible to calculate whether this incidence is higher than would be predicted by the SEER database.
Connell et al: Chart review of 755 patients treated for IBD. 2 mg/kg daily for a median of 12.5 months. Median follow-up was 9 years. Types of malignancies: SCC: anal canal, SCC: skin Adenocarcinoma: Rectum and colon, Stomach Cancer, Carcinomatosis, Carcinoma of the Bronchus, Breast cancer, Cervical cancer, AML, BCC, Dysgerminoma, PRV, Secondary Adeno.
Warman et al: Retrospective chart review from 1980 to 1999, 410 patients with IBD treated with 6-MP, 2 centers in NYC (Lenox Hill Hospital and private practice sites). Initial dose of 6-MP was 50 mg/d, with gradually increasing dosage per need. Types of malignancies: Colorectal cancer: rectum and descending colon, Ileum cancer, Ileocolic anastamosis, Colocutaneous fistula: descending colon, Adenocarcinoma, Cancer of the: Breast, Lung, Stomach, Testicle, Ovary, and Uterine Cervix, Melanoma, Islet cell carcinoma, Lymphoma: Brain and Abdomen, Leukemia, Waldenstrom’s macroglobulinemia
Present et al: Assessment of toxicity related to 6-MP in the treatment of IBD. 396 patients observed over 18 years, follow-up data for a mean period of 60.3 months obtained for 90% of patients. Types of malignancies: Histiocytic lymphoma: brain, Melanoma, Islet-cell carcinoma, Adenocarcinoma: lung, Carcinoma: colon, BCC, Breast cancer, Bladder, Thyroid, Prolactinoma
*Including 0.7% with lymphoma
1Connell WR et al., Lancet. 1994;343:1249– Warman JI. J Clin Gastroenterology. 2003;37(3):220– Present D et al., Annals of Internal Medicine. 1989;111:641–9.

32. Clinical Trials 32
Malignancies in Controlled Portions of Clinical Trials Compared with General Population
Patient-years of F/U
Expected # From SEER Database** General U.S. Population
Observed Number in Infliximab Trials
Placebo
892
5.65 1
Infliximab
4990
29.04 29
With regard to overall malignancies, the incidence of malignancies in the infliximab-treated patients during the controlled portion of clinical trials has been similar to what would be expected in a population matched for age, race and gender from the SEER database. However, the rate of malignancies in placebo-treated patients during the controlled portions of infliximab clinical trials has been lower than expected. The reasons for this latter observation are not known.
**Excludes non-melanoma skin cancers because also excluded in SEER database
Data on file, Centocor, Inc.

33. Malignancy: Context
At the present time, it is not possible to be certain whether the use of anti-TNF agents increases a patient’s chance of developing a malignancy
There is also concern conventional immunomodulators may increase the risk of malignancy
Risks must always be weighed against the risks of inadequate treatment of the underlying disease
Caution should be exercised when treating any patient with a current or past history of malignancy
Concerns about the potentially-increased risk of lymphoma and other malignancies with the use of infliximab must be considered in a number of contexts. However, even if an added risk exists, it has to be considered in the context of the benefit patients derive from these drugs. It must be borne in mind that the appropriate candidates for infliximab therapy in IBD already have a serious disease that has inadequately responded to conventional therapy. There are serious consequences of inadequately-treated IBD and these must be appropriately weighed against the concerns about malignancy.

38. PRECiSE 2: Clinical Response at Week 26 (ITT)
3 inj. Certolizumab pegol + Placebo
100
Certolizumab pegol 400 mg sc 80
p<0.001
p<0.001
62.8
61.6 60
% of Patients
36.2 40
33.7 20
All
CRP 10 mg/L
(n=210)
(n=215)
(n=101)
(n=112)
Schreiber, et al. Gut 2005; 54 (Suppl VII) A82

39. PRECiSE 2: Clinical Response at Week 26 by Prior Anti-TNF Use
Certolizumab pegol 400 mg
3 inj. Certolizumab pegol
+ Placebo
100
p<0.001 80
68.7
P=0.018 60
44.2
% of Patients
39.6 40
25.5 20
No prior Anti-TNF
Prior Anti-TNF (IFX)
(n=159)
(n=163)
(n=51)
(n=52)
UCB, Inc. Data on File
© UCB All rights reserved

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

41. PRECISE 2: Conclusions cont.
Certolizumab demonstrated efficacy across a broad patient population and well tolerated safety profile.
Certolizumab 400 mg q 4wk with an additional induction dose at wk 2, will be a valuable addition to the Crohn’s disease treatment armamentarium, when approved.

42. PRECiSE Phase III studies (Pegylated antibody fRagment Evaluation in Crohn’s disease Safety and Efficacy)
PRECiSE 1 and 2 are large international, Phase III, placebo-controlled studies designed to demonstrate the safety and efficacy of certolizumab pegol in inducing and maintaining response and remission in patients with moderate to severe Crohn’s disease

43. BIOLOGICS (TNF-Abs) In CROHN'S DISEASE
Name
Route
Humanized antibody %
Efficacy
Immunogenicity
INFLIXIMAB/REMICADE IV 75
Yes
High
CERTOLIZUMAB/CIMZIA SC
100
Low
ADALIMUMAB/HUMIRA
ETANERCEPT No
ONERCEPT
CD571

44. Infliximab Benefit:Risk in IBD: Summary
The natural history of inflammatory bowel disease results in a poor quality of life for many patients
Infliximab has been a major advance in treating IBD
Infliximab therapy is associated with risks, but these risks must be placed in context:
Benefits patients derive from infliximab
Risks of under-treating IBD
Risks of surgeries, other immunosuppressive medications and corticosteroids used for IBD
For most patients, the benefit of infliximab will outweigh its risks, but treatment decisions need to be individualized

45. Infections in All Completed Clinical Trials
Placebo Infliximab
Patients treated
Average wks follow-up
# infections per 100 pt-yrs
# infections requiring treatment per 100 pt-yrs
# serious infections per 100 pt-yrs Pneumonia
Abscess
Cellulitis
Sepsis
Tuberculosis
The risk of infections, in particular serious infections, must be considered when any immunosuppressive drug is used, and infliximab is no exception. Infliximab is an immunosuppressive drug, so it is not surprising more infections occur when it is used. However, for patients with IBD, especially moderate-to-severe IBD, there are unfortunately often no effective alternatives other than drugs suppressing the immune system, including corticosteroids, conventional immunomodulators and infliximab. The risk of serious infection must thus be balanced against the risk of inadequately-controlled IBD.
In clinical trials, the rate of serious infections in the infliximab group was 6.4 per 100 patient-years of follow-up and the rate of serious infections in the placebo group was 5.6 per 100 patient-years of follow-up. Thus, infliximab confers the risk of approximately one additional serious infection per year.
Data on file, Centocor, Inc.

46. Important Safety Information: Risk of Infection
Tuberculosis (tb) (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections, have been observed in patients receiving infliximab. Some of these infections have been fatal. Patients should be evaluated for latent tb infection with a skin test.1 treatment of latent tb infection should be initiated prior to therapy with infliximab. Active tb has developed in patients receiving infliximab who were tuberculin skin test–negative prior to receiving infliximab. Monitor patients receiving infliximab for signs and symptoms of active tb, including those who 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.

47. Lymphomas Observed During Infliximab Clinical Trials47
Lymphomas Observed During Infliximab Clinical Trials
Pt Yrs follow-up
Observed
Lymphomas
Expected Lymphomas in Non-RA Population*
All Studies
4996 5
1.10
RA Studies
2428 2
0.62
The above table describes the standardized incidence ratio across patients treated with infliximab and placebo-treated patients in all infliximab clinical trials.
The lymphomas observed in clinical trials was compared with the general population. The SEER database for 2002 was used to estimate the expected incidence of malignancies based on the general U.S. population, adjusted for age, gender, and duration of follow-up. Note the comparator population here is the general US population, and not a population of patients with RA or CD. The standardized incidence ratio for infliximab across all studies was It is not possible to determine from this whether the risk of lymphoma in infliximab-treated patients is increased beyond what it is in the population of patients with these diseases.
Nevertheless caution should be exercised when treating any patient with a current or past history of malignancies and any potential for risks should be weighed against the potential benefit for each individual patient.
Data on file, Centocor, Inc.

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

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

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

51. Rationale for Protocol C87042
Infliximab (IFX), a chimeric monoclonal antibody against TNF-alpha, is the only approved biological therapy for treatment of Crohn’s disease.
IFX contains substantial murine protein sequences in the variable region. Thus, it is immunogenic and intermittent administration results in antibodies to IFX (ATIs).
Humanized monoclonal antibodies are relatively less immunogenic than chimeric antibodies.
We hypothesize that the pegylated humanized anti-TNF-alpha monoclonal antibody Fab' fragment (certolizumab pegol) could be a valuable treatment alternative to IFX in patients previously treated successfully with IFX but who have lost response or who have 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: