1. Positioning Our Recent & Future Therapy in Crohn’s disease
Ahmad Alfadhli MD, FRCPC
Gastroenterology Unite
Haya Al-Habeeb Center
Mubarak Al-Kabeer Hospital
KUWAIT

2. New Therapeutic Goals in CD
Modification of long-term course of CD
Complete and persistent healing of bowel mucosa
Avoidance of complications, including stenoses, abscesses, and fistulae
Avoidance of hospitalization, surgeries, and ICU stay
Improved cost-to-efficacy ratio of treatment
Normal bowel function and improved QOL

3. Corticosteroid

4. Steroids for the treatment of Crohn’s Disease – benefit for the patient
prolonged
response
remission
“positive”
outcome
steroid
dependent
partial
remission
“negative”
outcome
surgery no
response
Faubion WA et al. Gastroenterology 2001;121:255

5. Benefit risk profile of major CD therapies: infections and mortality
TREAT
Benefit risk profile of major CD therapies: infections and mortality
Multivariate analysis
4.5
Mortality
Serious infections 4
3.5 3
HAZARD RATIO
2.5
IFX †
AZA
6-MP
MTX *
IFX
AZA
6-MP
MTX 2
Safety of Infliximab and Other Crohn’s Disease Therapies – TREAT™ Registry Data with Nearly 20,000 Patient-Years of Follow-Up
GR Lichtenstein, RD Cohen, BG Feagan, WJ Sandborn, BA Salzberg, DM Chen, MP Turner, DR Mink, DL Broussard, RH Diamond
Background and Methods: TREAT, a prospective registry, was established to study the long-term safety of infliximab (IFX) and other therapies in Crohn’s disease (CD).
Results: pts were enrolled as of 8/06, of whom 3334 received IFX (10,796 pt-yrs (py)) (86.5% ≥2 infusions) and 2939 received other therapies only (8277 py) with a mean follow-up of 3.4 yrs. More IFX-treated pts had moderate-to-severe (31.1% vs 10.7%, p<0.0001) or severe-fulminant (2.6% vs 0.6%, p<0.0001) CD. Also, more IFX-treated pts had been hospitalized (27.3% vs. 19.0%, p<0.0001) in the year prior to enrollment, and more were taking prednisone (27.1% vs. 15.9%, p<0.0001) or immunomodulators (49.1% vs. 31.6%, p<0.0001) at enrollment. Infusion reactions occurred in 3.7% of 35,189 infusions; severe reactions in 0.09%. Mortality was similar for both IFX- and non-IFX-treated pts (0.52 per 100 py vs 0.50; RR=1.02, 95% CI= ). In an adjusted Cox proportional hazards analysis, the use of prednisone (HR=1.96, CI= , p=0.002) and narcotics (HR=2.06, CI= , p<0.001) were the only medications associated with increased risk of mortality. The incidence of malignancies in the two groups was similar (0.39 per 100 py in IFX pts vs 0.53 in non-IFX pts; RR=0.74, 95% CI= ), as was the incidence of lymphoma (0.04 per 100 py in IFX pts vs 0.05 in non-IFX pts; RR=0.8, 95% CI= ). The incidence of serious infections (SI) was 1.19 per 100 py within 3 months of an IFX infusion and 0.67 not within 3 months of an IFX infusion (RR=1.77, 95% CI = , p=<0.001). However, an adjusted Cox analysis showed IFX was not a predictor of SI (HR=1.28, 95% CI= ). The only medications associated with SI were prednisone (HR=2.04, CI= , p<0.001) and narcotics (HR=2.17, 95% CI= , p<0.001). To date, one IFX-treated pt with known latent TB, who did not receive adequate prophylaxis, developed active TB.
Conclusions: IFX safety is similar to that of conventional immunomodulators. Despite having more severe CD, IFX pts had similar rates of mortality, neoplasm and lymphoma as pts not treated with IFX. IFX-treated pts have an increased risk of serious infection but Cox proportional hazard analysis suggests that this increased risk is independently associated with prednisone and narcotic use, and not IFX therapy.
1.5
Steroids
Steroids 1
0.5
*p=0.002; †p<0.001
Data on file (Lichtenstein et al. DDW 2007 poster with abstract S1124)

6. Complication of long term corticosteroid use
Hyperglycemia
Infection
Myopathy
Psychological- dementia
Hypertension
Osteoporosis
Adrenal insufficiency
Hepatic steatosis
Glaucoma
Growth suppression

7. Azathioprine

8. Maintenance of clinical remission with Azathioprine in CD patients
Remission induced by prednisolone; tapered over 12 weeks
100 80 60 40 20
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33) 80 60 40 20
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33)
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33) 80 60
% patients not failing trial 40 20
ster +
AZA
AZA 15
Duration of trial (months)
Candy et al. Gut 1995;37:674

9. Continuous Immunotherapy is Required to Treat a Chronic Disease
Patients in clinical remission with AZA for at least 3.5 years before randomisation
1.0
7.9
0.8
% relapse
21.3
0.6
Remission (months)
Percentage of Patients
in Remission
mean ± SE
17.3 ± 0.5
0.4
Here, the point should be made that you cannot simply “stop” immune suppression in CD as then the patients relapse.
NB: These are patients that have been maintained for 3.5 years and are then discontinued – therefore, the results cannot be compared with Candy!
Immune suppression should be maintained for life
Azathioprine Withdrawal Trial in Crohn’s Disease (after 5 years main. Aza)
15.9 ± 0.7
0.2
Azathioprine
Placebo
0.0 6 12 18
Months after randomisation
Lemann et al. Gastroenterol Jun;128(7):

10. Analysis of 2573 patients (retrospective, 25 years)
More frequent use of immunosuppressives did not decrease the need for surgery in CD
Analysis of 2573 patients (retrospective, 25 years)
100 90
Immunosuppressive Use (P<0.001) 80
Resection (P=0.5) 70 60
Cumulative percentage 50 40 30 20 10
Adapted from Cosnes et al. Gut 2005;54:237

11. Complications from 6-MP/Azathioprine
Pancreatitis – 1.0%
Abn liver tests – 2.4%
Leucopenia – 10.0%
Significant infection – 5.2%
Lymphoma – 0.005%
Malignancy - unclear
O’Brien Wt al, gastroenterology 101:39-46, 1991
Khan et al, digestion 62:

12. Methotrexate

13. Methotrexate: Induction & Maintenance of Remission in CD
100 90
P=0.04 80 70
Methotrexate
Remission (%) 60 50
Methotrexate is effective in inducing remission in patients with CD. The study by Feagan, et al evaluated methotrexate as a maintenance therapy in patients whose disease was in remission.
Once achieving remission with 25 mg methotrexate once weekly, patients were randomly assigned to receive either 15 mg methotrexate once weekly or placebo for 40 weeks. No other treatments for CD were permitted. The primary endpoint was the proportion of patients remaining in remission (defined as a CDAI score of 150 or less) at week 40.
Although the number of patients maintaining remission declined over the course of the study, at week 40 a significantly greater proportion of patients in the methotrexate group (65%) were in remission compared with those receiving placebo (39%; P=0.04).
Reference
Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med. 2000;342:
Placebo 40 30 4 8 12 16 20 24 28 32 36 40
Weeks since randomization
Feagan BG, et al. N Engl J Med. 2000;342:

15. Side effects of Methotrexate
Common & mild
Uncommon
Rare
Nausea
Abdominal pain
Leukopenia
Abnormal LFT
Fatigue
Headache
Vomiting
Thrompcytopenia
Hair loss
Stomatitis
Fever
Dizziness
Anorexia
pneumonitis

16. Infliximab Inflammatory CD

17. Healing of Colonic Ulceration With Infliximab
Pre-treatment
4 weeks post-treatment
van Dullemen HM et al. Gastroenterology. 1995;109:

18. Mucosal Healing With Infliximab
Histologic H&E staining
4 Weeks post-
treatment
Pre-treatment
Courtesy of K. Geboes, MD.

19. Targan SR et al. N Engl J Med. 1997;337:1029-1035
Inflammatory CD
Study design
N = 108
Randomized, double-blind, placebo-controlled, multicenter trial
CD > 6 months duration
CDAI score between 220 and 400, inclusive
Stable concomitant medications allowed by protocol: aminosalicylates, prednisone (< 40 mg/d), 6-MP/AZA
Targan SR et al. N Engl J Med. 1997;337:

20. Clinical Remission With Infliximab at 4 Weeks
Clinical remission defined
as a CDAI score < 150.
Targan SR et al. N Engl J Med. 1997;337:

22. Infliximab Fistulizing CD

23. Infliximab Treatment of Fistulae in CD
Study Design
N = 94
Single or multiple draining enterocutaneous fistulae
Stable concomitant medications permitted (aminosalicylates, corticosteroids, 6-MP/AZA, antibiotics)
Treatment (infusion at Weeks 0, 2, and 6)
Infliximab 5 mg/kg
Infliximab 10 mg/kg
Placebo
Present DH et al. Am J Gastroenterol. 1997;92(suppl):A1746. Abstract

25. Perianal Fistula: Case Study
Patient was a 42-year-old man with a draining fistula of 3 to 6 months duration who received infliximab 5 mg/kg.
2 Weeks
Baseline

26. Perianal Fistula: Case Study (cont)
18 Weeks
10 Weeks

27. Infliximab Treatment of Fistulae in CD: Conclusions
Primary endpoint: 2/3 demonstrated > 50% reduction in draining fistulae
Secondary endpoint: 1/2 demonstrated closure of all fistulae

28. From Trial to Clinic How Has Practice Changed?

29. Previous Drug Exposure Disease Duration (Years)
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
GETAID3
ACCENT I4
Targan5
AZA-failure IS CS
5-ASA
SONIC2
AZA/6-MP naïve
Previous Drug Exposure
SUTD1 1 2 3 4 5 6 7 8 9 10 11 12
Disease Duration (Years)
1D’Haens G, et al. Lancet. 2008;371: ; 2Colombel J-F, et al. Presented at UEGW OP001; 3Lemann M, et al. Gastroenterology 2006;130(4): ; 4Rutgeerts P, et al. Gastroenterology. 2004;126: ; 5Targan SR, et al. N Engl J Med. 1997;337(15):

30. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
Scheduled therapy is better than episodic
GETAID3
ACCENT I4
Targan5
AZA-failure IS CS
5-ASA
SONIC2
AZA/6-MP naïve
Previous Drug Exposure
SUTD1 1 2 3 4 5 6 7 8 9 10 11 12
Disease Duration (Years)
1D’Haens G, et al. Lancet. 2008;371: ; 2Colombel J-F, et al. Presented at UEGW OP001; 3Lemann M, et al. Gastroenterology 2006;130(4): ; 4Rutgeerts P, et al. Gastroenterology. 2004;126: ; 5Targan SR, et al. N Engl J Med. 1997;337(15):

31. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
Better results in AZA naïve, ‘bridging’ does not work
GETAID3
ACCENT I4
Targan5
AZA-failure IS CS
5-ASA
SONIC2
AZA/6-MP naïve
Previous Drug Exposure
SUTD1 1 2 3 4 5 6 7 8 9 10 11 12
Disease Duration (Years)
1D’Haens G, et al. Lancet. 2008;371: ; 2Colombel J-F, et al. Presented at UEGW OP001; 3Lemann M, et al. Gastroenterology 2006;130(4): ; 4Rutgeerts P, et al. Gastroenterology. 2004;126: ; 5Targan SR, et al. N Engl J Med. 1997;337(15):

32. Top-down therapy works Previous Drug Exposure Disease Duration (Years)
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
Top-down therapy works
GETAID3
ACCENT I4
Targan5
AZA-failure IS CS
5-ASA
SONIC2
AZA/6-MP naïve
Previous Drug Exposure
SUTD1 1 2 3 4 5 6 7 8 9 10 11 12
Disease Duration (Years)
1D’Haens G, et al. Lancet. 2008;371: ; 2Colombel J-F, et al. Presented at UEGW OP001; 3Lemann M, et al. Gastroenterology 2006;130(4): ; 4Rutgeerts P, et al. Gastroenterology. 2004;126: ; 5Targan SR, et al. N Engl J Med. 1997;337(15):

33. Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
Remicade®-based treatment strategy is superior for AZA-naïve patients
GETAID3
ACCENT I4
Targan5
AZA-failure IS CS
5-ASA
SONIC2
AZA/6-MP naïve
Previous Drug Exposure
SUTD1 1 2 3 4 5 6 7 8 9 10 11 12
Disease Duration (Years)
1D’Haens G, et al. Lancet. 2008;371: ; 2Colombel J-F, et al. Presented at UEGW OP001; 3Lemann M, et al. Gastroenterology 2006;130(4): ; 4Rutgeerts P, et al. Gastroenterology. 2004;126: ; 5Targan SR, et al. N Engl J Med. 1997;337(15):

34. Adalimumab

35. HUMIRA Crohn’s Development Program
CLASSIC II
Long-term maintenance
CLASSIC I Induction of clinical remission/response
CHARM Maintenance of clinical remission/response
M Long-term follow-up
GAIN Infliximab Failures Induction trial
Induction
Maintenance
Long term F/U

36. Percentage of Subjects
Greatest and Most Rapid Remission with 160/80 mg Induction Dose of HUMIRA (Week 4)
Placebo/placebo
40/20 mg
80/40 mg
160/80 mg * 60
n=74
n=74
n=75
n=76 *
57.9 *
54.7 *
52.7 50
48.7 * 40
37.3
35.5
33.8
32.4
Percentage of Subjects 30
24.0
24.3 20
17.6
12.2 10
Clinical Remission
Clinical Response 100
Clinical Response 70
Hanauer, S. et al. Gastroenterol. 2006, Hanauer, late-breaking abstract, DDW Panaccione, et al. Oral Presentation UEGW 2005, Data on file.
*p<0.05 vs. placebo (ITT population).

37. Rapid and Significant Δ 70 Response Rates With All doses of HUMIRA80
Placebo 70
40/20 mg #
80/40 mg ** ‡ 60 †
160/80 mg 50 *
Patients achieving 40
70-point response (%) 30 20 10
Week 1
Week 2
Week 3
Week 4
As observed; ITT population
*p= /40 vs PBO
**p= /40 vs PBO; p= /80 vs PBO
#p= /20 vs PBO; p= /40 vs PBO; p= /80 vs PBO
Based on Hanauer, S. et al. Gastroenterol. 2006

38. Significant Rates of Remission with adalimumab treatment
Placebo
160/80 mg
Week
% of Patients 6 4 7 * 21 30 25 20 15 10 5
Stats table run 1 2 3 4
*P<0.001 vs. placebo
Full analysis population
Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas

39. What is “Early”? Which “Outcomes”?
Disability
Health
Subclinical Inflammation
Symptomatic Inflammation
Complications
Disease Prevention
Prevention of Complications
Prevention of Symptomatic Disease
Prevention of Relapse

40. New Approaches to Therapeutic Intervention in CD?
+IFX
IFX+
AZA
+AZA MTX
+(episodic) IFX
Steroids
Steroids
Steroids
Hommes D, et al. Presented at DDW 2006.

41. Step-Up Versus Top-Down Trial
Treatment Success* From Week 14 Through 2 Years
CDAI<150 & No Steroids
P = 0.03
P = 0.19
P < 0.001 29 60 41 61 50
Steroid Use
P < 0.001
P < 0.001 31 5 17
*Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection. Hommes D, et al. Presented at DDW [Abstract 749].

42. Safety Considerations With TNF Inhibitors
Infections
Lymphoma
Antibodies against the compound
Infusion/injection site reactions
Other
Autoimmunity and autoantibodies
Demyelination
Congestive heart failure (CHF)
Hematologic disorders
Liver toxicity
In clinical trials, the use of all 3 TNF inhibitors was associated with infections requiring treatment. Most infections were minor and were treated with either outpatient antibiotic therapy and/or temporary withdrawal of the drug.
Most commonly observed were infections of the urinary and upper respiratory tracts. TNF inhibitors are associated with an increased risk of serious infections compared with the general population, but the rate is similar to RA patients treated with other disease-modifying agents. However, administration of TNF inhibitors has been shown to cause reactivation of TB.
Issues relating to the risk of TB reactivation and other infections are discussed in the following slides.
Reference
Khanna D, McMahon M, Furst DE. Safety of tumour necrosis factor- antagonists. Drug Safe. 2004;27:

43. Remission more than symptom control
Evolving Goals in IBD
Perspective
Society
Clinician
Patient
Improved outcomes Normal laboratory data Remission off steroids Mucosal healing Improved signs, symptoms and quality of life
Goals
Remission more than symptom control

44. Accomplishments in IBD
Shift in the treatment paradigm
Optimal use of Anti-TNF
Appropriate patient identification
Raising the bar for treatment standards
Steroid-free remission
Complete mucosal healing
Improved outcomes
Ultimately strive for changing the natural course of disease

45. GCSO 2013 Business Planning
Current & Future Landscape : Biologic IBD market map
1998–2018
paediatric CD
Pfizer launch tofacitinib (JAK-3) for UC
Humira launch for UC
Abbott launch Humira in CD (US and EU)
Takeda launch vedolizumab IV for CD
UCB launch Cimzia for CD (US)
Takeda launch vedolizumab IV for UC
Launch of infliximab biosimilars
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
Simponi launch for UC
Remicade ulcerative colitis launch
Janssen
(JAK-3)
for UC
Remicade approved
for moderate CD
US Remicade launch in Crohn’s disease (1998 US)
Stelara
launch for
CD (2015)
Remicade paediatric CD launch
Remicade approved for paediatric UC
26 June 2012
GCSO 2013 Business Planning

46. Looking to The Future