1. No category

Positioning Our Recent & Future
Therapy in Crohn’s disease
Ahmad Alfadhli MD, FRCPC
Gastroenterology Unite
Haya Al-Habeeb Center
Mubarak Al-Kabeer Hospital
KUWAIT
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
Corticosteroid
Steroids for the treatment of Crohn’s Disease
– benefit for the patient
N = 74
N = 73
100%
Proportion of patients
90%
80%
70% remission
32
prolonged
response
28
steroid
dependent
38
surgery
58
“positive”
outcome
60%
50%
40%
30%
20%
10%
0%
partial
remission
no
response
26
“negative”
outcome
16
1 month
1 year
Faubion WA et al. Gastroenterology 2001;121:255
TREAT
Benefit risk profile of major CD
therapies: infections and mortality
Multivariate analysis
4.5
Mortality
HAZARD RATIO
4
Serious infections
3.5
3
2.5
2
1.5
1
IFX
AZA
6-MP
MTX
*
Steroids
IFX
AZA
6-MP
MTX
†
Steroids
0.5
0
*p=0.002; †p<0.001 Data on file (Lichtenstein et al. DDW 2007 poster with abstract S1124)
Complication of long term
corticosteroid use
•
•
•
•
•
•
•
•
•
•
Hyperglycemia
Infection
Myopathy
Psychological- dementia
Hypertension
Osteoporosis
Adrenal insufficiency
Hepatic steatosis
Glaucoma
Growth suppression
Azathioprine
Maintenance of clinical remission
with Azathioprine in CD patients
Remission induced by prednisolone; tapered over 12 weeks
% patients not failing trial
100
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33)
80
60
40
20
ster +
AZA
AZA
0
0
15
Duration of trial (months)
Candy et al. Gut 1995;37:674
Continuous Immunotherapy is Required
to Treat a Chronic Disease
1.0
Patients in clinical remission with AZA for at
least 3.5 years before randomisation
Percentage of Patients
in Remission
7.9
% relapse
0.8
21.3
0.6
Remission (months)
mean ± SE
17.3 ± 0.5
15.9 ± 0.7
0.4
Azathioprine
Placebo
0.2
0.0
0
6
12
Months after randomisation
18
Lemann et al. Gastroenterol. 2005 Jun;128(7):1812-8.
More frequent use of immunosuppressives did
not decrease the need for surgery in CD
Cumulative percentage
Analysis of 2573 patients (retrospective, 25 years)
100
90
80
70
60
50
40
Immunosuppressive Use (P<0.001)
Resection (P=0.5)
30
20
10
0
1978-1982 1983-1987 1988-1992 1993-1997 1998-2002
Adapted from Cosnes et al. Gut 2005;54:237
Complications from 6-MP/Azathioprine
•
•
•
•
•
•
•
N = 806
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 62:249-54. 2000
Methotrexate
Methotrexate: Induction & Maintenance of
Remission
in CD
100
P=0.04
90
Remission (%)
80
70
Methotrexate
60
50
Placebo
40
30
0
0
4
8
12
16
20
24
28
32
36
40
Weeks since randomization
Feagan BG, et al. N Engl J Med. 2000;342:1627-1632.
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
Infliximab
Inflammatory CD
Healing of Colonic Ulceration
With Infliximab
Pre-treatment
4 weeks post-treatment
van Dullemen HM et al. Gastroenterology. 1995;109:129-135
Mucosal Healing With Infliximab
Histologic H&E staining
Pretreatment
4 Weeks
posttreatment
Courtesy of K. Geboes, MD.
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;337:1029-1035
Clinical Remission With
Infliximab at 4 Weeks
Clinical remission defined
as a CDAI score < 150.
Targan SR et al. N Engl J Med. 1997;337:1029-1035
Infliximab
Fistulizing CD
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
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.
Baseline
2 Weeks
Perianal Fistula: Case Study (cont)
10 Weeks
18 Weeks
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
From Trial to Clinic
How Has Practice Changed?
Previous Drug Exposure
Remicade® Trials Have Demonstrated
Key Learnings in the Management of CD
GETAID3
ACCENT I4
Targan5
AZA-failure
IS
SONIC2
AZA/6-MP
naïve
CS SUTD1
5-ASA
1
2
3
4
5
6
7
8
9
10
11
12
Disease Duration (Years)
1D’Haens
G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al.
Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J
Med. 1997;337(15):1029-1035.
Remicade® Trials Have Demonstrated
Key Learnings in the Management of CD
Previous Drug Exposure
Scheduled therapy is
better than episodic
GETAID3
ACCENT I4
Targan5
AZA-failure
IS
SONIC2
AZA/6-MP
naïve
CS SUTD1
5-ASA
1
2
3
4
5
6
7
8
9
10
11
12
Disease Duration (Years)
1D’Haens
G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al.
Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J
Med. 1997;337(15):1029-1035.
Remicade® Trials Have Demonstrated
Key Learnings in the Management of CD
Previous Drug Exposure
Better results in AZA naïve,
‘bridging’ does not work
GETAID3
ACCENT I4
Targan5
AZA-failure
IS
SONIC2
AZA/6-MP
naïve
CS SUTD1
5-ASA
1
2
3
4
5
6
7
8
9
10
11
12
Disease Duration (Years)
1D’Haens
G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al.
Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J
Med. 1997;337(15):1029-1035.
Remicade® Trials Have Demonstrated
Key Learnings in the Management of CD
Previous Drug Exposure
Top-down therapy works
GETAID3
ACCENT I4
Targan5
AZA-failure
IS
SONIC2
AZA/6-MP
naïve
CS SUTD1
5-ASA
1
2
3
4
5
6
7
8
9
10
11
12
Disease Duration (Years)
1D’Haens
G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al.
Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J
Med. 1997;337(15):1029-1035.
Remicade® Trials Have Demonstrated
Key Learnings in the Management of CD
Previous Drug Exposure
Remicade®-based treatment strategy
is superior for AZA-naïve patients
GETAID3
ACCENT I4
Targan5
AZA-failure
IS
SONIC2
AZA/6-MP
naïve
CS SUTD1
5-ASA
1
2
3
4
5
6
7
8
9
10
11
12
Disease Duration (Years)
1D’Haens
G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al.
Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J
Med. 1997;337(15):1029-1035.
Adalimumab
HUMIRA Crohn’s
Development Program
CLASSIC II
CLASSIC I Induction
Long-term maintenance
of clinical remission/response
CHARM Maintenance
of clinical remission/response
M04-690
Long-term follow-up
GAIN
Infliximab Failures Induction trial
Induction
Maintenance
Long term F/U
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
n=74
n=74
n=75
n=76
60
*
*
57.9
48.7
50
Percentage of Subjects
*
54.7
*
52.7
*
40
37.3
35.5
32.4
33.8
30
24.0
20
24.3
17.6
12.2
10
0
Clinical
Remission
*p<0.05 vs. placebo (ITT population).
Clinical Response
100
Clinical Response
70
Hanauer, S. et al. Gastroenterol. 2006, Hanauer, late-breaking
abstract, DDW 2004. Panaccione, et al. Oral Presentation UEGW
2005, Data on file.
Patients achieving
70-point response (%)
Rapid and Significant Δ 70 Response
Rates With All doses of HUMIRA
80
Placebo
70
40/20 mg
60
80/40 mg
160/80 mg
‡#
†
**
50
*
40
30
20
10
0
0
Week 1
Week 2
Week 3
Week 4
As observed; ITT population
*p=0.025 80/40 vs PBO
**p=0.002 80/40 vs PBO; p=0.038 160/80 vs PBO
#p=0.02 40/20 vs PBO; p=0.01 80/40 vs PBO; p=0.003 160/80 vs PBO
Based on Hanauer, S. et al. Gastroenterol. 2006
Significant Rates of Remission with
adalimumab treatment
% of Patients
Placebo
160/80 mg
30
*
*
25
21
21
20
15
6
10
5
7
6
4
0
0
1
2
Week
*P<0.001 vs. placebo
Full analysis population
Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas
3
4
What is “Early”?
Which “Outcomes”?
Health
Disease
Prevention
Symptomatic
Inflammation
Subclinical
Inflammation
Complications Disability
Prevention of
Complications
Prevention of
Symptomatic Disease
Prevention of
Relapse
New Approaches to Therapeutic
Intervention in CD?
+IFX
IFX+
AZA
+AZA MTX
Steroids
Steroids
+(episodic)
IFX
Steroids
Hommes D, et al. Presented at DDW 2006.
Step-Up Versus Top-Down Trial
Top Down
Treatment Success* From
Week 14 Through 2 Years
Step Up
P = 0.19
P = 0.03
80
60
40
20
0
60 41
61 50
12 Months
Steroid Use
% of Patients
P < 0.001
30
6 Months
40
30
20
10
0
35
P < 0.001
0
31
6 Months
P < 0.001
0
Percent of Patients
% of Patients
CDAI<150 & No Steroids
25
29
20
15
10
5
17
12 Months
5
0
*Remission (CDAI < 150), discontinuation of steroids and
infliximab, and no resection.
Hommes D, et al. Presented at DDW 2006. [Abstract 749].
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
Evolving Goals in IBD
Perspective
Goals
Society
Improved outcomes
Clinician
Normal laboratory data
Remission off steroids
Mucosal healing
Patient
Remission
more than
symptom
control
Improved signs, symptoms
and quality of life
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
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 UCB launch Cimzia
(US and EU) for CD (US)
Takeda
launch
vedolizumab
IV for UC
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Remicade ulcerative
colitis launch
US Remicade launch
in Crohn’s disease
(1998 US)
2011
Launch of
infliximab
biosimilars
2012 2013 2014 2015
Remicade approved
for moderate CD
Remicade
paediatric CD
launch
Takeda
launch
vedolizumab
IV for CD
Simponi
launch for
UC
Remicade approved for
paediatric UC
26 June 2012
GCSO 2013 Business Planning
2016
2017 2018
Janssen
(JAK-3)
for UC
Stelara
launch for
CD (2015)
Looking to The Future