Positioning Our Recent & Future Therapy in Crohn’s disease Ahmad Alfadhli MD, FRCPC Gastroenterology Unite Haya Al-Habeeb Center Mubarak Al-Kabeer Hospital KUWAIT
Feb 24, 2016
Positioning Our Recent & Future Therapy in Crohn’s disease
Ahmad Alfadhli MD, FRCPCGastroenterology UniteHaya Al-Habeeb Center
Mubarak Al-Kabeer HospitalKUWAIT
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
1638
26
58
32
28
0%10%20%30%40%50%60%70%80%90%
100%
1 month 1 year
Prop
ortio
n of
pat
ient
sSteroids for the treatment of Crohn’s Disease
– benefit for the patient
remission
partialremission
no response
prolongedresponse
steroiddependent
surgery
N = 74 N = 73
“positive”outcome
“negative”outcome
Faubion WA et al. Gastroenterology 2001;121:255
Benefit risk profile of major CD therapies: infections and mortality
TREAT
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
HA
ZAR
D R
ATIO
*p=0.002; †p<0.001
IFX AZA6-MPMTX
Steroids
IFXAZA6-MPMTX
Steroids
*
Serious infectionsMortality
Multivariate analysis
†
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
80
60
40
20
0
Placebo (n=30)AZA 2.5 mg/kg per d (n=33)
80
60
40
20
0
Placebo (n=30)AZA 2.5 mg/kg per d (n=33)
80
60
40
20
0
Placebo (n=30)AZA 2.5 mg/kg per d (n=33)
% p
atie
nts
not f
ailin
g tri
al
Duration of trial (months)
Candy et al. Gut 1995;37:674
0 15
Remission induced by prednisolone; tapered over 12 weeks
100
ster +AZA AZA
Continuous Immunotherapy is Required to Treat a Chronic Disease
Lemann et al. Gastroenterol. 2005 Jun;128(7):1812-8.
Months after randomisation
Patients in clinical remission with AZA for at least 3.5 years before randomisation
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18
Perc
enta
ge o
f Pat
ient
sin
Rem
issi
on
AzathioprinePlacebo
Remission (months)mean ± SE17.3 ± 0.515.9 ± 0.7
% relapse7.9
21.3
Analysis of 2573 patients (retrospective, 25 years)
0102030405060708090
100
1978-1982 1983-1987 1988-1992 1993-1997 1998-2002
Cum
ulat
ive
perc
enta
ge
Immunosuppressive Use (P<0.001)
Resection (P=0.5)
Adapted from Cosnes et al. Gut 2005;54:237
More frequent use of immunosuppressives did not decrease the need for surgery in CD
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, 1991Khan et al, digestion 62:249-54. 2000
Methotrexate
Methotrexate: Induction & Maintenance of Remission
in CD
Feagan BG, et al. N Engl J Med. 2000;342:1627-1632.
0 4 8 12 16 20 24 28 32 36 400
30
40
50
60
70
80
90
100
Weeks since randomization
Rem
issi
on (%
)P=0.04
Methotrexate
Placebo
Side effects of Methotrexate
Common & mild
Uncommon Rare
NauseaAbdominal painLeukopeniaAbnormal LFT
FatigueHeadacheVomitingThrompcytopeniaHair loss
StomatitisFeverDizzinessAnorexiapneumonitis
InfliximabInflammatory CD
Pre-treatment 4 weeks post-treatment
van Dullemen HM et al. Gastroenterology. 1995;109:129-135
Healing of Colonic UlcerationWith Infliximab
Mucosal Healing With Infliximab
Pre-treatment
4 Weeks post-treatment
Courtesy of K. Geboes, MD.
Histologic H&E staining
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
Inflammatory CD
Targan SR et al. N Engl J Med. 1997;337:1029-1035
Clinical Remission With Infliximab at 4 Weeks
Targan SR et al. N Engl J Med. 1997;337:1029-1035
Clinical remission defined as a CDAI score < 150.
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 StudyPatient 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 ClinicHow Has Practice Changed?
IS
CS
5-ASA
1 2 43 765 8 129 1110
Targan5ACCENT I4GETAID3
SONIC2
SUTD1
Disease Duration (Years)
Prev
ious
Dru
g Ex
posu
re
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.
AZA-failure
AZA/6-MP naïve
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
Targan5ACCENT I4GETAID3
SONIC2
SUTD1
AZA-failure
AZA/6-MP naïve
Scheduled therapy is better than episodic
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
IS
CS
5-ASA
Prev
ious
Dru
g Ex
posu
re
1 2 43 765 8 129 1110Disease 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.
Targan5ACCENT I4GETAID3
SONIC2
SUTD1
AZA-failure
AZA/6-MP naïve
Better results in AZA naïve, ‘bridging’ does not work
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
IS
CS
5-ASA
Prev
ious
Dru
g Ex
posu
re
1 2 43 765 8 129 1110Disease 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.
Targan5ACCENT I4GETAID3
SONIC2
SUTD1
AZA-failure
AZA/6-MP naïve
Top-down therapy works
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
IS
CS
5-ASA
Prev
ious
Dru
g Ex
posu
re
1 2 43 765 8 129 1110Disease 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.
Targan5ACCENT I4GETAID3
SONIC2
SUTD1
AZA-failure
AZA/6-MP naïve
Remicade®-based treatment strategy is superior for AZA-naïve patients
Remicade® Trials Have Demonstrated Key Learnings in the Management of CD
IS
CS
5-ASA
Prev
ious
Dru
g Ex
posu
re
1 2 43 765 8 129 1110Disease 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
Induction Maintenance
CHARM Maintenanceof clinical remission/response
GAIN Infliximab Failures Induction trial
M04-690Long-term follow-up
CLASSIC I Inductionof clinical remission/response
CLASSIC IILong-term maintenance
Long term F/U
Greatest and Most Rapid Remission with 160/80 mg Induction Dose
of HUMIRA (Week 4)
Clinical Remission
Clinical Response 100
Clinical Response 70
*p<0.05 vs. placebo (ITT population).
48.7
37.3
32.4
24.3
57.954.7
52.7
33.835.5
24.0
17.6
12.2
Perc
enta
ge o
f Sub
ject
s
*
**
* *n=74 n=74 n=75 n=76
0
10
20
30
40
50
60Placebo/placebo 40/20 mg 80/40 mg 160/80 mg
Hanauer, S. et al. Gastroenterol. 2006, Hanauer, late-breaking abstract, DDW 2004. Panaccione, et al. Oral Presentation UEGW
2005, Data on file.
Rapid and Significant Δ 70 Response Rates With All doses of HUMIRA
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
#
0
10
20
30
40
50
60
70
80
0 Week 1 Week 2 Week 3 Week 4
Patie
nts
achi
evin
g70
-poi
nt re
spon
se (%
)
Placebo40/20 mg80/40 mg160/80 mg
Significant Rates of Remission with adalimumab treatment
*P<0.001 vs. placeboFull analysis population
Week
% o
f Pat
ient
s
6
46 7
*
21 21
*
0
5
10
15
20
25
30
0 1 2 3 4
Placebo 160/80 mg
Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas
Disability
What is “Early”?Which “Outcomes”?
DiseasePrevention
Prevention ofSymptomatic Disease
Prevention ofComplications
Prevention ofRelapse
Health SubclinicalInflammation
SymptomaticInflammation Complications
New Approaches to Therapeutic Intervention in CD?
Steroids
Steroids
+AZA MTX
+IFX
Steroids
+(episodic) IFX
IFX+AZA
Hommes D, et al. Presented at DDW 2006.
Step-Up Versus Top-Down Trial
0
5
10
15
20
25
30
35
Perc
ent o
f Pat
ient
s
020406080
6 Months 12 Months
% o
f Pat
ient
s
010203040
6 Months 12 Months
% o
f Pat
ient
s
*Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection.
Hommes D, et al. Presented at DDW 2006. [Abstract 749].
CDAI<150 & No Steroids
Steroid Use
Treatment Success* From Week 14 Through 2 Years
P = 0.03 P = 0.19
P < 0.001 P < 0.001
P < 0.001
0 0
Top Down Step Up
60 41 61 50
3117
29
5
Safety Considerations WithTNF 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
Society
Clinician
Patient
Improved outcomes
Normal laboratory dataRemission off steroidsMucosal healing
Improved signs, symptomsand quality of life
Goals
Remission more than symptom control
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
26 June 2012GCSO 2013 Business Planning
1999
UCB launch Cimzia for CD (US)
Remicade ulcerative colitis launch
Abbott launch Humira in CD (US and EU)
US Remicade launch in Crohn’s disease (1998 US)
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Remicade paediatric CD launch
Current & Future Landscape : Biologic IBD market map 1998–2018
2011 2012 20142013 2015 201820172016
Stelara launch for CD (2015)
Humira launch for UC
Simponi launch for UC
Remicade approved for paediatric UC
Launch of infliximab biosimilars
Takeda launch vedolizumab IV for UC
Takeda launch vedolizumab IV for CD
Remicade approved for moderate CD
Pfizer launch tofacitinib (JAK-3) for UC
Janssen(JAK-3) for UC
paediatric CD
Looking to The Future