Top Down vs. Step Up Therapy Biologics in IBD: Treatment Algorithms Top Down vs. Step Up Therapy Top Down vs. Step Up Therapy Biologics in IBD: Biologics in IBD: Treatment Algorithms Treatment Algorithms Stephen B. Hanauer, M.D. University of Chicago
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Top Down vs. Step Up Therapy Biologics in IBD:
Treatment Algorithms
Top Down vs. Step Up TherapyTop Down vs. Step Up Therapy Biologics in IBD:Biologics in IBD:
• Patients attain remission with less toxic therapies
• Potentially more toxic therapies reserved for more severe or refractory disease
• Minimizes risk of adverse events
• Cost sparing (short-term?)
Disadvantages
• Patients have to “earn” most effective treatments
• Decrease in quality-of-life before patients obtain optimal therapy
• Likelihood of surgery is high
• Disease is not modified
IBDs are chronic, life-longIBDsIBDs are chronic, lifeare chronic, life--longlong
We cannot just look at the short-term induction therapy
LongLong--Term Therapy for IBD Term Therapy for IBD is Sequentialis Sequential
Induction Maintenance
Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression Impact of Therapy will Depend on Degree of Impact of Therapy will Depend on Degree of Structural Damage & Velocity of ProgressionStructural Damage & Velocity of Progression
Efficacy of AZA as Crohn’s Disease Maintenance Therapy
After Steroids in Adults*
Efficacy of AZA as Efficacy of AZA as CrohnCrohn’’ss Disease Disease Maintenance TherapyMaintenance Therapy
After Steroids in AdultsAfter Steroids in Adults*
Candy S, et al. Gut. 1995;37(4):674-678.
100
80
60
40
20
0
% P
atie
nts
Not
Fai
ling
Tria
l
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of Trial (months)
AZA 2.5 mg/kg per dPlacebo
*Remission induced by prednisolone tapered over 12 wkInclusion: Patients were not steroid dependent
p=0.001
42%
7%
Efficacy of 6-MP as Crohn’s Disease Maintenance Therapy
After Steroids in Steroid-naïve Children
Efficacy of 6Efficacy of 6--MP as CrohnMP as Crohn’’s Disease s Disease Maintenance TherapyMaintenance Therapy
After Steroids in SteroidAfter Steroids in Steroid--nanaïïve Childrenve Children
Markowitz J et al. Gastroenterology. 2000;119:895.
30
40
50
60
70
80
90
100
0 50 100 150 200 250 300 350 400 450 500 550 600
Days Since Remission Induction
% o
f Pat
ient
s in
Rem
issi
on
P<.007
91%
53%
N=55
6-MP
Control
At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission.
Three classes of anti-TNF:Fusion protein, antibodies and PEGylated Fab' fragment
Three classes of antiThree classes of anti--TNF:TNF:Fusion protein, Fusion protein, antibodies and PEGylated Fab' fragmentantibodies and PEGylated Fab' fragment
Coutesy of Stephen B. Hanauer, M.D.
Infliximab Adalimumab
IgG1 Fc
Fab
Etanercept
IgG1Fc
Receptor
Monoclonal antibody
Human
Human recombinant
receptor/Fc fusion protein
Chimeric
Fab′
Certolizumab pegol
PEG
PEGylated humanized
Fab′
fragment2 ×
20 kDa PEG
Clinical Trials with Anti-TNF Biologics in Refractory Crohn’s disease
Clinical Trials with AntiClinical Trials with Anti--TNF Biologics in TNF Biologics in Refractory CrohnRefractory Crohn’’s diseases disease
Comparing ACCENT I, CHARM, and Comparing ACCENT I, CHARM, and PRECiSE 2 ResultsPRECiSE 2 Results
30.747.9
64.1
020406080
Week 6Response
Week 26Remission
OverallRemissionWeek 26
PRECiSE 2(certolizumab pegol)
ACCENT I*(infliximab)
CHARM**(adalimumab)
*5 mg/kg dose.**Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4. Week 26 remission among randomized responders on 40 mg every other week dosing.
2460
40
020406080
100
Week 4Response
Week 26Remission
OverallRemission
Week 26
22.839.0
58.5
020406080
Week 2Response
Week 30Remission
OverallRemission
Week 30
Patie
nts
(%)
Patie
nts
(%)
Patie
nts
(%)
Impact of Disease DurationImpact of Disease Duration
Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM study
Clinical Remission at Weeks 26 by Disease Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM studyDuration in adalimumab CHARM study
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147
*p=0.002, **p<0.001, †p=0.014, ‡p=0.001 all vs placebo
Placebo All Adalimumab
1425
17
59*
40 41**
010203040506070
% o
f pat
ient
s
<2 years 2 to <5 years ≥5 years
N=23 N=39 N=36 N=57 N=111 N=233
Week 26 Remission with certolizumab by Duration Of Crohn’s Disease In PRECiSE 2
Week 26 Remission with certolizumabWeek 26 Remission with certolizumab by Duration Of Crohnby Duration Of Crohn’’s Disease In PRECiSE 2s Disease In PRECiSE 2
68%
55%47% 44%
37% 36%29%
24%
0%
20%
40%
60%
80%
100%
< 1 Year 1 - 2 Years 2 - 5 Years > 5 Years
Certolizumab Remission
Placebo Remission
Impact of Concomitant Impact of Concomitant ImmunomodulatorsImmunomodulators
ACCENT I: Comparable clinical outcomes with or without immunomodulators
ACCENT I: ACCENT I: Comparable clinical outcomes Comparable clinical outcomes with or without immunomodulatorswith or without immunomodulators
Lichtenstein et al, Gastroenterology 2007; 132: A-146 (No. 982)
6350 52
3753
41 3932
0
100
Week 30 Week 54 Week 30 Week 54
With concomitant IMM
Without concomitant IMM
Patients (%)
Response Remission
CHARM: Effect of concomitant adalimumab and immunosuppressive therapy on remission at
week 26 and 56
CHARM:CHARM: Effect of concomitant adalimumab Effect of concomitant adalimumab and immunosuppressive therapy on remission at and immunosuppressive therapy on remission at
week 26 and 56week 26 and 56
Colombel et al, Gastroenterology 2007; 132: 52
Patie
nts
in re
mis
sion
(%)
131 136 121 39 36 36 Without IMMWith IMM
Week 56Remission defined as CDAI <150
Placebo
Adalimumab 40 mg EOW, sc
Adalimumab 40 mg q-weekly, sc
12 13
37 3339
50
0
100
Continuous vs interrupted use of immunomodulators in the long-term efficacy
of infliximab (IFX): The IMID Trial
Continuous vs interrupted use of Continuous vs interrupted use of immunomodulators in the longimmunomodulators in the long--term efficacy term efficacy
of infliximab (IFX):of infliximab (IFX): The IMID TrialThe IMID Trial
Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)
• 80 patients randomized to continue (+CON , n=40) or to interrupt (++DIS, n=40) immunomodulators (azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV)
Early Aggressive Biologic Therapy vs Conventional Management of Crohn’s Disease
Early Aggressive Biologic Therapy vs Early Aggressive Biologic Therapy vs Conventional Management of CrohnConventional Management of Crohn’’s Diseases Disease
D’Haens et al. Lancet 2008;371:660
Newly diagnosed, antimetabolite, anti-TNF, or steroid-naïve
CD patients (n=133)
Conventional therapy (n=66)
Early aggressive (n=67)+ IFX
+ AZA MTX
Steroids
Steroids
IFX (0,2,6 weeks) + AZA
+ (episodic) IFX
Steroids
Step-Up vs. Top-Down: ResultsStepStep--Up vs. TopUp vs. Top--Down: ResultsDown: Results
D'Haens G, et al. Lancet 2008;371:660-667
0
5
10
15
20
25
30
35
Perc
ent o
f Pat
ient
s020406080
6 Months 12 Months
% o
f Pat
ient
s
010203040
6 Months 12 Months
% o
f Pat
ient
s
CDAI < 150 & No Steroids
Steroid Use
Treatment Success* From Week 14 Through 2 YearsP = 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
*Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection.
Step Up vs. Top Down: Complete Endoscopic Remission at 2 Years
Step Up vs. Top Down: Step Up vs. Top Down: Complete Endoscopic Remission at 2 YearsComplete Endoscopic Remission at 2 Years
D’Haens et al. Lancet 2008;371:660
(n=26)Early aggressive
(n=23)Conventional therapy
**p=0.003
Patie
nts
(%)
73
30
0
100
**
COMMITT: MTX plus IFX in CD (1)COMMITT: COMMITT: MTX plus IFX in CD (1)MTX plus IFX in CD (1)
Feagan B, et al. DDW 2008: #682C
– Patients with active CD on corticosteroids within last 6 weeks