Immunomodulators and Biologics
Maria T. Abreu, MD
University of Miami Miller School of Medicine
Miami, Florida
What is there left to talk about…
What do we know?
Are UC and
Crohn’s disease
treatment
different?
Are there any new
tools for
clinicians?
Picking the patient
based on disease
burden
Induction of
remission
IBD
Maintenance of
remission
Maintenance
of remission
off steroids
and/or
Mucosal
healing
(histology)
What do we know: Guiding
principles
 Combination therapy is better than
monotherapy
 Early therapy is better than late therapy
(esp Crohn’s disease)
 Well timed surgery is ok
First-line Biologic Agents for
the Treatment of CD
Infliximab
Adalimumab
Certolizumab
Pegol
VL
No Fc
VH
CH1
PEG
IgG1
Chimeric monoclonal
antibody (75% human
IgG1 isotype)
Mouse
Human
PEG, polyethylene glycol.
IgG1
Human recombinant
antibody (100% human
IgG1 isotype)
PEG
Humanized Fab’
fragment (95% human
IgG1 isotype)
SONIC
•Moderate-to-severe CD in patients with no prior
exposure to biologic agents or immunomodulators
•Excluded intermediate TPMT activity
•Average disease duration 2.3 years
AZA 2.5mg/kg
IFX 5mg/kg
IFX + AZA
• 1° endpoint: Induction + maintenance of steroid-free
remission
• 2° endpoint: Mucosal healing
8
SONIC
Clinical Remission
Without Corticosteroids at Week 26
Primary Endpoint
Proportion of Patients (%)
100
p<0.001
80
p=0.009
p=0.022
57
60
45
40
30
20
0
52/170
AZA + placebo
75/169
IFX + placebo
96/169
IFX+ AZA
Colombel, J.F., et al., N Engl J Med. 362(15): p. 1383-95.
9
SONIC
Mucosal Healing at Week 26
Proportion of Patients (%)
100
p<0.001
80
p=0.023
60
p=0.055
44
40
20
0
30
16
18/109
AZA + placebo
28/93
IFX + placebo
47/107
IFX+ AZA
Colombel, J.F., et al., N Engl J Med. 362(15): p. 1383-95.
Median Serum Trough
Levels (mg/ml)
SONIC: IFX Trough Levels at Week
30* are Higher with Concomitant AZA
(N=97)
(N=109)
* Patients who had 1 or more PK samples obtained after their
first study agent administration were included in the analysis
Sandborn, W. et al. NEJM, 2010
Trough Concentration of Infliximab
is Higher With Concurrent
Methotrexate
Infliximab plus
µG/L
6.35
3.75
MTX+IFX
Feagan B et al. DDW 2008. Abs no. 682C.
IFX alone
Are UC and Crohn’s disease
treatments different?
IBD has common genetic origins
CD Genes
NOD2
ATG16L1
IRGM
PTGER4
CCR6
ITLN1
UC Genes
IL23R
ECM1
IL19
NKX2-3
FCGR2A
CDKAL1
STAT3
IFNG
FCGR2C
NKX2-3
IL12B
IL26
REL
PTPN2
JAK2
ORMDL3
CCDC139
MST1
LYRM4
RNF186
PUS10
BTLN2
IL18RAP
OTUD3
MST1
PLA2G2E
CEP72
IL10
TPPP
Genes in common
Brant SR. Gastroenterology. 2009;136:396.
McGovern D et al. Nat Genet. 2010;42:332.
UC SUCCESS
•Moderate-to-severe UC (Mayo score ≥6)
•Failing corticosteroids
•No prior exposure to biologic agents; no current
immunomodulators
AZA 2.5mg/kg
IFX 5mg/kg
IFX + AZA
– 1° endpoint: Steroid-free remission at week 16 (total
Mayo score ≤2)
Patients (%)
UC SUCCESS study
*
*P<.05 compared to IFX; #P<.05 compared to AZA
Panccione R et al. DDW 2011; Abstract 835
Why do immunomodulators alone
not look so good?
 Take longer to work
 Studies have excluded intermediate
metabolizers
 Weight-based dosing underestimates
dose about half the time1
Morales A et al Inflamm Bowel Dis. 2007 Apr;13(4):380-5.
6-MP: Corticosteroid withdrawal
and/or maintenance of remission*
3/53
22/58
5/39
23/44
•Complete fistula closure
•Complete steroid d/c
•Disappearance of symptoms
Present DH, et al. N Eng J Med. 1980;302:981-7.
Percent of Patients Not Failing Trial
AZA: Corticosteroid withdrawal and
maintenance of remission
100
Placebo (n=30)
AZA 2.5 mg/kg per day (n=33)
80
60
42%
40
P=.001
35%
20
7%
0
0
1
2
3
4
5
6
7
8
9
10 11 12
13
14 15
Duration of Trial (months)
•Remission induced by prednisolone 1mg/kg tapered over 12 wk
•Permitted CDAI <175 as definition of remission at month 15
Candy S et al. Gut. 1995;37:674.
Comparing across studies
AZA or 6-MP
Response-guided therapy
Mucosal healing +
Histologic healing
=
Deep remission
Mucosal healing in IBD :
effect of different therapies
Crohn
UC
No
+
Steroids
+
+
Azathioprine
+
+
Methotrexate
+
?
Infliximab
+ (Sonic trial)
+
Certolizumab
+ (Music trial)
?
Adalimumab
+ (Extend trial)
+
Natalizumab
?
?
Enteral nutrition
+
-
5-ASA
Early mucosal healing a favorable
prognostic factor in UC
Patients in Corticosteroid-free
remission %
100
ACT 1 and
ACT 2
Infliximab-treated patients
P<0.0001
80
Week 8 endoscopy
60
46
40
34
20
11
6.5
0
Week 30 (ACT 1 and 2)
Endoscopic Score 0 (n=120)
Endoscopic Score 1 (n=175)
Endoscopic Score 2 (n=114)
Endoscopic Score 3 (n=57)
Colombel JF et al. Gastroenterology. 2011 Jun 29. [Epub ahead of print].
Week 8
endoscopic score
Patients with mucosal healing
at week 12 (%)
The best opportunity to induce mucosal
healing is early in Crohn’s disease (EXTEND
study)
Adalimumab,
50
45
40
35
30
25
20
15
10
5
0
induction-only (placebo)
44
40
Adalimumab,
every other week
18
21
7
0
4/9
<2 years
1/14
4/10
2 to <5 years
7/39
9/43
5 years
p=0.029 for adalimumab vs placebo for disease duration <5 years vs. ≥5years
All patients (n=135) received open-label adalimumab 160-/80-mg induction therapy at Weeks 0/2 and 129 patients
were randomised at Week 4 to maintenance therapy with adalimumab 40 mg every other week or placebo
Sandborn WJ, et al. J Crohn’s Colitis 2010; 4:S36 (Abstract P060)
New tools for guiding therapy
Detectable levels of infliximab at trough
are associated with better outcomes
Clinical Remission
*P<.001
*
C-reactive Protein
*P<.001
Endoscopic Change
*P<.001
*
*
Undetectable 2.0 ug/ml
Undetectable 2.0 ug/ml
Undetectable 2.0 ug/ml
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-1254.
Clinical outcomes in UC patients treated
with infliximab correlate with detectable
trough levels
P< 0.001
P< 0.001
76
69
28
15
P< 0.001
55
7
Seow C H et al. Gut 2010;59:49-54
Patients developed
undetectable levels
of infliximab and
then developed
ATIs
All anti-TNFs are immunogenic—
esp as monotherapy
Patients, %
Episodic Maintenance
Infliximab1
(CD 5 mg/kg)
(CD 10 mg/kg)
Infliximab2
IMS-
IMS+
IMS-
IMS+
38%
16%
11%
8%
7%
4%
19%
9%
2%
4%
10%
4%
12%
2%
28%
8% (latest
JAMA)
4%
0%
(UC 5 mg/kg)
(UC 10 mg/kg)
Certolizumab3
(PRECiSE I)
Certolizumab4
(PRECiSE II)
Adalimumab5
(RA, all doses)
Adalimumab6
(CLASSIC II)
Scheduled Maintenance
No data
24%
8%
No data
IMS = immunosuppressant.
1.Hanauer SB et al. Clin Gastroenterol Hepatol. 2004;2:542-553; 2. Sandborn WJ et al. DDW 2007 Poster and abstract
T1273; 3. Sandborn WJ et al. N Engl J Med. 2007;357:228-238; 4. Schreiber S et al. N Engl J Med. 2007;357:239-250;
5. Adalimumab [package insert]. Abbott Laboratories. July 2007; 6. Sandborn WJ et al. Gut. 2007;56:1232-1239.
2.7. JAMA, April 13, 2011—Vol 305, No. 14
Algorithm Based on Therapeutic
Anti-TNF Agent Concentrations
Sub-therapeutic
IFX
concentration
* Therapeutic
IFX
concentration
increase
infliximab dose or
frequency
endoscopy/CTE
with active
disease
endoscopy/CTE
with inactive
disease
Afif W et al. Am J Gastroenteterol. 2010;105:1133-1139.
If no response,
change to different
anti-TNF agent or
change mechanism of
action
change to Rx with
different mechanism
of action
(non anti-TNF agent)
investigate for alternate
etiology of symptoms
How do you pick the right patients
for these interventions?
Picking therapy based on patient
Symptoms
Mild—bothered but
functions at a normal
capacity
Moderate (affects daily
life)
Severe (close to or
needing
hospitalization)
Severity of
Inflammation
Superficial ulcerations
Deep
ulcerations/inflammatory stricture
Fibrotic stricture
Location
Limited ileal
disease
Extensive small
bowel
involvement
Internal perforating
disease (+/- abscess)
Extensive colonic
involvement
Perianal perforating
Rectal disease
Who needs combination therapy?
When can we use sequential
monotherapy?
Immunomodulators:
Thiopurines
MTX
•Mechanistic synergy
•Higher levels of biologic
Anti-TNFs
Biologics
(immunogenic)
•Moderate-to-severe disease
•Steroid-refractory disease
•Severe prognostic markers
•A lot to lose
Who needs combination therapy?
When can we use sequential
monotherapy?
Immunomodulators:
Thiopurines
MTX
Steroid-dependent disease
(applies to both CD/UC)
Anti-TNFs
Biologics (immunogenic)
•Steroid-refractory disease
•Mild course/ prognostic
markers
•Hi-risk for complications
from combo therapy?
Key Takeaways
 Patients should be risk stratified for
disease severity and potential for longterm complications of their IBD
 Combination therapy better than
monotherapy for most patients
 Still role for immunomodulators in
steroid-dependent disease
 Mucosal healing should be a goal
 Therapeutic drug monitoring is useful and
may become more widely available