management of biologic therapies in ibd stephen b. hanauer, md clifford joseph barborka professor of...
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Management of Biologic Therapies in IBD
Stephen B. Hanauer, MDClifford Joseph Barborka Professor of Medicine
Northwestern University Feinberg School of Medicine
Defining Maintenance Treatment
• Simply: A maintenance therapy prevents “relapse”- In contrast to episodic therapy or re-treatment
• Levels of Maintenance- Maintenance of Response- Maintenance of Clinical (or Post-operative) Remission
• Maintenance of Steroid-free remission
- Maintenance of Mucosal Healing- Prevention of Hospitalizations/Surgery- Disease Modification
Clinical Trial Data
Re-Treatment Benefit With Infliximab
Clinical response defined as a ³ 70-point decrease in CDAI score from baseline.* Patients responding to an initial infusion.
Resp
onse
(%)
WeekInfusion
Rutgeerts et al. (1999). Gastroenterology 117(4): 761-769.
CD: Comparing ACCENT I, CHARM, and PRECiSE 2 Remission Results
30.747.9
64.1
020406080
Week 6Response
Week 26Remission
OverallRemission
Week 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.
24
60
40
0
20
40
60
80
100
Week 4
Response
Week 26
Remission
Overall
Remission
Week 26
Pat
ien
ts (
%)
Pat
ien
ts (
%)
Pat
ien
ts (
%)
Health Claims Data
Loss of Response to Infliximab in Crohn’s Disease: Health-Care Claims Data
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 8000%
20%
40%
60%
80%
100%
Days from Index Date
Loss
of-
Resp
onse
Rat
e
2 years, 77%
– Loss of response
• Health-care claims database (1999–2005)
• Selected patients with CD receiving infliximab maintenance therapy with an initial response
• Loss of response inferred from:
– Upward dose adjustment
– New drug therapy for CD
– CD-related emergency room or inpatient visits
• Annual total health-care and CD-related costs estimated and adjusted for inflation to 2005 US dollars
Wu EQ et al. Value Health. 2008;11:820-829.
1 year, ~50%
Comparative Effectiveness of Infliximab and Adalimumab for Crohn's Disease
• Retrospective cohort study by using U.S. Medicare data from 2006 through 2010. • Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871)
after January 31, 2007. • Primary outcome measures were disease persistence on therapy at week 26
Osterman, M. CGH 2014;12:811-17
After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug,compared with 47% of those receiving adalimumab
Kane Svet al. Adv Ther. 2009;26(10):936-946; Fasanmade AA, et al. Eur J Clin Pharmacol.2009;65(12):1211-1228; Ben-Horin S, et al. Autoimmun Rev. 2014;13(1):24-30; Farrell RJ, et al. Gastroenterology. 2003;124(4):917-924.
Causes of Treatment Failure With Anti-TNF Agents
• Poor adherence reported in one-third of patients
• Suboptimal drug concentrations result from pharmacokinetic (PK) differences- Weight-based dosing- Measure serum concentrations
• Antidrug antibodies (ADAs) production
• Concomitant Infection (C. Diff & CMV)
Therapeutic Windows with Biologics
0 2 6 14 22 wks.
1
10
100
µg/mL
AUC
Sub-treshold trough levels associated with:• Loss of response • Immunogenicity
Peak
Trough
0
20
40
60
80
100
Trough Levels of Infliximab Are Predictor of Continued Response
0
10
20
30
Undetectable 2.0 ug/ml
* P < 0.001
0
20
40
60
80
100
Undetectable 2.0 ug/mlUndetectable 2.0 ug/ml
* P < 0.001 * P < 0.001
CLINICAL REMISSION C- REACTIVE PROTEIN ENDOSCOPIC CHANGE
**
*
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-54
Prospective cohort study of relationship between serum infliximab level and efficacy in luminal CD
Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:1126-35.
Higher Serum Infliximab Concentration is Associated with a Higher Response Rate in CD
• Study design: prospective, cohort study
• N=125, 30% Rx for fistula • Median follow-up: 36 months• Efficacy
- Infliximab concentrations ≥12 μg/mL were associated with greater median duration of response
- Immunosuppressant use was associated with IFX concentrations ≥12 μg/mL
Baert F, et al. N Engl J Med. 2003;348:601.
Duration of Response Based onIFX Concentrations
≥12.0 μg/mL <12.0 μg/mL0
20
40
60
80
100
81.5
68.5
Du
rati
on
of
Re
sp
on
se
(d
ay
s)
P<0.01
·Pr
opor
tion
of P
atien
ts (%
)
IFX Concentration (mcg/ml) at Wk 30
Clinical Remission Without Corticosteroids by Trough IFX Concentration at Week 26: SONIC
Primary Endpoint
·*IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis
0 >0-1 >1-3 >3-6 >60
102030405060708090
100
59 57
73 74 72
31/4336/4943/5913/2319/32
·Colombel JF, et al. N Engl J Med. 2010.
Higher Serum Infliximab Level is Associated with Longer Remission and Better Endoscopy Score in CD
• Study design: prospective cohort in moderate-severe CD
• N=105• Median follow-up: 88 weeks• Efficacy
- Infliximab concentrations were positively correlated with the interval of clinical remission and change in endoscopic score
Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248.
40
50
60
70
80
90
100
Rem
issi
on (%
)
Serum Infliximab (µg/ml)
R2= 0.61P<0.001
0 2 4 6 8 10 12
-100
50
0
50
100
Endo
scop
ic Im
prov
emen
t (%
)
Serum Infliximab (µg/ml)
R2= 0.46P<0.001
0 2 4 6 8 10 12
High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease
• Serum samples in 210 CD patients undergoing treatment with infliximab were collected
• Infliximab trough levels were correlated with endoscopic healing (complete, partial or none)
Complete Partial None0
1
2
3
4
5
6
7
5.77
3.89
0.950000000000001
Tro
ug
h l
ev
el
(mc
g/m
L)
· Van Moerkercke W. et al. DDW 2010. Abs #405
Implications of Low Trough Levels
•Disease Recurs- No longer maintenance but re-treatment
•Development of anti-drug antibodies- Eventual loss of response
•Do Not Administer Intermittently!
Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
Presence of ADAs Decreases drug concentration Increases clearanceWorse clinical outcomes
Concomitant use of immunosuppressives Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes
Low serum albumin concentration Increases drug clearanceWorse clinical outcome
High baseline CRP concentration Increase drug clearance
High baseline TNF concentration May decrease drug concentration by increasing clearance
High body size May increase drug clearance
Sex Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 18
Therapeutic drug monitoring with biologic therapy
• Relationship of exposure to response?• Define a minimum effective concentration?• Define a maximum therapeutic concentration above which
- no additional benefit?- increased risk of toxicity?
• Relationship between drug concentration and anti-drug antibodies, and treatment strategy?
• Is TDM cost-effective?• In what clinical situations should TDM be used?
- Induction?- Maintenance?- Loss of response?- Toxicity?
ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in CD
Sustained Clinical Outcome<3.5 μg/mL Week 14
Serum IFX Level≥3.5 μg/mL Week 14
Serum IFX Level P-value*
Subjects included in analysis 96 51
Subjects with sustained response 17 (17.7%) 20 (39.2%) 0.0042
Subjects without sustained response 79 (82.3%) 31 (60.8%)
*Chi-square test
.Cornillie F, et al., Gut. 2014;63: 1721-7
Infliximab Trough Between Weeks 14 and 22 May Predict Sustained Response in Crohn’s Disease
• Retrospective adult cohort • 84 patients• IFX trough level measured at 14 or
22 wks
• Sustained clinical response• IFX Trough level > 3 μg/ml
• Increase in ATI• IFX Trough level < 3 μg/ml
Bortlik M, et al. J Crohns Colitis 2013;7:736-743.
Detectable Serum Trough Infliximab Associated with Higher Remission Rate and Endoscopic Improvement in UC
• Study design: cohort study• N=115 patients with moderate to
severe UC• Follow-up time: median 13.9
months• Efficacy
- Detectable serum IFX was associated with• Higher remission rates (69% vs. 15%;
P<0.001)• Endoscopic improvement
(76% vs. 28%; P<0.001)
Seow CH, et al. Gut. 2010;59:49-54.
Undetectable Detectable0
10
20
30
40
50
60
70
80
15
69
Re
mis
sio
n (
% o
f P
ati
en
ts)
P<0.001
Presence of Detectable Trough Infliximab Levels Reduces Colectomy Rates in Ulcerative Colitis
Seow CH, et al. Gut. 2010;59:49.
Undetectable Detectable0
20
40
60
80
100
55
7
Cole
ctom
y (%
of P
atien
ts) P < 0.001
Proportion of Patients Achieving Clinical Remission by Serum IFX Concentration: ACT 1 and 2
IFX Conc.(% patients)
1stQuartile
2nd Quartile
3rd Quartile
4thQuartile P-values
Week 826.3%
(<21.3μg/mL)37.9%
(≥21.3-<33μg/mL)43.9%
(≥33-<47.9μg/mL)43.1%
(>47.9μg/mL)P=0.0504
Week 3014.6%
(<0.11μg/mL)25.5%
(≥0.11-<2.4μg/mL)59.6%
(≥2.4-<6.8μg/mL)52.1%
(>6.8μg/mL)P<0.0001
Week 5421.1%
(<1.4μg/mL)55.0%
(≥1.4-<3.6μg/mL)79.0%
(≥3.6-<8.1μg/mL)60.0%
(>8.1μg/mL)P=0.0066
At wks 8, 30 and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of IFX concentrations.
Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114
Week 54 Outcome IFX14 median level (μg/ml) P-value*
Persistent Remission (Y vs. N) 4.7 vs. 2.6P = 0.03
Clinical Remission (Y vs. N) 3.2 vs. 2.2P = 0.07
Deep Remission (Y vs. N) 4.2 vs. 3.0P = 0.07
Sustained Durable Remission 14 (Y vs. N) 5.5 vs. 3.1P = 0.05
Sustained Durable Remission 22 (Y vs. N) 5.1 vs. 3.0P = 0.04
Week 14 IFX levels predict week 54 outcomes
Singh N, et al. Inflamm Bowel Dis 2014;10:1708-13
* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed
Clinical outcomes in patients with detectable HACA (n=35)*
* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed
Clinical outcomes in patients with sub-therapeutic concentrations (n=69)*
Increasing dose of infliximab in the presence of ATI formation is inferior to changing anti-TNF
Com
plet
e / p
artia
l res
pons
e (%
)
P<0.004
Com
plet
e / p
artia
l res
pons
e (%
) P<0.016
Afif W, et al. Am J Gastroenterol 2010;105:1133-9.
Adalimumab & ATA Levels at LOR correlate with response to dose intensification
(A) ROC analysis of adalimumab level and active inflammation.
(B) Adalimumab levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.
(D) ATA levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.
(C) ROC analysis of adalimumab level and failure of early response to dose intensification.
Yanai, CGH 2015;13:522–530
Combined analysis for patients with a suspected LOR to either infliximab or adalimumab
Survival curve of regained response to dose intensification according to ADA titer status.
Survival curve for regained response among patients with high-titer ADA.
Yanai, CGH 2015;13:522–530
Combined analysis for patients with a suspected LOR to either infliximab or adalimumab
Survival curve for regained response among patients with no/low-titer ADA.
Anti-TNF drug level before and after dose intensification
Yanai, CGH 2015;13:522–530
Combined analysis for patients with a suspected LOR to either infliximab or adalimumab with adequate drug
levels
Survival curve for regained response among patients who received anti-TNF optimization (dose intensification or a switch within the anti-TNF class) vs expectant management
survival curve for regained response among patients who received anti-TNF optimization vs out-of-class intervention
Yanai, CGH 2015;13:522–530
Survival curves of regained response to adalimumab or infliximab dose intensification according to ATA/ATI titer status at the time of LOR.
Adalimumab Infliximab
Yanai, CGH 2015;13:522–530
Potential yield of drug/ADA tests as illustrated by cohort subgroups of PK measurements
Yanai, CGH 2015;13:522–530
Proposed algorithm for patients with loss of response to infliximab
Positive HACA
Change to another anti-TNF agent
Change to non–anti-TNF agent
persistent disease
Increase infliximab
dose or frequency
Change to non–
anti-TNF agent
Change to different anti-TNF
agent
Change to different anti-TNF
agent
Subtherapeutic IFX concentration
Therapeutic IFX concentration
Active disease on endoscopy/radiology?
Change to different anti-TNF
agent
Investigate alternate etiologies
yes no
Afif W et al. Am J Gastroenterol 2010;105:1133.
What About ADA in the Presence of Drug?
Therapeutic IFX Concentration had no effect on CRP in presence of ADA
• 66 patients: 27% with detectable ATA 59 (89%) CD, 7 (11%) UC
• Mean ADA levels were higher in patients with Undetectable ATA Mucosal healing Concomitant use of immunosuppressants
• ADA level ≥ 5 µg/ml is associated with lower CRP and healed mucosa
• Variables associated with positive ATA (≥ 1.7 µg/ml) ADA < 5µg/ml: OR 8.6, 95%CI (2.3-31) Mucosal inflammation: OR 3.8, 95% CI (1.1-13) Steroid use: OR 3.7, 95% CI (1.1-13)
Serum Adalimumab (ADA) Levels and Anti-Adalimumab Antibodies (ATA) Correlate with Endoscopic Inflammation
and Inflammatory Markers
Yarur, AJ, et al. Presented at DDW; May 21, 2013. Abstract Tu1147.
Endoscopic Inflammation
ad
alim
um
ab
[g
/mL
]
0
10
20
30
40
p=0.016
adal
imu
mab
[ g
/mL]
0
10
20
30
40
p=0.002
Immunosuppresant Use
adal
imum
ab [
g/m
L]
0
10
20
30
40
p=0.028
Cross-sectional study of ADA drug level as predictor of clinical response and CRP in CD
• ADA level of 5.85 μg/mL was optimal- Sensitivity 68%- Specificity 71%- Positive LR 2.3
• AAA were inversely related to ADA drug levels
Mazor Y, et al. Aliment Pharmcol Ther 2014;40:620-8.
Higher trough levels of adalimumab are associated with higher rates of mucosal healing
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.
Trough adalimumab levels are higher in patients with mucosal healing
6.5 μg/mL
4.2 μg/mL
P<0.005
Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.
Adalimumab Trough Serum Levels < 0.33 µg/mL Predicts a Lower Rate of Sustained Complete Response in Patients with Crohn’s Disease
Karmiris K, et al. Gastroenterology. 2009;137:1628.
Patie
nts
with
Sus
tain
edCl
inic
al R
espo
nse
(%)
0.0
0.2
0.4
0.6
0.8
1.0
0 210 240
LogRank: P=.01
Sustained Clinical Response (weeks)90 12030 15060 180
ADA TR>0.33 µg/mL, n=104
ADA TR<0.33 µg/mL, n=16
Proposed algorithm incorporating pharmacokinetics of adalimumab in IBD
AAA: antibodies against adalimumabADA: adalimumabTRA: trough levels of adalimumab
Low TRA: <4.9 μg/ml AAA present: >10 ng/ml
Roblin X, et al. Am J Gastroenterol 2014;109:1250-6.
• Single-center cohort of 125 steroid-refractory acute UC patients
• Standard infliximab induction/maintenance
• Fluid-phase assay for [IFX] and ATI
Trough Infliximab >2 µg/ml is Associated with Clinical Remission in Steroid-Refractory UC
Remission aOR [95%CI]
Colectomy aOR [95%CI]
Trough IFX > 2 µg/ml (vs. ≤ 2 µg/ml)
10 [3,35] 0.18 [0.07,0.44]
ATI (vs. no ATI) 0.64 [0.2,2.4] 1.0 [0.5,2.1]
IFX, infliximab Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.
Steroid-free Remission by IFX/ATI Status100
0
60
20
Pat
ien
ts i
n R
emis
sio
n (
%)
80
40
IFX+ATI-
70.0
16.6
28.5
13.0
IFX+ATI+
IFX-ATI-
IFX-ATI+
P=0.84
P=0.073
P<0.001
Steroid-free Remission by IFX Trough Status100
0
60
20
Pat
ien
ts i
nR
emis
sio
n (
%)
80
40
Serum IFX≤ 2µg/ml
17.5
69.4
Serum IFX> 2µg/ml
P<0.001
Colectomy by IFX Trough Status100
0
60
20Co
lect
om
y (%
)
80
40
Serum IFX≤ 2µg/ml
55.5
17.7
Serum IFX> 2µg/ml
P<0.001
Rapid IFX Clearance: Mechanism of Non-Response in UC
Kevans D, et al. Presented at DDW; May 19, 2012.
• Multicenter, propspective observational study in anti-TNF-naïve patients (N=19) with moderate-to-severe UC (Endoscopic Mayo 2/3)1
- IFX measured at 10 time points during first 6 weeks of induction therapy- Nonlinear mixed-effects modelling
• No difference in IFX concentration area under the curve (AUC) between endoscopic responders and endoscopic non-responders at week 8 (P=0.65 )
• Patients with CRP>50 µg/mL had lower IFX concentration (P=0.001)• 7/19 had positive ATI (homogeneous mobility shift assay)
- 6 of 8 endoscopic non-responders were ATI +- 2 of 8 endoscopic non-responders were ATI –
• Concomitant immunomodulator = 12/19 (P=NS)• IFX presumed to be lost in stool in severe IBD colitis2
Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe UC
1. Brandse JF, et al. Presented at DDW; May 5, 2014 A786. 2. Brandse JF, et al. Presented at DDW; May 18, 2013. A157.
Factors Affecting the Pharmacokinetics of Monoclonal Antibodies
Impact on Pharmacokinetics
Presence of ADAs • Decreases serum mAbs• Threefold-increased clearance• Worse clinical outcomes
Concomitant use of IS• Reduces formation• Increases serum mAbs• Decreases mAb clearance• Better clinical outcomes
High baseline TNF-α • May decrease mAbs by increasing clearance
Low albumin • Increases clearance• Worse clinical outcomes
High baseline CRP • Increases clearance
Body size • High BMI may increase clearance
Gender • Males have higher clearance
Ordas I et al. Clin Pharmacol Ther. 2012;91:635.
mAB, monoclonal antibody; ADA, antidrug antibody
Do early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment?
Vande Casteele N, et al. Gut 2012;61:321
ADA=anti-drug antibodyAfif W et al. Am J Gastroenterol. 2010;105:1133-1139.
Monitoring Biologics To Guide Treatment Decisions
•Neutralizing antibodies/low trough levels•Other immune pathways drive inflammation•Patient has no residual inflammation
Options•Increase dose, switch to other anti-TNF•Biological with other MOA, immunosuppress.•Surgery
What drives loss of response to monoclonalanti TNF Abs?
Utility of IFX and ATI assays
Afif, Am J Gastoenterol 2010
Detectable HACA Subtherapeutic concentration0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Increase infliximab
Change anti-TNF
Co
mp
lete
/par
tial
Res
po
nse
***
**P < 0.004*P < 0.016
Afif W, et al. Am J Gastroenterol. 2010;105(5):1133-1139.
Measuring Infliximab and HACA Concentrations in Patients With IBD: Clinical Outcomes
BRIDGe “anti-TNF optimizer”
www.BRIDGeIBD.com
BRIDGe “anti-TNF optimizer”
www.BRIDGeIBD.com
BRIDGe “anti-TNF optimizer”
www.BRIDGeIBD.com
BRIDGe “anti-TNF optimizer”
www.BRIDGeIBD.com
BRIDGe “anti-TNF optimizer”
www.BRIDGeIBD.com
Can you make antibodies go away?
Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447.
IFX levels closed squaresATI open squares