ATI - Imedex

Report
Optimizing the efficacy of
immunomodulators and biologics in
pediatric IBD
Marla Dubinsky, MD
Director, Pediatric IBD Center
Associate Professor of Pediatrics
Abe and Claire Levine Chair in Pediatric IBD
Cedars-Sinai Medical Center
Objectives
•
•
•
•
•
Causes of non response to therapies
Thiopurine drug monitoring
Anti-TNF drug monitoring
Impact of immunogenicity
The future of biologic use
Potential Causes of Drug Response
Heterogeneity

pathogenesis and severity of disease
 drug interactions
 age
 nutritional status
 renal and liver function
 concomitant illnesses
 genetic polymorphisms in targets of therapy
 inherited differences in metabolism and
disposition
Target 6-TGN Level to Optimize
Efficacy: >235
Frequency of Response
P< 0.001
78%
100%
80%
Odds Ratio 5.0 for
treatment response
when 6-TGN > 235
41%
60%
40%
20%
0%
n=44
0-173
n=42
174-235
n=43
236-367
n=44
368-1203
6-TGN QUARTILES
Dubinsky MC et al. Gastroenterol;118:2000
Meta-Analysis: 6-TGN levels and
Clinical Remission
Author & Year
Patients
(Remissi
on)
6TGN
Threshold
Odds
Ratio
95%
Confidence
Interval
Dubinsky 2000
92 (30)
235
.78
.40
5.07
2.62-9.83
Gupta
101 (47)
235
.56
.43
1.65
0.73-3.75
Belaiche 2001
28 (19)
230
.75
.65
1.62
0.26-10.2
Cuffari
82 (47)
250
.86
.35
11.63
3.78-35.7
Goldenberg
2004
74 (15)
235
.24
.18
1.47
0.47-6.42
Achkar
60 (24)
235
.51
.22
3.80
1.17-12.4
0.62
95% CI
0.430.80
0.36
95% CI
0.250.48
3.27
1.71-6.27
2001
2001
2004
Pooled
Estimate
Proportion Proportion
Above
Below
Threshold Threshold
in
in
Remission Remission
Lewis J et al. Gastroenterology 2006:130;1047-1053
Monitoring Levels of Thiopurines
is Useful Because….
1) Standard dosing only 30% effective
2) Safe dose escalation to maximize efficacy
3) Identify non compliance
4) Minimize toxicity
5) Identify preferential 6-MMP metabolism
6) Explain non response
7) Improves patient outcomes
Anti TNFα monitoring is Useful
Because….
• 150,000 IBD patients are currently on anti-TNFs
• 50% of IBD patients will require dose modification or
switch to another treatment1
• Many patients with IBD who have symptoms may not
have active inflammation
• Monitoring strategies that identify patients who have
insufficient drug, anti-drug antibodies, or patients
whose symptoms are due to causes other than
active IBD may help guide treatment outcomes for
individual patients
Alzafiri et al. Clinical and Experimental Gastroenterology 2011; (4):9-17
Effect of Trough Serum Infliximab Concentrations
on Clinical Outcome at >52 Weeks
Trough serum infliximab
Detectable
100
Undetectable
Patients with endoscopic improvement >75% (%)
Patients in remission (%)
100
82
88
p<0.001
33
p<0.001
6
0
0
Patients with CRP <5 mg/dL (%)
100
100
76
Patients with complete endoscopic remission (%)
p<0.001
47
32
p=0.03
19
0
Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54
0
ACCENT I: Week 54 Sustained Clinical Outcome and
Week 14 Serum Infliximab Level in Crohn’s Disease
<3.5 μg/mL Week
14 Serum IFX
Level
≥3.5 μg/mL Week
14 Serum IFX
Level
96
51
Subjects with sustained
response
17 (17.7%)
20 (39.2%)
Subjects without
sustained response
79 (82.3%)
31 (60.8%)
Sustained Clinical
Outcome
Subjects included in
analysis
P-value*
0.0042
*Chi-square test
Cornillie F, et al. Presented at the 19th Annual United European Gastroenterology Week (UEGW); October 25, 2011. Stockholm, Sweden.
Abstract P0919.
Detectable week 14 Infliximab Trough levels are
associated with week 54 Efficacy Outcomes
Week 54
Outcome
IFX14
Positive
P value
ATI14 *
Positive
P value
Persistent
Remission
70% vs. 36%
P < 0.049
50% vs. 60%
P = 0.58
Clinical Remission
77% vs. 50%
P = 0.09
50% vs. 70%
P > 0.99
Deep Remission
67% vs. 37%
P = 0.10
50% vs. 58%
P > 0.99
Sustained Durable
Remission 14
43% vs. 14%
P = 0.09
0% vs. 38%
P = 0.28
Sustained Durable
Remission 22
50% vs. 14%
P = 0.04
0% vs. 43%
P = 0.15
*Only 4 patients ATI14 positive
Rosenthal C et al 2013
Results: Optimal IFX14 Trough
Level
Persistent
Remission
(N = 26)
IFX14
<3
IFX14
>3
Fisher
P
value
IFX14
< 5.5
IFX14
> 5.5
Fisher
P
value
IFX14
< 6.8
IFX14
> 6.8*
Fisher
P
value
45%
65%
0.54
48%
85%
0.043
50%
100%
0.01
* Regression Tree analysis identified optimal cut point
Serum Infliximab Trough Levels and Steroid-free
Remission at Week 30 Sonic Study
Median IFX
Concentration
Steroid-free Clinical Remission at
Week 26 by IFX Trough Level at
Week 30
19/32
N=97
13/23
43/59
36/49
31/43
N=109
Web figures 5a and 5b. http://www.nejm.org/doi/suppl/10.1056/NEJMoa0904492/suppl_file/nejm_colombel_1383sa1.pdf;
Accessed on October 12, 2012.
ACT1 and ACT 2 cont’d
Proportion of Patients Achieving Clinical
Remission by Serum IFX Concentration:
ACT 1 and 2
At wks 8, 30 and 54, the proportion of patients achieving clinical remission increased with
increasing quartiles of IFX concentrations.
1st
Quartile
2nd
Quartile
3rd
Quartile
4th
Quartile
P-values
Week 8
26.3%
(<21.3μg/mL)
37.9%
(≥21.3-<33μg/mL)
43.9%
(≥33-<47.9μg/mL)
43.1%
(>47.9μg/mL)
P=0.0504
Week 30
14.6%
25.5%
(<0.11μg/mL) (≥0.11-<2.4μg/mL)
59.6%
(≥2.4-<6.8μg/mL)
52.1%
(>6.8μg/mL)
P<0.0001
Week 54
21.1%
(<1.4μg/mL)
79.0%
(≥3.6-<8.1μg/mL)
60.0%
(>8.1μg/mL)
P=0.0066
IFX Conc.
(% patients)
55.0%
(≥1.4-<3.6μg/mL)
Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114
% of patients
Detectable Serum Trough IFX Concentration is
Associated with Higher Remission Rate and
Endoscopic Improvement in UC Patients
P<0.001
Undetectable serum IFX predicted an increased risk for colectomy
(55% vs 7%; p<0.001)
Seow CH et al. Gut 2010;59:49-54
Rapid IFX clearance: Mechanism
of Non Response in UC
Kevans D, et al. Presented at DDW; May 19, 2012.
Effect of Patient Factors on
MAb Pharmacokinetics
0.40
• Impact on IFX clearance
is substantial and should
be considered for dose
selection
0.36
Clearance (L/day)
– Weight
– Albumin
– ADA
0.38
0.34
0.32
0.30
0.28
0.26
0.24
0.22
0.20
40
50
60
70
80
90
100
Weight (kg)
0.90
0.80
0.70
Clearance (L/day)
• Patient factors identified
with changes in IFX
clearance
0.60
0.50
0.40
0.30
0.20
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
Albumin (g/dL)
ADA, antidrug antibody ; IFX, infliximab
Fasanmade AA, et al. Eur J Clin Pharmacol. 2009;65(12):1211.
Xu Z, et al. A Population-based Pharmacokinetic Pooled Analysis of Infliximab in Pediatrics. Presented at the 41st Annual Meeting of the American College of Clinical
Pharmacology; September 23-25, 2012; San Diego, CA.
ADA Trough Above 0.33 µg/mL Predicts
Clinical Response
Patients with Sustained
Clinical Response (%)
1.0
Log Rank: P=0.01
0.8
ADA TR>0.33 µg/mL, n=104
ADA TR<0.33 µg/mL, n=16
0.6
0.4
0.2
0.0
0
30
60
90
120
150
180
Sustained Clinical Response (weeks)
Karmiris K, et al. Gastroenterology. 2009;137:1628.
210
240
PURSUIT – Golimumab for the Induction
and Maintenance of UC
Phase 2: Clinical Endpoints by Serum Golimumab Concentration
Quartile at Week 6
No exposure
< 1st Quartile
1st and < 2nd Quartile
2nd and < 3rd Quartile
3rd Quartile
Sandborn WJ, et al. Presented at DDW; May 22, 2012. Abstract 943d.
Factors Affecting Infliximab
Clearance in CD
Scheduled & Episodic Therapy ACCENT I (n=580)
Relative Strength of Effect
1
0.5
0.294
0
-0.1
-0.5
-1
-0.48
-0.394
-0.74
-0.82
-1.5
Serum
Albumin
ATI
Con. IS, concomitant immunosuppressant
Fasanmade AA, et al. Clin Ther. 2011;33(7):946.
Con. IS
Body Weight Body Weight Body Weight
(total
(central
(peripheral
clearance) clearance) clearance)
Immunogenicity
•
Immunogenicity is usually
dependent on antibody
construct, route of
administration, target of the
antibody, disease, and other
factors
– Therapeutic antibodies that
deplete B-cells are less
immunogenic than other
MAbs
Murine
Chimeric
HyperChimeric
Human
Immunogenicity
Half-Life
Complement and ADCC
Infliximab (chimeric) should be more immunogenic
than adalimumab (human), but immunogenicity is
similar.
Route of Administration: SC > IM > IV
ADCC, antibody-dependent cell cytotoxicity;
1. http://www.medversation.com/medversation/hcp/section/PRE/SED733445-07DB-4A2D-F2BCA717D20C0E0E.html
Immunogenicity of TNF Antagonists:
Patients With Detectable Antibodies to a TNF
Antagonist
Patients, %
Episodic Maintenance
Infliximab1 (CD 5 mg/kg)
(CD 10 mg/kg)
IMS-
IMS+
IMS-
IMS+
38%
16%
11%
8%
7%
4%
19%
9%
2%
4%
10%
4%
12%
2%
12%
1%
4%
0%
Infliximab2 (UC 5 mg/kg)
(UC 10 mg/kg)
No data
Certolizumab3 (PRECiSE I)
Certolizumab4 (PRECiSE II)
Adalimumab5 (RA, all doses)
Adalimumab6 (CLASSIC II)
Scheduled Maintenance
24%
8%
No data
IMS, immunosuppressant; RA, rheumatoid arthritis; UC, ulcerative colitis
1. Hanauer et al. Clin Gastroenterol Hepatol. 2004;2(7):542. 2. Sandborn WJ, et al. Presented at DDW; May 19-24, 2007. Abstract T1273.
3. Sandborn WJ, et al. N Engl J Med. 2007;357:228. 4. Schreiber S, et al. N Engl J Med. 2007;357:239. 5. Summary of Product
Characteristics for adalimumab. Abbott Laboratories. July 2007. 6. Sandborn WJ, et al. Gut. 2007;56:1232.
Presence of ATI is Associated with a Higher Nonresponse Rate and Shorter Duration of Response
ATI (+)
N=19
ATI (-)
N=33
P-value
52%
14%
0.0005
28 days
61 days
0.007
Incidence of
subsequent infusion
reactions
40%
5%
0.0001
Incidence of serious
infusion reactions
28%
0%
0.0001
Rate of
Non-response to
subsequent infusions
Median Duration of
Response
Farrell RJ, et al. Gastroenterology
2003;124:917-24
22
SONIC: Immunogenicity Results at
Week 30*
98
Percent of Patients (%)
100
94
80
68
60
40
14
20
1/89
0
1
15
0/89
87/89
0
AZA + placebo
Positive
15/106
16/106
72/106
IFX + placebo
Negative
1/120
2/120
1
2
113/120
AZA + IFX
Inconclusive
*Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. PK data at
week 30 was not available for 1 patient treated with AZA + placebo, 3 patients treated with IFX + placebo, and 4 patients treated with
AZA + IFX.
AZA, azathioprine; IFX, infliximab; PK, pharmacokinetic; SONIC, Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease
Colombel JF, et al. N Engl J Med. 2010;362(15):1383.
AAA Formation Lowers Adalimumab Trough Serum
Levels in Patients with Crohn’s Disease
•
92% of the patients with a trough serum concentration measured below the
threshold for detection were positive for AAA
AAA, antibodies against adalimumab; ADA, adalimumab; TR, trough serum concentration
Karmiris K, et al. Gastroenterology. 2009;137:1628.
Serum IFX at Week 4 After an Infusion Predicts
Eventual Appearance of ATI’s in Episodic Dosing
Week 4 Serum Level and
Subsequent ATI Titre
Serum IFX Level
(µg/ml)
100
P=NS
P<0.001
P<0.001
10
1
ATI
<8
ATI
>8
• “an IFX level of <4 μg/mL
measured 4 weeks after the
first infusion had a PPV of
81% to detect the
development of high ATIs
during the later course of
treatment”
• “an IFX level of >15 μg/mL
measured 4 weeks after the
first infusion was 80%
predictive for the absence of
ATIs during later follow-up”
ATI
??
ATI, antibodies to infliximab; IFX, infliximab; PPV, positive predictive value
Vermeire S et al. Gut. 2007;56(9);1226.
Transient versus Sustained Antibodies to Infliximab:
Possibility to Overcome Low Titer Antibody Responses
by Dose Optimization
• N=57, Patients were selected based on ATIs detected on at least one time point during follow-up
• 788 serum samples were analyzed for IFX trough levels (ITL) and ATIs
• Treatment decisions to optimize and stop therapy were made on clinical grounds and CRP and not on
ATI or ITL.
Early ATI Formation
Treatment Discontinuation after Dose Optimization
n=19
n=38
Before the second infusion 20% of pts who had
“late persisting ATIs“ had an undetectable ITL




Concomitant immunomodulator use was associated
with less ATI formation
ATIs may be transient and can disappear after dose optimization.
Sustained high levels of ATIs lead however to permanent loss of response.
When low or undetectable ITL are detected measuring ATIs is necessary.
Low titer ATIs can be overcome by treatment optimization. High ATIs necessitate treatment stop.
Van de Casteele N, et al. Presented at the 7th Congress of ECCO; February 16-18, 2012. Barcelona, Spain. Abstract P253.
Results: IFX Liquid Phase ROC Analysis
0.8
TPR
• Goal: Find objective
IFX cutoff using CRP
• High CRP should
predict low IFX &
vice versa
1.0
0.6
0.8
0.6
AUC=0.735
0.0
0.0
0.2
0.4
0.6
0.8
FPR
Cutoff
(μg/ml)
ROC
AUC
95% C.I
0.1
0.697
0.666, 0.728
3.0
0.735
0.711, 0.760
5.0
0.702
0.677, 0.728
AUC, area under the curve; CRP, c-reactive protein; FPR, false positive rate; IFX, infliximab; ROC, receiver operating characteristic;
TPR, true positive rate
Feagan B, et al. Gastroenterology. 2012;142(5) Suppl 1: S-114. Abstract 565.
1.0
IFX & ATI Counts
ATI−
ATI+
IFX−
3.7%
13.4%
IFX+
72.6%
10.4%
IFXIFX+
1,200
1,000
 IFX assay LLOQ 0.1 μg/ml
 ATI+ serum samples
significantly lower odds of
having detectable IFX
– Odds ratio = 0.040, P<0.0001
 154/353 (44%) ATI+ serum
samples had detectable IFX
LLOQ, lower limit of quantification
Count
800
600
1,079
400
154
200
199
0
55
ATIATI+
Serum IFX Concentration* (mg/ml)
Novel Infliximab and Antibody-to-Infliximab
Assays Are Predictive of Disease Activity in
Patients with CD
***
1,487 serum samples from 483
participants in 4 CD RCTs/cohorts
Disease activity measured by CRP
Predictors of higher CRP: ATI+,
infliximab < 3mcg/mL
25.0
CRP mg/L
1,205 pairs of samples taken
over sequential time points
(trough infliximab/ATI in first
sample, CRP in second sample)
50.0
10.0
5.0
***
294 59
244
890
2.5
1.0
0.5
Sample size
ATI-
ATI+
IFX < 3 µg/ml
5.98
11.92
IFX ≥ 3 µg/ml
1.98
11.57
Median CRP (mg/L)
Feagan B, et al. Presented at DDW; May 20, 2012. Abstract 565.
Elevating Infliximab Concentration from Sub-Therapeutic
Levels is Effective in Regaining Response in HACA (-)
Patients
Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or
Sub-therapeutic Infliximab Concentrations
Response to test
Complete/partial
response (%)
Detectable HACA
Increase infliximab
Change anti-TNF
1/6 (17)
11/12 (92)
P<0.004
Subtherapeutic
concentration
Increase infliximab
Change anti-TNF
25/29 (86)
2/6 (33)
P<0.016
HACA, Human anti-chimeric antibodies
Afif W, et al. Am J Gastroenterol. 2010;105(5):1133.
P value
Treatment Paradigms in Symptomatic Patients
that Lose Response to IFX
ATI IFX < threshold
IFX ≥ threshold
ATI+
Increase dose
Switch (high ATI)
or
Dose optimize (low ATI)
Check endoscopy
or Switch
Switch (high activity)
or
Monitor (low activity)
Individualized IFX Treatment Using Therapeutic Drug
Monitoring: A Prospective Controlled Trough Level
Adapted InfliXImab Treatment (TAXIT) Trial
• 270 IBD patients on IFX maintenance therapy. All pts had their IFX trough levels adjusted to 3-7
ug/ml.
• They were then randomized to dosing based on IFX trough levels (ITL)
– Group 1: ITL kept between 3 and 7 μg/ml
– Group 2: dosing and optimization based on clinical symptoms
Decreased dose
Increased dose
(77%) were
ATI positive
 Only 43% have optimal ITL. In the others dose adjustment was carried out.
 9% of the patients have undetectable ITL despite staying in remission.
 The current controlled study will show whether long term adjustment of treatment based on IFX levels is a superior strategy.
Infliximab EMEA SPC: 5 mg/kg IV infusion over a 2-hour period
Van de Casteele N, et al. Presented at the 7th Congress of ECCO; February 16-18, 2012. Barcelona, Spain. Abstract OP11.
Therapeutic Drug Monitoring for Anti-TNFα
• Measurable drug level associated with
improved response outcomes
• Anti-infliximab antibodies associated with
decreased efficacy
• ATI and drug levels can help guide treatment
decisions
• Dose ranges should be studied during drug
development given pharmacokinetic variability

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