Association Between Plasma Concentrations of … · After 1 week screening patients entered 52-wk treatment ... concentration quartiles at wk 8 and response or ... 210 CD patients

Association Between Plasma Concentrations of Certolizumab

Pegol and Endoscopic Outcomes of Patients With Crohn's Disease

Jean–Frédéric Colombel, William J. Sandborn, Matthieu Allez, Jean–Louis Dupas, Olivier Dewit, Geert D'Haens, Yoram Bouhnik, Gerald Parker,

Bosny Pierre–Louis and Xavier Hébuterne

Clinical Gastroenterology and HepatologyDOI: 10.1016/j.cgh.2013.10.025

Copyright © AGA Institute Terms and Conditions

Stephen B. HanauerStephen B. Hanauer

Potential ConflictsPrometheus, AbbVie, Janssen, UCB

Infliximab AdalimumabGolimumab

IgG1Fc

Fab

Monoclonal antibody

HumanChimeric

Fab′

Certolizumab pegol

PEG

PEGylated humanized

Fab′ fragment2 × 20 kDa

PEG

Anti-TNF Antibodies & PEGylated Fab' fragment for IBD

Anti-TNF Antibodies & PEGylated Fab' fragment for IBD

Background: Certolizumab pegolBackground: Certolizumab pegol

Anti–tumor necrosis factor-α (TNF-α) agent

IgG1 FAB fragment (Fc free) that is pegylated / univalent and ~ 95% humanized

Approved for treatment of moderate- severe active CD in United States, Switzerland, Russia, Mexico, Ecuador, Brazil, Argentina, Chile, Dominican Republic

Fab′ 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 Anti-TNF Biologics in Refractory Crohn’s disease

Drug

Placebo

Drug

Placebo

Drug

Placebo

Drug

Responder

ResponseMaintenance

Maintenance

Targan/InfliximabClassic I/Adalimumab

ACCENT I/InfliximabCHARM/AdalimumabPRECiSE 2/Certolizumab

CLASSIC II/AdalimumabPRECiSE1/Certolizumab

Recent Anti-TNF Biologic TrialsRecent Anti-TNF Biologic Trials

Step-up/Top-down (Steroid-naïve)

COMMITT(Steroid-induced, IS naive)

SONIC(Steroid-refractory, IS naïve)

SteroidsSteroidsIS

Infliximab + IS

Infliximab

Infliximab + MTX

Infliximab

Infliximab + AZA

AZA

BackgroundBackground

Monitoring plasma concentrations of anti–tumor necrosis factor agents could optimize treatment of patients with Crohn's Disease (CD). In post hoc analysis of data from a clinical trial

in patients with moderate to severe ileocolonic Crohn’s disease (MUSIC) Compared relationship between plasma

concentrations of certolizumab pegol (CZP) and: Endoscopic response Clinical response Clinical Remission

MUSIC TrialMUSIC Trial

After 1 week screening patients entered 52-wk treatment CZP 400 mg s.c at wks 0, 2, 4, then q4wk to wk 52 If no clinical response (CDAI 100)/ remission (CDAI<150) by

wk10 or if clinical resp. lost after wk 10, dose was escalated to 400 mg q2w **(not included in analysis)

CZP plasma concentrations collected at wks 8 (trough) & 54 (mid-2wk) and stratified by quartiles.

Rates of endoscopic response (CDEIS decrease from baseline, >5) and remission (CDEIS, <6) were determined at weeks 10 and 54.

Loss of clinical response was defined as CDAI greater than 150 and an increase in CDAI of 70 points or more at 2 consecutive visits vs week 10.

Analysis SetAnalysis Set

Pts who received loading dose of CZP 400 mg at 0, 2, and 4 weeks, and had an available CZP trough measurement at week 8, and endoscopic and clinical measurements available at week 10 (n = 45).

For wk 54 analyses subset of patients with: (1) availability of CZP plasma measurement at week 54; (2) endoscopic and clinical measurements available at week 54; (3) pts who stayed in every 4 wks dosing group until wk 54.

These criteria limited number of pts with available data at wk 54 to a total of only 18.

Statistical AnalysesStatistical Analyses

CZP plasma concentrations expressed as geometric means with coefficient of variation and related 95% confidence intervals (CIs). Relationship between CZP plasma

concentration quartiles at wk 8 and response or remission at week 10 analyzed using Mantel–Haenszel chi-square test. Logistic regression used to examine

association between plasma CZP levels and outcomes.

Statistical Analyses (cont)Statistical Analyses (cont)

Multivariate analyses conducted to evaluate influence of pt baseline characteristics on CZP trough concentration at week 8.

Effect of each covariate was investigated separately using a univariate linear regression model.

Stepwise multivariate regression subsequently used to identify baseline covariates most likely associated with CZP plasma concentration at week 8.

Covariates included in multivariate model: baseline body weight (kg), CRP, CDEIS, CDAI, gender, immunosuppressant

(azathioprine, 6-mercaptopurine, methotrexate) intake (no/yes), and albumin within normal range (yes/no).

Source: Clinical Gastroenterology and Hepatology (DOI:10.1016/j.cgh.2013.10.025 )Copyright © AGA Institute Terms and Conditions

MUSIC Trial DesignMUSIC Trial Design


Associations between clinical and endoscopic responses or remission at week 10 and plasma CZP concentrations at

week 8

Associations between clinical and endoscopic responses or remission at week 10 and plasma CZP concentrations at

week 8


Rates of endoscopic response and remission and clinical response and remission at week 10 by CZP plasma concentration quartiles (μg/mL) at week 8 (trough).

Rates of endoscopic response and remission and clinical response and remission at week 10 by CZP plasma concentration quartiles (μg/mL) at week 8 (trough).


Rates of endoscopic response and remission and clinical response and remission at week 54 by CZP plasma concentration quartiles (μg/mL) at week 54 (2-week

midpoint).

Rates of endoscopic response and remission and clinical response and remission at week 54 by CZP plasma concentration quartiles (μg/mL) at week 54 (2-week

midpoint).

Relationship Between Baseline Factors and CZP Plasma Concentration at Week 8

Relationship Between Baseline Factors and CZP Plasma Concentration at Week 8

Baseline variable P value

Univariate Stepwise regression regression

CRP level, mg/L .0019 .0014Body weight, kg .0500 .0373Albumin in normal range .1109 _Sex, female vs male .1020 _Immunosuppressants, no vs yes .3268 _CDAI score .5132 _CDEIS score .2446 _

LimitationsLimitations

Small sample sizes (week 10, n = 45; week 54, n = 18) Data showed an association but not causality CZP plasma concentrations not at steady state at week

8 after the loading dose, but rather are at a steady state at 4 weeks after the loading dose. Thus trough concentrations at week 8 cannot be compared with

a maintenance trough concentration. The pharmacokinetic data point from week 54 is 2 weeks after a

CZP 400-mg dose. Thus, the CZP plasma concentration from week 54 is at the midpoint in the dosing cycle and not a trough.

ConclusionsConclusions

Endoscopic response and remission associated with higher concentrations of CZP

The highest CZP plasma concentration quartiles associated with higher rates of endoscopic response and remission at week 10.

At week 54, rates of endoscopic remission correlated with the CZP plasma concentration.

Higher body weight and CRP concentrations were associated with lower CZP concentrations.

ConclusionsConclusions

Significant inverse relationship between CZP plasma concentration and baseline CRP suggests a high inflammatory burden may increase the clearance of the TNF antagonist. The association between endoscopic outcome

and CZP concentrations supports need to consider the PKs of TNF antagonists when optimizing drug treatment. Findings from post hoc analysis should be

evaluated further in a prospective randomized trial.

Chicken vs Egg Chicken vs Egg

It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing and, thus, higher rates of CDEIS response and remission at week 10.

Therapeutic Monitoring with BiologicsTherapeutic Monitoring with Biologics

Trough Levels of Infliximab May Be a Better Predictor of Continued

Response Than ATI

Trough Levels of Infliximab May Be a Better Predictor of Continued

Response Than ATI

Undetectable 2.0 ug/ml

* P < 0.001

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

High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease

High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease

Serum samples in 210 CD patients undergoing treatment with infliximab

Infliximab trough levels were correlated with endoscopic healing (complete, partial or none)

0

1

2

3

4

5

6

7

Complete Partial None

Trou

gh le

vel (

mcg

/mL)

Van Moerkercke W. et al. DDW 2010. Abs #405

Clinical Remission Without Corticosteroidsby Trough Infliximab Concentration:

Serum Infliximab Trough Levels at Week 30

Clinical Remission Without Corticosteroidsby Trough Infliximab Concentration:

Serum Infliximab Trough Levels at Week 30

59 57

73 74 72

0102030405060708090

100

0 >0-1 >1-3 >3-6 >6

% o

f Pat

ient

s

Serum IFX Concentration* (g/mL)

1.6

3.5

0123456789

10

IFX IFX + AZA

Seru

m IF

X C

once

ntra

tion*

(g/

mL)

P<0.001

Steroid-free Clinical Remission atWeek 26 by IFX Trough Level at Week 30Median IFX Concentration

* IFX- or IFX/AZA-treated patients who had serum samples collected prior to infusion at wk 30 (n=206).

N=97 N=109 19/32 13/23 43/59 36/49 31/43

SONIC

Colombel JF et al. N Engl J Med. 2010;362:1383-1395.

Concentration–effect relationship of IFX in CD: Results of a cohort study

Concentration–effect relationship of IFX in CD: Results of a cohort study

The aim was to study concentration–effect relationships of IFX in a cohort of CD patients.

Relationship between C-reactive protein concentrations and infliximab trough concentration. Observed data are represented by open circles and model predicted data are represented by the curve.

Lamblin et al. ECCO 2012, abstract P334

• 44 pts included (20 in remission)

• IFX concentrations were higher in pts in remission (6.33 mg/L vs 3.39 ug/ml p<0.02)

• Estimated IFX concentration leading to 50% decrease CRP level was 1.1 ug/ml

• CRP below 5mg/L was obtained by > 5.6 ug/ml IFX

• Optimal trough level of IFX is suggested to be 5 ug/ml

Time (days)

Sim

ulat

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nti-T

NF

biol

ogic

con

c

0 20 40 60 80 100 120

0.5

1.0

5.0

10.0

50.0

Time (days)

Sim

ulat

ed a

nti-T

NF

biol

ogic

con

c

0 20 40 60 80 100 120

0.5

1.0

5.0

10.0

50.0

Time (days)

Sim

ulat

ed a

nti-T

NF

biol

ogic

con

c

0 20 40 60 80 100 120

0.5

1.0

5.0

10.0

50.0

Time (days)

Sim

ulat

ed a

nti-T

NF

biol

ogic

con

c

0 20 40 60 80 100 120

0.5

1.0

5.0

10.0

50.0

Time (days)

Sim

ulat

ed a

nti-T

NF

biol

ogic

con

c

0 20 40 60 80 100 120

0.5

1.0

5.0

10.0

50.0

Adalimumab 160 mg (day 1), 80 mg (day8)and 40 mg every two weeks Adalimumab 40 mg every two weeks

Infliximab 5 mg/kg at day 1, day 15, day 43 and every 8 weeksInfliximab 3 mg/kg at day 1, day 15, day 43 and every 8 weeks

Theoretical threshold

Subtherapeutic

Implications of Low Trough LevelsImplications of Low Trough Levels

Disease RecursNo longer maintenance but re-

treatmentDevelopment of anti-drug

antibodiesEventual loss of response

Factors that Influence the PK of TNF Antagonists


Impact on TNF antagonist PKPresence of ADAs Decreases drug concentration

Increases clearanceWorse clinical outcomes

Ordas I et. al. Clin Gastroenterol Hepatol.

28



Impact on TNF antagonist PK

Concomitant use of immunosuppressives

Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes


29




Low serum albumin concentration Increases drug clearanceWorse clinical outcome

High baseline CRP concentration Increase drug clearanceHigh baseline TNF concentration May decrease drug concentration by

increasing clearance


30




High body size May increase drug clearanceSex Males have higher clearance


31



Impact on TNF antagonist PKPresence 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 clearanceHigh baseline TNF concentration May decrease drug concentration by

increasing clearanceHigh body size May increase drug clearanceSex Males have higher clearance


32

What drives loss of response to monoclonalanti TNF Abs?

•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

Algorithm for loss of response to Anti-TNFAlgorithm for loss of response to Anti-TNF

Is there active disease?

Yes

Measure mAb and ADA Low [mAb]

undetectable ADA

Suboptimal PK

Increase mAb dose or frequency

Undetectable [mAb]Detectable ADA

Loss of response due to ADA

Switch mAb

Therapeutic [mAb]

IBD refractory to anti‐TNF

Alternative MOA(Natalizumab)

No IBS SBBOBile‐acid diarrheaStrictures

Utility of Drug and ADA for Loss of Response


Afif, Am J Gastoenterol 2010

If Drug Level is Low, Increase the Dose


If Anti-Drug Antibodies, Switch






No benefit of substituting one mAB for another if adequate concentrations

If Drug is Present, Switch Mechanisms

Preventing Loss of ResponsePreventing Loss of Response

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease: A single cohort

study

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease: A single cohort

study N = 84, responded to 3 dose induction followed by scheduled

maintenance therapy Blood samples: prior to 1st or 2nd maintenance infusion (TLcut-off 3 μg/ml)

Sustained Response (SR) to IFX in 47 (56%) patients after FU of 25 mo

Bortlik et al. ECCO 2012, abstract P360

• After a median follow up of 2 years, SR to IFX was observed in slightly more than half of CD patients. IFX TL >3 μg/ml at the start of maintenance regime was predictive of SR to IFX.

Univariate Analysis Multivariate AnalysisIFX TL TLs >3 μg/ml associated with a

decreased probability of loss of SR

(HR 0.31; 95%CI: 0.16–0.62),

Had impact on SR to IFX

(HR 0.34; 95%CI: 0.16-0.74

Corticosteroids increased the risk of treatment failure (HR 2.34, 95%CI: 1.13–4.84).

No impact

Thiopurines No impact No impact

• Only 43% have optimal ITL. In the others dose adjustment was carried out. • 9% of the patients have undetectable ITL despite staying in remission. •Dose escalation improved outcomes (HBS & CRP)•After initial dose optimization, no benefit of TDM vs clinical and CRP monitoring

Individualized IFX Treatment using Therapeutic Drug Monitoring: a Prospective Controlled Trough Level Adapted InfliXImab Treatment

(TAXIT) Trial

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

Vande Casteele et al. UEGW 2013

Perc

enta

ge o

f pat

ient

s (%

)

Decreased dose

Increased dose

Baseline trough levels

(77%) were ATI positive

Post-induction serum infliximab trough level and

decrease of C-reactive protein level are associated with sustained response to

infliximab: a retrospective analysis of the ACCENT I trial

Post-induction serum infliximab trough level and

decrease of C-reactive protein level are associated with sustained response to

infliximab: a retrospective analysis of the ACCENT I trial

Cornillie F, Hanauer SB, Diamond RH, Wang J,Tang KL, Xu Z, Rutgeerts , Vermiere S

Gut, in Press

MethodsMethods

ACCENT I was a multicentre, randomised,placebo-controlled study. Week 14 trough levels and CRP percentage

decrease from baseline to week 14 compared between patients with/without sustained response through week 54. Sensitivity and specificity determined to predict

sustained response. Receiver operating characteristic (ROC) curves

identified optimal cut-off points; logistic regression determined ORs.

ResultsResults

After induction with 5 mg/kg infliximab, 25%(37/147) and 33% (47/144) of pts sustained week 14response to infliximab 5 or 10 mg/kg without dose-

escalation through week 54.

Median week 14 trough levels of patients with and without sustained response to infliximab 5 mg/kg were 4.0 and 1.9 mg/mL (p=0.0331).

Results (cont)Results (cont)

Optimal predictors of sustained response to maintenance infliximab 5 mg/kg were week 14 trough level ≥3.5 mg/mL and ≥60% CRP decrease [ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)] in patients with raised baseline CRP Area under the ROC curve was 0.75 for both

predictors. A ≥3.5 mg/mL week 14 infliximab serum level did

not predict sustained response to 10 mg/kg maintenance infliximab.

CRP may be surrogate for adequate Drug Trough?

CRP may be surrogate for adequate Drug Trough?

Therapeutic Drug Monitoring with BiologicsTherapeutic Drug Monitoring with Biologics

Assessing loss of response Also cost effective vs. empiric changes

Preventing loss of response Preventing complications Pharmacoeconomics

✔

✔−

??

Association Between Plasma Concentrations of … · After 1 week screening patients entered 52-wk treatment ... concentration quartiles at wk 8 and response or ... 210 CD patients

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