Association Between Plasma Concentrations of Certolizumab Pegol and Endoscopic Outcomes of Patients With Crohn's Disease

Transcription

1 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 Hepatology DOI: /j.cgh Copyright AGA Institute Terms and Conditions

2 Stephen B. Hanauer Potential Conflicts Prometheus, AbbVie, Janssen, UCB

3 Anti-TNF Antibodies & PEGylated Fab' fragment for IBD Infliximab Fab Adalimumab Golimumab Fab Certolizumab pegol IgG1 Fc PEG Chimeric Human Monoclonal antibody PEGylated humanized Fab fragment 2 20 kda PEG

4 Background: Certolizumab pegol Anti tumor necrosis factor-α (TNF-α) agent Fab 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 PEG Certolizumab pegol PEGylated humanized Fab fragment 2 20 kda PEG

5 Clinical Trials with Anti-TNF Biologics in Refractory Crohn s disease Drug Targan/Infliximab Classic I/Adalimumab Placebo ACCENT I/Infliximab CHARM/Adalimumab Drug PRECiSE 2/Certolizumab Responder Drug Placebo Maintenance Drug Response Maintenance CLASSIC II/Adalimumab PRECiSE1/Certolizumab Placebo

6 Recent Anti-TNF Biologic Trials Steroids Steroids IS Step-up/Top-down (Steroid-naïve) Infliximab + IS COMMITT (Steroid-induced, IS naive) SONIC (Steroid-refractory, IS naïve) Infliximab Infliximab + MTX Infliximab Infliximab + AZA AZA

7 Background 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

8 MUSIC 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.

9 Analysis 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.

10 Statistical 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.

11 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).

12 MUSIC Trial Design Source: Clinical Gastroenterology and Hepatology (DOI: /j.cgh ) Copyright AGA Institute Terms and Conditions

13 Associations between clinical and endoscopic responses or remission at week 10 and plasma CZP concentrations at week 8 Source: Clinical Gastroenterology and Hepatology (DOI: /j.cgh ) Copyright AGA Institute Terms and Conditions

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

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

16 Relationship Between Baseline Factors and CZP Plasma Concentration at Week 8 Baseline variable P value Univariate Stepwise regression regression CRP level, mg/l Body weight, kg Albumin in normal range.1109 _ Sex, female vs male.1020 _ Immunosuppressants, no vs yes.3268 _ CDAI score.5132 _ CDEIS score.2446 _

17 Limitations 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.

18 Conclusions 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.

19 Conclusions 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.

20 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.

21 Therapeutic Monitoring with Biologics

22 Trough Levels of Infliximab May Be a Better Predictor of Continued Response Than ATI CLINICAL REMISSION C- REACTIVE PROTEIN ENDOSCOPIC CHANGE * * P < * P < * P < * * Undetectable 2.0 ug/ml Undetectable 2.0 ug/ml Undetectable 2.0 ug/ml Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:

23 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) Trough level (mcg/ml) Complete Partial None Van Moerkercke W. et al. DDW Abs #405

24 Clinical Remission Without Corticosteroids by Trough Infliximab Concentration: Serum Infliximab Trough Levels at Week 30 Serum IFX Concentration* ( g/ml) Median IFX Concentration 1.6 IFX P< IFX + AZA % of Patients Steroid-free Clinical Remission at Week 26 by IFX Trough Level at Week N=97 N=109 19/32 13/23 43/59 36/49 31/43 0 >0-1 >1-3 >3-6 >6 Serum IFX Concentration* ( g/ml) * IFX- or IFX/AZA-treated patients who had serum samples collected prior to infusion at wk 30 (n=206). Colombel JF et al. N Engl J Med. 2010;362: SONIC

25 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. 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 Lamblin et al. ECCO 2012, abstract P334

26 Infliximab 5 mg/kg at day 1, day 15, day 43 and every 8 weeks Infliximab 3 mg/kg at day 1, day 15, day 43 and every 8 weeks Theoretical threshold Adalimumab 160 mg (day 1), 80 mg (day8) and 40 mg every two weeks Adalimumab 40 mg every two weeks Subtherapeutic Time (days) Simulated anti-tnf biologic conc

27 Implications of Low Trough Levels Disease Recurs No longer maintenance but retreatment Development of anti-drug antibodies Eventual loss of response

28 Factors that Influence the PK of TNF Antagonists Presence of ADAs Impact on TNF antagonist PK Decreases drug concentration Increases clearance Worse clinical outcomes Ordas I et. al. Clin Gastroenterol Hepatol. 28

29 Factors that Influence the PK of TNF Antagonists Impact on TNF antagonist PK Concomitant use of immunosuppressives Reduces ADA formation Increases drug concentration Decreases drug clearance Better clinical outcomes Ordas I et. al. Clin Gastroenterol Hepatol. 29

30 Factors that Influence the PK of TNF Antagonists Impact on TNF antagonist PK Low serum albumin concentration High baseline CRP concentration High baseline TNF concentration Increases drug clearance Worse clinical outcome Increase drug clearance May decrease drug concentration by increasing clearance Ordas I et. al. Clin Gastroenterol Hepatol. 30

31 Factors that Influence the PK of TNF Antagonists Impact on TNF antagonist PK High body size Sex May increase drug clearance Males have higher clearance Ordas I et. al. Clin 31 Gastroenterol Hepatol.

32 Factors that Influence the PK of TNF Antagonists Presence of ADAs Concomitant use of immunosuppressives Low serum albumin concentration High baseline CRP concentration High baseline TNF concentration High body size Sex Impact on TNF antagonist PK Decreases drug concentration Increases clearance Worse clinical outcomes Reduces ADA formation Increases drug concentration Decreases drug clearance Better clinical outcomes Increases drug clearance Worse clinical outcome Increase drug clearance May decrease drug concentration by increasing clearance May increase drug clearance Males have higher clearance Ordas I et. al. Clin 32 Gastroenterol Hepatol.

33 What drives loss of response to monoclonal anti 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

34 Algorithm for loss of response to Anti-TNF Is there active disease? Therapeutic [mab] Yes Measure mab and ADA Low [mab] undetectable ADA No Undetectable [mab] Detectable ADA IBS SBBO Bile acid diarrhea Strictures IBD refractory to anti TNF Suboptimal PK Loss of response due to ADA Alternative MOA (Natalizumab) Increase mab dose or frequency Switch mab

35 Utility of Drug and ADA for Loss of Response If Drug Level is Low, Increase the Dose Afif, Am J Gastoenterol 2010

36 Utility of Drug and ADA for Loss of Response If Anti-Drug Antibodies, Switch Afif, Am J Gastoenterol 2010

37 Utility of Drug and ADA for Loss of Response If Drug is Present, Switch Mechanisms No benefit of substituting one mab for another if adequate concentrations Afif, Am J Gastoenterol 2010

38 Preventing Loss of Response

39 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 1 st or 2 nd maintenance infusion (TLcut-off 3 μg/ml) Sustained Response (SR) to IFX in 47 (56%) patients after FU of 25 mo IFX TL Univariate Analysis TLs >3 μg/ml associated with a decreased probability of loss of SR (HR 0.31; 95%CI: ), Corticosteroids increased the risk of treatment failure No impact (HR 2.34, 95%CI: ). Thiopurines No impact No impact Multivariate Analysis Had impact on SR to IFX (HR 0.34; 95%CI: 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. Bortlik et al. ECCO 2012, abstract P360

40 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 Percentage of patients (%) group 2: dosing and optimization based on clinical symptoms Baseline trough levels 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. Dose escalation improved outcomes (HBS & CRP) After initial dose optimization, no benefit of TDM vs clinical and CRP monitoring Vande Casteele et al. UEGW 2013

41 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

42 Methods 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.

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

44 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.

45 CRP may be surrogate for adequate Drug Trough?

46 Therapeutic Drug Monitoring with Biologics Assessing loss of response Also cost effective vs. empiric changes Preventing loss of response Preventing complications Pharmacoeconomics??