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Optimizing the efficacy of immunomodulators and biologics in pediatric IBD

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

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Optimizing the efficacy of immunomodulators and biologics in pediatric IBD

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  1. 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

  2. Objectives • Causes of non response to therapies • Thiopurine drug monitoring • Anti-TNF drug monitoring • Impact of immunogenicity • The future of biologic use

  3. 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 inmetabolism and • disposition

  4. Target 6-TGN Level to Optimize Efficacy: >235 P< 0.001 78% Frequency of Response Odds Ratio 5.0 for treatment response when 6-TGN > 235 41% 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

  5. Meta-Analysis: 6-TGN levels and Clinical Remission Lewis J et al. Gastroenterology 2006:130;1047-1053

  6. 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

  7. 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

  8. Effect of Trough Serum Infliximab Concentrations on Clinical Outcome at >52 Weeks Trough serum infliximab Detectable Undetectable Patients with endoscopic improvement >75% (%) Patients in remission (%) 100 100 88 82 p<0.001 33 p<0.001 6 0 0 Patients with CRP <5 mg/dL (%) Patients with complete endoscopic remission (%) 100 100 76 p<0.001 47 32 p=0.03 19 0 0 Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54

  9. ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in Crohn’s Disease *Chi-square test Cornillie F, et al. Presented at the 19th Annual United European Gastroenterology Week (UEGW); October 25, 2011. Stockholm, Sweden. Abstract P0919.

  10. Detectable week 14 Infliximab Trough levels are associated with week 54 Efficacy Outcomes *Only 4 patients ATI14 positive Rosenthal C et al 2013

  11. Results: Optimal IFX14 Trough Level * Regression Tree analysis identified optimal cut point

  12. Serum Infliximab Trough Levels and Steroid-free Remission at Week 30 Sonic Study Steroid-free Clinical Remission at Week 26 by IFX Trough Level at Week 30 Median IFX Concentration 19/32 13/23 43/59 36/49 31/43 N=97 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.

  13. 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. Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114

  14. Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and Endoscopic Improvement in UC Patients P<0.001 % of patients Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<0.001) Seow CH et al. Gut 2010;59:49-54

  15. Rapid IFX clearance: Mechanism of Non Response in UC Kevans D, et al. Presented at DDW; May 19, 2012.

  16. Effect of Patient Factors on MAb Pharmacokinetics 0.40 • Patient factors identified with changes in IFX clearance • Weight • Albumin • ADA • Impact on IFX clearance is substantial and should be considered for dose selection 0.38 0.36 0.34 0.32 Clearance (L/day) 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 0.60 Clearance (L/day) 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 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. Albumin (g/dL)

  17. ADA Trough Above 0.33 µg/mL Predicts Clinical Response 1.0 Log Rank: P=0.01 ADA TR>0.33 µg/mL, n=104 ADA TR<0.33 µg/mL, n=16 0.8 Patients with Sustained Clinical Response (%) 0.6 0.4 0.2 0.0 0 30 60 90 120 150 180 210 240 Sustained Clinical Response (weeks) Karmiris K, et al. Gastroenterology. 2009;137:1628.

  18. PURSUIT – Golimumab for the Induction and Maintenance of UC Phase 2: Clinical Endpoints by Serum Golimumab ConcentrationQuartile 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.

  19. Factors Affecting Infliximab Clearance in CD Scheduled & Episodic Therapy ACCENT I (n=580) Con. IS, concomitant immunosuppressant Fasanmade AA, et al. Clin Ther. 2011;33(7):946.

  20. 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 Hyper- Chimeric Murine Chimeric 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-F2BC-A717D20C0E0E.html

  21. Immunogenicity of TNF Antagonists:Patients With Detectable Antibodies to a TNF Antagonist 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.

  22. Presence of ATI is Associated with a Higher Non-response Rate and Shorter Duration of Response Farrell RJ, et al. Gastroenterology 2003;124:917-24

  23. SONIC: Immunogenicity Results at Week 30* 98 100 94 80 68 60 Percent of Patients (%) 40 15 14 20 2/120 1/89 1/120 0/89 2 1 1 0 87/89 113/120 15/106 16/106 72/106 0 AZA + placebo IFX + placebo AZA + IFX Positive Negative 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.

  24. 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.

  25. 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 100 P=NS • “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” P<0.001 P<0.001 Serum IFX Level (µg/ml) 10 1 ATI <8 ATI >8 ATI ?? ATI, antibodies to infliximab; IFX, infliximab; PPV, positive predictive value Vermeire S et al. Gut. 2007;56(9);1226.

  26. 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.

  27. Results: IFX Liquid Phase ROC Analysis 1.0 • Goal: Find objective IFX cutoff using CRP • High CRP should predict low IFX & vice versa 0.8 0.6 TPR 0.8 0.6 AUC=0.735 0.0 0.0 0.2 0.4 0.6 0.8 1.0 FPR 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.

  28. IFX & ATI Counts IFX- IFX+ • 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

  29. 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 1,205 pairs of samples taken over sequential time points (trough infliximab/ATI in first sample, CRP in second sample) Predictors of higher CRP: ATI+, infliximab < 3mcg/mL *** 50.0 59 294 25.0 244 10.0 890 5.0 CRP mg/L 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.

  30. Elevating Infliximab Concentration from Sub-Therapeutic Levels is Effective in Regaining Response in HACA (-) Patients HACA, Human anti-chimeric antibodies Afif W, et al. Am J Gastroenterol. 2010;105(5):1133.

  31. Treatment Paradigms in Symptomatic Patients that Lose Response to IFX • ATI - ATI+ IFX < threshold Increase dose Switch (high ATI) or Dose optimize (low ATI) IFX ≥ threshold Check endoscopy Switch (high activity) or Switch or Monitor (low activity)

  32. 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. InfliximabEMEA 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.

  33. 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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