How to use infliximab?

Transcription

1 How to use infliximab? Séverine Vermeire, MD, PhD Division of Gastroenterology University Hospital Gasthuisberg Leuven

2 The how to use infliximab rules Before starting IFX: try optimizing chances for response! Once response: maintain the efficacy! Avoid immunogenicity! When to stop?

3 The how to use infliximab rules Before starting IFX: try optimizing chances for response! Once response: maintain the efficacy! Avoid immunogenicity! When to stop?

4 Optimizing induction of remission 3 Dose Induction vs. Single Dose? 3 dose induction Single dose % pats. Responding P= Weeks Infusions Hanauer S et al; Lancet 2002; 359:

5 Optimizing induction of remission: cotreatment? p< response (%) Luminal CD Fistulising CD imunosuppressives no immunosuppressives Parsi et al; Gastroenterol 2002; 123: Arnott et al; APT. 2003;17:1451-7

6 Optimizing induction of remission: cotreatment? Vermeire S et al, Am J Gastroenterol 2002; 97:

7 Optimizing induction of remission: smoking 100 p< response (%) Luminal CD Fistulising CD Smokers Non smokers Parsi et al; Gastroenterology 2002; 123: Arnott et al; APT. 2003;17:1451-7

8 Conclusion: Predictive factors for response to infliximab Clinical Genetic Other Confirmed Concom immunosuppression Increased CRP Colonic disease Non Smoking Short duration of disease Not confirmed young age LTA haplotype ASCA/pANCA early age at onset FcGR III a-158 Non stricturing FasL-843 TUCAN Cys10* No impact Severity of disease TNF previous therapies NOD2/CARD15 previous resections

9 The how to use infliximab rules Before starting IFX: try optimizing chances for response! Once response: maintain the efficacy! Avoid immunogenicity! When to stop?

10 70 60 Initial Treatment Phase Retreatment Phase Responders at 8 weeks (n=73) % Responding Infliximab (n=37) Placebo (n=36) Week Infusions Most patients will need retreatment! Rutgeerts P, et al. Gastroenterology. 1999; 117:76-69

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12 ACCENT II

13 which strategy is the best? 1. IFX episodic in monotherapy? 2. IFX episodic + IS? 3. IFX every 8 weeks in monotherapy? 4. IFX every eight weeks + IS? 5. IFX as bridge for IS? Main goal: maintain efficacy and avoid loss of response = optimize not immunize

14 Mouse antibody The problem of immunogenicity Humanized antibody Mouse sequences Chimeric antibody Human sequences

15 Mouse antibody The problem of immunogenicity Humanized antibody Chimeric antibody Infliximab (Remicade ) Mouse sequences Human sequences CDP571 (Humicade ) CDP870 (PEGylated) Adalimumab (Humira )

16 Antibodies to infliximab (ATI) (formerly HACA) % of Patients Antibody (+) 100% 80% 60% 40% 20% 0% N=125 61% Number of infusions Baert F-Noman M et al NEJM 2003; 348;

17 Duration of Response by ATI Days until subsequent Infusion P<0.001 Negative µg/ml µg/ml > 20 µg/ml [Antibodies to Infliximab] Baert F-Noman M et al NEJM 2003; 348;

18 ATI and Immunosuppressant Tx P<0.01 % of patients antibody (+) 100% 80% 60% 40% 20% 0% 43.0% n= 56 Taking Immunossuppressant 75.0% n= 69 Not taking Immunosuppressants Baert F-Noman M et al NEJM 2003; 348;

19 Infliximab and Immunosuppressant Tx Taking Immunosuppressants Not Taking Immunosuppressants Median serum concentration µg/ml Non-fistula Fistula Non-fistula Fistula Baert F-Noman M et al NEJM 2003; 348;

20 % of patients ATI and MTX or AZA? Does it matter? p = NS neg 73 pos inconcl No IS MTX AZA treatment group Noman M et al DDW 2004

21 ATI Formation and steroid pretreatment Farrell et al, Gastro 2003

22 which strategy is the best? 1. IFX episodic in monotherapy? NO 2. IFX episodic + IS? YES 3. IFX every 8 weeks in monotherapy? 4. IFX every eight weeks + IS? 5. IFX as bridge for IS?

23 which strategy is the best? 1. IFX episodic in monotherapy? NO 2. IFX episodic + IS? YES 3. IFX every 8 weeks in monotherapy? YES 4. IFX every eight weeks + IS? YES 5. IFX as bridge for IS? YES

24 Clinical Response Through Week 54 All Patients Including Episodic Retreatment 80 Proportion of Patients (%) Weeks from the Initial Infusion Single dose (n = 188) 5 mg/kg q 8 wks (n = 192) 10 mg/kg q 8 wks (n = 193) Hanauer S et al; Lancet 2002; 359:

25 Antibodies to Infliximab % of patients Overall No IS IS 0 Episodic Treatment 5 mg/kg q 8wks 10 mg/kg q 8wks Hanauer S et al. Clin Gastroenterol Hepatol. 2004;2: ACCENT I

26 ACCENT I Infliximab: Endoscopic Healing Single dose Patients Demonstrating Endoscopic Healing (%) P=0.007 P= % 46% P= % 7% 0/17 10/32 1/14 5/11 8/15 Week 10 Week 54 Combined dose group (5 mg/kg & 10 mg/kg infliximab maintenance) 5 mg/kg infliximab maintenance 10 mg/kg infliximab maintenance Rutgeerts P et al. Gastroenterology. 2002;122(suppl):A-618

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29 Fistulizing CD: time to loss of response at week 54 Patients without loss of response (%) Week 14 responders P<0.001 Induction Maintenance Weeks Episodic (n=99) Infliximab maintenance 5 mg/kg (n=96) Sands B et al; NEJM 2004;350:

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31 Loss of response over time Step up to 10 mg/kg Shorten interval to less than 8 weeks Consider more humanized antibodies

32 IFX as a bridge for immunosuppressives Infliximab (Week 0, 2, 6) + AZA/MP Steroid dependence > 6 months Stratum 1 ( AZA failure ) AZA 2-3 mg/kg/d (or MP)> 6 mo continued Stratum 2 ( AZA naive ) AZA 2-2,5 mg/kg/d Steroid tapering standardized scheme increase of dose in case of relapse withdrawal if resistance to pred>40 mg/d for 2 wks Placebo (Week 0, 2, 6) + AZA/MP Week 24 End-point Week 52 Follow-up Lemann et al Gut Suppl 2003; 52: A44

33 Remission (CDAI<150) & off steroids 100% 80% 60% 40% 20% 0% P=0.009 P=0.03 P=0.02 P= % 64% 63% 50% 41% 34% 32% 26% Naive Failure Naive Failure Week 12 Week 24 AZA failure (n=56) AZA naive (n=59) Placebo week 0, 2, 6 + AZA/MP Infliximab 5 mg/kg week 0, 2, 6 + AZA/MP Lemann et al Gut 2003; 52: A44

34 Conclusion: optimizing IFX: induction of remission Consider 3-induction regimen (certainly for fistulizing CD) Give/optimize concomitant immunosuppressive therapy Advise patients to stop smoking

35 Conclusion: optimizing IFX: maintenance Eight-weekly IFX preferred over episodic strategy (less immunogenicity, better mucosal healing) Concomitant immunosuppression when episodic strategy is used Eight-weekly IFX for fistulizing CD (long term) Consider pretreatment with hydrocortisone How long to continue immunosuppressives when IFX is given eight-weekly? Consider step up dose to 10 mg/kg if loss of response over time More humanized antibodies for future

36 How long should we continue IFX? No controlled data beyond one year Experience from large centers up to 10 years Try to stop when treatment goal is reached: discontinuation of GCS with maintained remission complete external healing of fistulas continue with immunosuppressives Restart IFX when relapse Placebo-controlled IFX discontinuation study needed