How to Optimize Induction and Maintenance Responses: Definitions and Dosing Advances in Inflammatory Bowel Disease December 6, 2009

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1 How to Optimize Induction and Maintenance Responses: Definitions and Dosing 2009 Advances in Inflammatory Bowel Disease December 6, 2009 Fernando Velayos MD MPH University of California, San Francisco To Optimize Pronunciation: \äp-tə-mīz\ Function: transitive verb Definition: to make as perfect, effective, or functional as possible Goal of today s talk How to make as perfect, effective, or functional each medication class of IBD therapy Review data on what make and does not make a difference in response and remission in each medication class 1

2 5-ASA IMM Biol Formulation Optimizing Induction and Maintenance Responses Dose/Dosing Monitoring drug levels Use of Adjuncts? Formulation and Outcomes: 5-ASA Rectal Preparations Azo-bonded Pro-drug Moisture Dependent Delayed Release Delayed + Extended Release Rowasa (mesalamine) Azulfidine (sulfasalazine) Pentasa (mesalamine) Asacol (mesalamine) APRISO (mesalamine) Canasa (mesalamine) Dipentum (olsalazine) Lialda (mesalamine) Colazal (balsalazide capsules) The systemic exposure to 5ASA, as measured by urinary excretion of total 5ASA, and the faecal excretion of total 5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus, selection of a mesalazine therapy for the treatment of ulcerative colitis should be based on other factors such as efficacy, dose response, toxicity of the parent compound and its metabolites, compliance issues related to dose forms and dosing schedules, and costs Sandborn WJ and Hanauer SB. Aliment Pharmacol Ther 2003; 17:29 2

Formulation and Outcomes: IMM AZA/6MP vs. MTX (maintenance of remission) 2 studies (Oren 1997, Mate-Jimenez 2000, n=50) MTX: 17/22 (78%); 6MP : 16/28 (57%) OR 2.6 (95%CI: 0.8-9.4) AZA vs.

3 Formulation and Outcomes: IMM AZA/6MP vs. MTX (maintenance of remission) 2 studies (Oren 1997, Mate-Jimenez 2000, n=50) MTX: 17/22 (78%); 6MP : 16/28 (57%) OR 2.6 (95%CI: ) AZA vs. 6MP (maintenance remission) No head to head studies Higher remission in AZA vs. 6MP studies studies (71% vs. 51%)-but low doses 6MP used (50 mg/day) Prefontaine E et. al. Cochrane Database 2009; online Patel V. et. al. Cochrane Database 2009; online Therapeutic Antibodies Used in IBD Chimeric monoclonal antibody Human monoclonal antibody Humanized fab fragment Humanized monoclonal antibody PEG PEG Infliximab anti-tnf Adalimumab anti-tnf Certolizumab pegol anti-tnf Natalizumab anti-a4 integrin Adapted from Accessed 0708/09. 3

4 Formulation and Outcomes: Biologics P<0.001 P=0.001 P<0.001 P=0.007 INFLIXIMAB ACCENT 1 ADALIMUMAB CHARM 2 *CERTOLIZUMAB PRECISE 2 3 Wk26 NATALIZUMAB ENACT-2 4 Maintenance of Remission at 1 year Note: From separate and independent studies 1. Remicade Prescribing Information Colombel et al. DDW Schreiber et al NEJM 2007; 357: Sandborn et al. NEJM 2005; 353: ASA IMM Biol Formulation No No No Optimizing Induction and Maintenance Responses Dose/Dosing Monitoring drug levels Use of Adjuncts? 4

5 Dose and Outcomes: 5-ASA Patients Responding to 5-ASA Therapy Without Intolerance, % Treatment Dose Hanauer SB. Lancet. 1993;342: Schroeder KW, et al. N Engl J Med. 1987;317: Sninsky CA, et al. Ann Intern Med. 1991;115: Dose and Outcomes: 5-ASA Induction studies (6-8 weeks) Mild/Moderate Moderate ASCEND I (success) (57 vs. 72.4%)* ASCEND II (success) (59.2 vs. 71.8%)* ASCEND I (success) (51.3 vs. 55.9%) ASCEND III (success) (65.5 vs. 70.2%) SPD (clin/endo R) (40.5 vs. 41.2%) SPD (clin/endo R) (34.1 vs. 29.2%) 2.4 gm 4.8 gm 2.4 gm 4.8 gm Hanauer SB et. al. Can J Gastroenterol 2007; 21:827 Hanauer SB et. al. Am J Gastoenterol 2005; 100:2478 Sandborn WJ. Et. al. Gastroenterol 2009; [epub] Kamm M et. al. Gastroenterol 2007; 132:66 Lichtenstein G. et. al. Clin Gastroenterol 2007; 5:95 5

6 History of More-Difficult-to-Treat Disease Predicts Response to Higher Dose for Moderate UC ASCEND I and II 1 ASCEND III 2 Previous Therapy 2 Medications 71* 51 Steroids Rectal therapies Oral 5-ASAs * 72* 72* * Patients With Treatment Success at Week 6 (%) 2.4 g/day delayed-release mesalamine 4.8 g/day delayed-release mesalamine *P<0.05; mesalamine Hanauer SB et al. Gastroenterology. 2008;134 (Suppl 1):A490. Abstract T Sandborn WJ et al. Gastroenterology 2008;134 (Suppl 1):A99. Abstract 702. Dosing and Outcomes: 5-ASA Maintenance Studies 58.9% 70.9% (p=0.02) 93.2% 88.9% 91.8 % 90.5% bid qd bid qd bid qd Dignass mo RCT 2gm/d Clinical remission Kamm mo rand open label 2.4 gm/d Clinical remission Sandborn mo rand open label gm/d Clinical remission 6

7 Dose and Outcomes: IMM Azathioprine Dose (pooled maintenance CD studies) 2.5 mg/kg/d 2.0 mg/kg/d 1.0 mg/kg/d 6MP Dose 1 trial (50 mg/d): OR 3.3 ( ) 1 study: 6MP >=1.5 mg/kg higher 6TGN than <1.0 Weak correlation of 6TGN and weight-based dosing Standard dosing resulted low 6TGN most patients MTX Dose (pooled maintenance CD studies) 2 studies vs. PBO 15 mg/wk IM: OR 3.1 ( ) OR: 4.1 (95%CI: ) OR: 3.0 (95%CI: ) OR: 1.2 (95%CI: ) Prefontaine E et. al. Cochrane Database 2009; online Morales A. et. al. Inflamm Bowel Dis 2007; 13: 380 Patel V. et. al. Cochrane Database 2009; online Dose/Dosing and Outcomes: Biologics Agent Route Induction Infliximab IV 5 mg/kg at weeks 0, 2, and 6 Adalimumab SC 160 mg week 0, 80 mg week 2, 40 mg week 4 Certolizumab SC 400 mg at weeks 0, 2, and 4 Dosing Regimen Maintenance 5 mg/kg every 8 weeks (10 mg/kg in patients who lose response) 40 mg every 2 weeks 400 mg every 4 weeks Natalizumab IV mg every 4 weeks Adapted from Accessed 0708/09. 7

8 5-ASA IMM Biol Formulation Optimizing Induction and Maintenance Responses Dose/Dosing Monitoring drug levels Selective 4.8gm/d; Yes-daily for maint Yes AZA mg/kg/d Std Use of Adjuncts? Relationship between metabolite levels of 6MP and AZA with clinical efficacy and toxicities AZA 6MP 6TGN TPMT 6MMPR Hepatotoxicity (>=5700) Osterman et. al. Gastro 2006; 130: Bone Marrow Toxicity (>=450) 6-TG (pmole/8 X10-8 RBC) 235 Clinical Efficacy (>= ) Increasing Risk of Bone Marrow Toxicity 6-TG Therapeutic Range Insufficient Dosage or Lack Adherence Increasing Risk of Hepatotoxicity 5,700 6-MMP (pmole/8x10-8 RBC) 8

9 Monitoring and Outcomes: IMM RCT standard dosing (weight-based dosing) vs. individualized dosing (weight-based+6tgn based dosing starting at week 5) 25 per group enrolled, AZA 2.5 mg/kg/day Stopped at 2.5 years (early due to slow enrollment) Week 16 clinical remission: 16% SD vs. 40% ID Low power, not statistically significant Dassopoulos T et. al. DDW 2009;T ASA IMM Biol Formulation Optimizing Induction and Maintenance Responses Dose/Dosing Monitoring drug levels NA Maybe ND Use of Adjuncts? 9

10 Adjuncts and Outcomes: 5-ASA Induction studies (RCT 6-8 wks) Maintenance studies (RCT 12 mo) % Remission o e c o c o c p c p c Safdi 1997* Distal dz p: 2.4g e: 4 g c: Vecchi 2001 Dist/Prox p: 4g c: 2g+2g Marteau 2005 Prox only p: 4g c: 4g+1g D Albasio 1997 Dist/Prox p: 1.6g c: 1.6+4g Hiroshi 1997 Dist/Prox p: 3g c: 3g+1g wkend *Outcome rectal bleeding Adjuncts and Outcomes: 5-ASA Induction studies (RCT 6-8 wks) Maintenance studies (RCT 12 mo) % Remission p e c p c p c o c o c Safdi 1997* Distal dz p: 2.4g e: 4 g c: Vecchi 2001 Dist/Prox p: 4g c: 2g+2g Marteau 2005 Prox only p: 4g c: 4g+1g D Albasio 1997 Dist/Prox p: 1.6g c: 1.6+4g Hiroshi 1997 Dist/Prox p: 3g c: 3g+1g wkend *Outcome rectal bleeding 10

11 Adjuncts and Outcomes: IMM Allopurinol in AZA nonresponders with 6TGN < 230 and 6MMP> 5000 All received allopurinol 100 mg, AZA/6MP reduced 25-50% 6TGN increased from to (p<0.001) 6MMP reduced from 10, 604 to (p<0.01) Disease activity reduced (HBI 4.9 to 1.3 (p=0.01) and Mayo 4.9 to 2.1 (p=.13)) Prednisone dose reduced (17.6 mg/d to 1.9 mg/d (p<0.01) 6-TG (pmole/8 X10-8 RBC) Increasing Risk of Bone Marrow Toxicity 6-TG Therapeutic Range Insufficient Dosage or Lack Adherence Increasing Risk of Hepatotoxicity 5,700 6-MMP (pmole/8x10-8 RBC) Sparrow M et. al. Clin Gastroenterol 2007; 5:209 Adjuncts and Outcomes: IMM SONIC ENTRY CRITERIA Corticosteroid-dependent Considered for second (or more) course of steroids (prednisone or equivalent) in past year 5-ASA failures Inadequate response to mesalamine 2.4 g/day or more (or equivalent) for at least 4 weeks Budesonide failures Inadequate response to budesonide 6 mg/day or more for at least 4 weeks Patients (%) Corticosteroid Free Clinical Remission at Wk 50 24% 41/ 170 All Randomized Patients (n=508)* p= % 59/ 169 p= % 78/ 169 Sandborn WJ et al. Gastroenterology 2009;136(Suppl 1):A-116. AZA + Placebo IFX + Placebo IFX + AZA * Patients who did not enter the Study Extension were treated as non-responders 11

12 Adjuncts and Outcomes: Biologics Patients With Detectable Antibodies to a TNF Antagonist Infliximab 1 (CD 5 mg/kg) (CD 10 mg/kg) Infliximab 2 (UC 5 mg/kg) (UC 10 mg/kg) Patients, % Episodic Maintenance Scheduled Maintenance IMS- IMS+ IMS- IMS+ 38% 16% No data 11% 8% 19% Certolizumab 3 (PRECiSE I) 10% 4% 24% 8% Certolizumab 4 (PRECiSE II) 12% 2% Adalimumab 5 (RA, all doses) 12% 1% No data Adalimumab 6 (CLASSIC II) 4% 0% IMS = immunosuppressant. 1. Hanauer et al. Clin Gastroenterol Hepatol. 2004;2(7): ; 2. Data on file, Centocor (Sandborn et al. DDW 2007 Poster and abstract T1273); 3. Sandborn WJ, et al. N Engl J Med. 2007;357: ; 4. Schreiber S, et al. N Engl J Med. 2007;357: ; 5. Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6. Sandborn WJ, et al. Gut. 2007;56: % 7% 4% 2% 4% Adjuncts and Outcomes: Biologics IMM + IMM - % Patients ACT II Wk 54 Remission ACCENT I Wk 54 Remission CHARM Wk 56 Remission Sandborn WJ et al. NEJM 2005;353:2462 Hanauer SB. Et. al. Lancet 2002; 359:1541 Colombel JF et. al. Gastroenterol 2007; 132:52 12

13 Adjuncts and Outcomes: Biologics Post-hoc analyses of RCT-no difference Prospective RCT COMMIT: Active CD on steroids-ifx+mtx vs. IFX alone Wk vs. 57.1% remission IMID: In Remission on IFX+AZA/6MP/MTX >6 mo 2 year: 28% vs. 23% discontinued (combo vs. mono) 55% vs. 60% change in dosing ATI 5% vs. 12.5% Higher median IFX levels in combo group (p<0.05) Feagan B et. al. DDW 2008;682C Van Assche G, et al. Gastroenterology 2008;134: ASA IMM Biol Formulation Optimizing Induction and Maintenance Responses Dose/Dosing Monitoring drug levels Use of Adjuncts? Yes (enema) Yes (With caution allopurinol, Yes Biologics No (Yes drug levels, Ab) 13

Earlier Use of Biologics and Outcomes % in CDAI Response or Remission 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 90% n=19 37% n=35 68% n=19 37% n=35 75% n=20 50% n=22 55% 36% 62% 36% 47% 29% 57% 33%

14 Earlier Use of Biologics and Outcomes % in CDAI Response or Remission 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 90% n=19 37% n=35 68% n=19 37% n=35 75% n=20 50% n=22 55% 36% 62% 36% 47% 29% 57% 33% 44% <1 Year 1-<2 years 2-<5 years >=5 years Response Remission PRECiSE 2 (certolizumab pegol) Sandborn WJ, et al. Am J Gastroenterol. 2006;101:S [Abstract 1109]. Schreiber S, et al. N Engl J Med. 2007;357(3): n=20 n=22 n=45 n=55 n=45 n=55 n=131 Placebo Response Placebo Remission n=98 n=131 24% n=98 Earlier Use of Biologics/Combination Therapy and Outcomes Corticosteroid Free Clinical Remission at Wk 50 Patients (%) All Randomized Patients (n=508)* p=0.028 p= / 170 AZA + Placebo Sandborn WJ et al. Gastroenterology 2009;136(Suppl 1):A / 169 IFX + Placebo 78/ 169 IFX + AZA * Patients who did not enter the Study Extension were treated as non-responders 14

15 Earlier Use of Biologics/Combination Therapy and Outcomes Proportion of patients in remission (CDAI <150, absence of bowel resection, complete corticosteroid withdrawal) Early Combined Immunosuppressio % of Patients Conventional Management P P=0.006 P=0.028 P=0.797 P= Wk 14 Wk 26 Wk 52 Wk 78 Wk 104 N=133 D Haens G et al. Lancet. 2008;371: % of Patients Earlier Use of Biologics/Combination Therapy and Outcomes a 30.4 Complete Healing Mucosal Healing 88 b 47 Ulcer Reduction Points Early Combined Immunosuppression (n=24) Conventional Management (n=20) ReductioninEndoscopic Score Endoscopic healing was scored in 5 ileal and colonic segments as follows: 0=no ulcers, 1= aphthoid ulcers, 2=larger ulcers, 3= ulcerated stenosis. a P=.0028; b P<.001 D Haens G et al. Lancet. 2008;371: b 15

16 Whether earlier use of biologics/ combination therapy will change long-term natural history and risk/benefit is unknown Natural course of disease Disability Treatment at diagnosis Later treatment Later intervention Intervention at diagnosis Disease onset Time Adapted from Panaccione et al. Current Opinion Gastroenterology ASA IMM Biol Choice of Formulation Optimizing Induction and Maintenance Responses Choice of Dose/Dosing Monitoring drug levels Use of Adjuncts Early Biol/Combo Therapy NA Yes-short term, No-at 2 years, but.. (Yes-mucosal healing) 16

17 Summary Data shown regarding what optimizes (make as perfect, effective, or functional) and does not optimize induction and maintenance for each medication class Mesalamine Dose: Consider 4.8 gm in patients on lower dose of 5-ASA (dose escalate), more difficult to treat disease Dosing: Daily dosing for maintenance Adjuncts: mesalamine enema regardless of extent Thiopurines Dose: AZA mg/kg/day; 6MP 1.5 mg/kg/d if normal TPMT Adjuncts: Allopurinol 100 mg if low 6TGN/high 6MMP, reduce 6MP 25-50% and monitor closely. Biologic when starting thiopurine Monitoring: selective use metabolite testing and dose escalation Biologics Adjuncts: Co-treatment steroids with IFX, avoiding breaks in therapy, cotreating with immunomodulators (reduce immunogenicity and increase drug levels) Earlier use in disease course along with IMM (mucosal healing) 17

18 Change Target Outcome to Natural History? Cumulative Probability (%) Inflammatory Penetrating Stricturing Months Cosnes J, et al. Inflamm Bowel Dis. 2002;8:

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