Mono Combination Therapy with Biologics i in IBD: Developing an Individualized Approach David T. Rubin, MD, FACG Co-Direct, Inflammaty Bowel Disease Center Fellowship Program Direct University of Chicago drubin@uchicago.edu Nomenclature f IBD Management THEN Step Up Top Down Aggressive therapy Last ditch Hail Mary Save f last Avoid at all cost NOW Individualized care Deep remission: (clinical remission + mucosal healing) Optimization of therapy: therapeutic moniting and metabolic assessment Accelerated step care 1
Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Patient #2: 18 yo male Crohn s colitis and perianal Newly diagnosed, presents with diarrhea, skin tags Patient #3: 31 yo female Crohn s ileitis and jejunum Failed step care with 5-ASA, steroids, thiopurine Responded to addition of anti-tnf to thiopurine f the last 6 months Patient #4: 50 yo male UC failing 5-ASA, steroids What prevents us from using biologics earlier and maximizing combination therapy? Perception that biologics should be saved f last Perception that biologic therapies are riskier than other therapies Fear of complications of combination therapy Cost of biologics i Physician uncertainty about how to use combination therapy: the step up mindset 2
Mono vs. Combo Therapy of TNFinhibits in IBD: What are the issues? Artificial construct Monotherapy Combination Therapy Less expensive in sht term Patients preference? Easier f healthcare team Previous clinical trial data suppts this approach As effective as combo after failing IMM Me effective in prospective randomized trials Reduces rates of antibody fmation Results in higher blood concentrations of the biologic Similar side effect profile to monotherapy The Rationale Behind Combination Therapy in IBD There is much room f improvement in current treatment strategies (>50% failure rate in sht and long term) Multiple drugs = multiple therapeutic targets Biologic therapy + IMM reduces immunogenicity, preserves response over time Stable disease control results in disease modification 3
What s the Evidence f Combination Therapy? Know the Study Designs! Patients failing IMMs befe biologic therapy may not benefit from combination approach Patients who failed IMMs befe biologic therapy and are stable on combination therapy may be withdrawn from the IMMs, without loss of response to the biologic f at least two years Patients who are IMMs-naïve have efficacy benefit of combination therapy (particularly with endoscopic evidence of disease and elevated CRP) Do Concomitant Immune-modulats modulats Improve Efficacy of Infliximab in CD and UC? tients % pat tients % pat 60 40 20 60 40 20 0 0 45 50 45 ACT I 54 wk Response 41 34 36 37 IMM + IMM - 32 7.2 55 53 43 36 48 27 Ulcerative colitis 5.1 3.9 5.8 ACT I 54 wk ACT I ACT II 30 wk ACT II 30 wk Patients Remission failing 54 wk IMMs Hosp befe Response biologic Remission therapy may not benefit from All p-values = NS combination approach ACCENT I 54 wk Response ACCENT I 54 wk Remission ACT II 30 wk Hosp Crohn s disease 1.9 5.3 3.3 4.6 ACCENT I 54 wk Hosp ACCENT II 54 wk Response ACCENT II 54 wk Response Lichtenstein GR, Aliment Pharmacol Ther. 2009 Aug;30(3):210-26. Epub 2009 Apr 21. 4
The Patient not Responding to Thiopurine: Consider Metabolites 6-TGn 6-MMP Possible cause Recommendation undetectable undetectable Non-adherent Understand why pt not taking med underdosed increase dose Adapted from: Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11. The Patient not Responding to Thiopurine: Consider Metabolites 6-TGn 6-MMP Possible cause Recommendation undetectable undetectable Non-adherent Understand why pt not taking med underdosed increase dose Low (<230) Low Non-adherent Discuss adherence, undetectable underdosed increase dose Adapted from: Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11. 5
The Patient not Responding to Thiopurine: Consider Metabolites 6-TGn 6-MMP Possible cause Recommendation undetectable undetectable Non-adherent Understand why pt not taking med underdosed increase dose Low (<230) Low Non-adherent Discuss adherence, undetectable underdosed increase dose Low (<230) High (>5700) 6-MMP shunter 1. Increase thiopurine, 2. Consider allopurinol, 3. Switch agents Adapted from: Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11. The Patient not Responding to Thiopurine: Consider Metabolites 6-TGn 6-MMP Possible cause Recommendation undetectable undetectable Non-adherent Understand why pt not taking med underdosed increase dose Low (<230) Low Non-adherent Discuss adherence, undetectable underdosed increase dose Low (<230) High (>5700) 6-MMP shunter 1. Increase thiopurine, 2. Consider allopurinol, 3. Switch agents Therapeutic (>230-<400) High (>400) Nmal range high Primary nonresponder 1. Assess disease 2. Switch to different mechanism Adapted from: Dubinsky. Curr Gastroenterol Rep. 2003;5(6):506-11. 6
Withdrawal of Concomitant IMM in Crohn s disease while on Infliximab (failure of IMM befe IFX) No need f early rescue IFX: primary endpoint Median IFX levels, Week 8 to Week 104 combined Cum mulative survival 1.0 0.8 0.6 0.4 0.2 0.0 Log Rank (Cox): 0735; Breslow: 0.906 CONTINUED rough levels (μg) 100 10 p<0.005 Patients who failed IMMs befe biologic therapy and are stable on combination therapy may be withdrawn from the IMMs, without loss of response to the 0 20 40 60 80 100 Time (weeks) biologic f at least two years (caveat- know your patient) DISCONTINUED IFX tr 1 0 Continued Discontinued Van Asche G, et al. Gastroenterology. 2008 Jun;134(7):1861-8. Epub 2008 Mar 8.. Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Cticosteroid-Free Clinical Remission at Wk 26 Primary Endpoint ) Propo tion of Patients (%) 100 80 60 40 20 0 p<0.001001 p=0.009 p=0.022 56.8 44.4 30.6 52/170 75/169 96/169 Naïve to IMM and anti-tnf TPMT nmal Median dz duration 2.4y AZA + placebo IFX + placebo IFX+ AZA Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. 7
Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Mucosal Healing at Week 26 100 (%) Pro option of Patients 80 60 40 20 0 p<0.001 p=0.023 p=0.055 43.9 30.1 16.5 18/109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Cticosteroid-Free Clinical Remission at Wk 50 All randomized patients (N=508)* 100 Pro option of Patients (%) 80 60 40 20 0 p<0.001 p=0.028 p=0.035 46.2 34.9 24.1 41/170 59/169 78/169 AZA + placebo IFX + placebo IFX+ AZA * Patients who did not enter the Study Extension were treated as non-responders Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. 8
COMMIT: MTX plus IFX in new onset CD patients 100 Patients in remission off steroids (%) p=0.83 77.8 76.2 p=0.63 57.1 55.6 IFX alone IFX + MTX +steroids 0 Week 14 Week 50 No difference in ITT analsyis, duration of disease <2 years, by CDAI sce No difference in infectious AEs (58.7% MTX vs 61.9% PBO) Feagan et al. Gastroenterology. 2008; 135:294 8 What about Ulcerative Colitis? 9
Infliximab, Azathioprine, Infliximab + Azathioprine f Moderate to Severe Ulcerative Colitis (UC SUCCESS) 100 Primary Endpoint: Steroid-Free Remission at Week 16 Percent of Patients (% %) 80 60 40 20 24% P=.813 P=.032 22% P=.017 40% 0 N=18 N=17 N=31 AZA (N=76) IFX (N=77) IFX+AZA (N=78) Panaccione R, DDW 2011. Abstract. Infliximab, Azathioprine, Infliximab + Azathioprine f Moderate to Severe Ulcerative Colitis (UC SUCCESS) Secondary Endpoint: Mucosal Healing at Week 16 Perc cent of Patients (%) 100 80 60 40 20 0 P=.295 P=.001 P=.028 63% 55% 37% N=28 N=42 N=49 AZA (N=76) IFX (N=77) IFX+AZA (N=78) Panaccione R, DDW 2011. Abstract. 10
Immunogenicity of Combination Therapy Immunogenicity of TNF Antagonists with and without Concomitant Immune Modulats (IMS) Patients, % Episodic Maintenance Scheduled Maintenance IMS- IMS+ IMS- IMS+ Infliximab 1 (CD 5 mg/kg) (CD 10 mg/kg) 38% 16% 11% 8% 7% 4% Infliximab 2 (UC 5 mg/kg) 19% 2% (UC 10 mg/kg) No data 9% 4% Certolizumab 3 (PRECiSE I) 10% 4% Certolizumab 4 (PRECiSE II) 24% 8% 12% 2% Adalimumab 5 (RA, all doses) 12% 1% No data Adalimumab 6 (CLASSIC II) 4% 0% 1 Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2 Sandbn et al. DDW 2007 Poster and abstract T1273; 3 Sandbn WJ, et al. N Engl J Med. 2007; 4 Schreiber S, et al. N Engl J Med. 2007; 5 Summary of Product Characteristics f adalimumab. Abbott Labaties. July 2007; 6 Sandbn WJ, et al. Gut. 2007. 11
Immunogenicity of TNF Antagonists with and without Concomitant Immune Modulats (IMS) Patients, % Episodic Maintenance Scheduled Maintenance IMS- IMS+ IMS- IMS+ Infliximab 1 (CD 5 mg/kg) (CD 10 mg/kg) 38% 16% 11% 8% 7% 4% Infliximab 2 (UC 5 mg/kg) 19% 2% (UC 10 mg/kg) No data 9% 4% Certolizumab 3 (PRECiSE I) 10% 4% Certolizumab 4 (PRECiSE II) 24% 8% 12% 2% Adalimumab 5 (RA, all doses) 12% 1% No data Adalimumab 6 (CLASSIC II) 4% 0% 1 Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2 Sandbn et al. DDW 2007 Poster and abstract T1273; 3 Sandbn WJ, et al. N Engl J Med. 2007; 4 Schreiber S, et al. N Engl J Med. 2007; 5 Summary of Product Characteristics f adalimumab. Abbott Labaties. July 2007; 6 Sandbn WJ, et al. Gut. 2007. Safety of Combination Therapy in IBD Risks of therapy compared to risks of ineffectively treated disease 12
Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Adverse Events AZA + placebo IFX + placebo IFX + AZA (N=161) (N=163) (N=179) Pts with 1 AE, N (%) 144 (89.4%) 145 (89.0%) 161 (89.9%) Pts with 1 SAE, N (%) 43 (26.7%) 39 (23.9%) 27 (15.1%) Serious infections 9 (5.6%) 8 (4.9%) 7 (3.9%) >1 Infusion reactions 8 (5.0%) 22 (13.5%) 9 (5.0%) TB - 1 patient treated with infliximab and azathioprine Colon cancer - 2 patients treated with azathioprine monotherapy Death - Post colectomy, in a patient treated with azathioprine monotherapy Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Adverse Events AZA + placebo IFX + placebo IFX + AZA (N=161) (N=163) (N=179) Pts with 1 AE, N (%) 144 (89.4%) 145 (89.0%) 161 (89.9%) Pts with 1 SAE, N (%) 43 (26.7%) 39 (23.9%) 27 (15.1%) Serious infections 9 (5.6%) 8 (4.9%) 7 (3.9%) >1 Infusion reactions 8 (5.0%) 22 (13.5%) 9 (5.0%) TB - 1 patient treated with infliximab and azathioprine Colon cancer - 2 patients treated with azathioprine monotherapy Death - Post colectomy, in a patient treated with azathioprine monotherapy Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. 13
Azathioprine, Infliximab Combination Therapy f Crohn s Disease (SONIC) Immunogenicity Results at Week 30* Percent of Patie ents (%) 100 80 60 40 20 0 1/89 1 98 14 15 68 0/89 1/120 2/120 87/89 0 1 2 15/106 16/106 72/106 113/120 AZA +placebo IFX + placebo AZA + IFX 94 Positive Negative Inconclusive * Patients who had 1 me PK samples obtained after their first study agent administration were included in the analysis. PK data at Wk 30 was not available f 1 patient treated with AZA + placebo, 3 patients treated with IFX + placebo, and 4 patients treated with AZA + IFX. Colombel, Sandbn, et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.. Effect of trough serum infliximab concentrations on clinical outcome at >52 weeks Trough serum infliximab Detectable Undetectable Patients in remission (%) Patients with endoscopic improvement >75% (%) 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 76 100 p<0.001 32 47 p=0.03 19 0 0 Maser et al. Clin Gastroenterol Hepatol. 2006; 4:1248-54 14
Infliximab (IFX) levels in patients taking concomitant immunosuppressives Increased IFX blood levels in IMM takers IFX levels (median + IQR) Max IFX No immunosupressives 2.42 μg/ml (1 10.8) 21 μg/ml Immunosupressives 6.45 μg/ml (3 11.6) 33.4 μg/ml AZA MTX IFX levels 6.15 μg/ml 5.65 μg/ml (median + IQR) (3 11.6) (2.87 10.8) Max IFX 33.4 μg/ml 31 μg/ml p=0.065 Vermeire et al. Gut. 2007; 56:1226-31 The Lymphoma Discussion NHL risk with thiopurines +/- anti-tnf Hepatosplenic T-cell lymphoma drives many decisions. Should it? Many unanswered questions Duration Dose Attenuated t risk with dose reduction withdrawal? 15
Proposed Approach to Mono Combo Therapy in IBD Failing Thiopurine Reassess disease reassess adherence optimize therapy (metabolites?) Add anti-tnf therapy If Response 6 months Withdraw Thiopurine? Dose reduction Unproven Proposed Approach to Mono Combo Therapy in IBD IMM/anti-TNF naive What is prognosis? High Risk Low Risk Combo IMM/TNF Step Care Male? MTX instead If deep remission If not deep remission If achieve deep remission 12 months Possible withdraw Therapy (which one?) Dose reduction Unproven 16
Proposed Approach to Mono Combo Therapy in IBD Anti-TNF Monotherapy Stay the course adherence to maintenance schedule Losing Response? Reassess Disease Assess drug level/antibodies l/ Add IMM? Change drug/mechanism Unproven Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Patient #2: 18 yo male Crohn s colitis and perianal Newly diagnosed, presents with diarrhea, skin tags Patient #3: 31 yo female Crohn s ileitis and jejunum Failed step care with 5-ASA, steroids, thiopurine Responded to addition of anti-tnf to thiopurine f the last 6 months Patient #4: Same as #3 but male Patient #5: 50 yo male UC failing 5-ASA, steroids 17
Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Proposed Approach to Mono Combo Therapy in IBD Failing Thiopurine Reassess disease reassess adherence optimize therapy (metabolites?) Add anti-tnf therapy If Response 6 months Withdraw Thiopurine? Dose reduction Unproven 18
Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Patient #2: 18 yo male Crohn s colitis and perianal Newly diagnosed, presents with diarrhea, skin tags Proposed Approach to Mono Combo Therapy in IBD IMM/anti-TNF naive What is prognosis? High Risk Combo IMM/TNF Male? MTX instead If achieve deep remission Possible withdraw Therapy (which one?) 12 months Dose reduction Unproven 19
Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Patient #2: 18 yo male Crohn s colitis and perianal Newly diagnosed, presents with diarrhea, skin tags Patient #3: 31 yo female Crohn s ileitis and jejunum Failed step care with 5-ASA, steroids, thiopurine Responded to addition of anti-tnf to thiopurine f the last 6 months Proposed Approach to Mono Combo Therapy in IBD Failing Thiopurine Reassess disease reassess adherence optimize therapy (metabolites?) Add anti-tnf therapy If Response 6 months Withdraw Thiopurine? Dose reduction Unproven 20
Patients in Your Practice Patient #1: 26 yo female Crohn s ileocolitis * 3 years Steroids Thiopurine * 2 years Active symptoms me than 25% of the year Patient #2: 18 yo male Crohn s colitis and perianal Newly diagnosed, presents with diarrhea, skin tags Patient #3: 31 yo female Crohn s ileitis and jejunum Failed step care with 5-ASA, steroids, thiopurine Responded to addition of anti-tnf to thiopurine f the last 6 months Patient #4: 50 yo male UC failing 5-ASA, steroids Proposed Approach to Mono Combo Therapy in IBD IMM/anti-TNF naive What is prognosis? High Risk Low Risk Combo IMM/TNF Step Care Male? MTX instead If deep remission If not deep remission If achieve deep remission Possible withdraw Therapy (which one?) 12 months Dose reduction Unproven 21
Individualized Approach to IBD Management 2011-2012 Priitize: Review goals of therapy Understand prognosis of your patient- is this newly diagnosed? Optimize: Use the best treatment available f your patient Choose objective time points and endpoints of your treatments Prevent complications (screen, vaccinate) Educate about adherence and safety Maximize: Use the right dose! Minimize immunogenicity (load, combine, maintain) Monit f relapse Strategize: How long befe you reassess? How long befe you move on to another treatment? Would you adjust dosing strategy after some time? Proposed Approach to Mono Combo Therapy in IBD Failing Thiopurine IMM/anti-TNF naive Anti-TNF Monotherapy Reassess disease reassess adherence optimize therapy (metabolites?) Add anti-tnf therapy What is prognosis? High Risk Combo IMM/TNF Male? MTX instead If deep remission Low Risk Step Care If not deep remission Stay the course adherence to maintenance schedule Losing Response? Reassess Disease If Response 6 months If achieve deep remission 12 months Assess drug level/antibodies l/ Withdraw Thiopurine? Dose reduction Possible withdraw Therapy (which one?) Add IMM? Dose reduction drubin@uchicago.edu Change drug/mechanism Unproven 22