Update on Biologic Therapy in 2015 September 12, 2015 Millie D. Long MD, MPH, FACG Assistant Professor of Medicine Inflammatory Bowel Disease Center University of North Carolina-Chapel Hill Outline Crohn s disease induction and maintenance Role of combined therapy with anti-tnf (Aza/6MP vs. MTX) Comparative effectiveness with different anti-tnf Recapturing response with a second anti-tnf Anti-integrin therapy efficacy and timing Ulcerative colitis induction and maintenance Role of combined therapy with anti-tnf (Aza/6MP) Anti-integrin therapy efficacy and timing Specific role of escalated anti-tnf dosing in severe UC 1
Anti-TNF Therapy + 6MP/Aza or MTX in Crohn s Disease SONIC: Corticosteroid-Free Clinical Remission at Week 26 and 50 p<0.001 p<0.02 p<0.001 p<0.006 p<0.04 p<0.03 *250/508 (55%) entered study extension at week 26, results assume patients not entering extension trial were not in remission in week 26 Colombel et al. 2010 N Engl J Med. 2010 Apr 15;362(15):1383-95 2
SONIC: Trough Levels at Week 46 on Mono versus Combination Therapy Colombel et al. 2010 N Engl J Med. 2010 Apr 15;362(15):1383-95 COMMIT (Methotrexate+ Infliximab (IFX) or IFX Feagan et al. Gastroenterology. 2014 Mar;146(3):681-688. 3
COMMIT: IFX-Trough and IFX Antibody Levels n=126 patients, 63 IFX+MTX, 63 IFX Detectable p-value IFX Trough- p-value Antibody + p-value IFX level mg/ml IFX+MTX 52% 6.4 4% 0.84 <0.08 IFX 44% 3.8 20% <0.01 Feagan et al. Gastroenterology. 2014 Mar;146(3):681-688. Differences SONIC and COMMIT Disease duration SONIC vs COMMIT (2.2 years vs 9 years). Immunosuppression SONIC no previous immunosuppression vs COMMIT 25% previous exposure and failure of azathioprine Inclusion criterion SONIC: CDAI > 220 and need for steroids, COMMIT patient in need for steroids (15-40mg) in the previous 4 weeks SONIC >70% prednisone naive at inclusion vs. COMMIT mean dose of prednisone 22 mg Trial Design SONIC: Dual therapy (IFX + AZA) vs COMMIT initial Steroid taper which might have masked the effects of MTX 4
Comparative Effectiveness of Anti-TNF in Crohn s disease Anti-TNF Timeline in Crohn s disease Infliximab Adalimumab Certolizumab FDA approval for Crohn s disease 1998 2007 2008 5
Anti-TNF Timeline in Crohn s disease Infliximab Adalimumab Certolizumab FDA approval for Crohn s disease 1998 2007 2008 Anti-TNF Agents: Induction and Maintenance of Remission in Crohn s Disease Network Meta-analysis Overall Anti-TNF for Induction and Maintenance vs. Placebo Induction Remission RR: 1.66, 95% CI: 1.17 2.36; Maintenance of Remission RR: 1.78, 95% CI: 1.51 2.09 Induction therapy Comparison Infliximab (IFX) non-significant superiority to adalimumab (ADA) and certolizumab (CTZ) ADA superior to CTZ (RR: 2.93 for ADA vs. CZP, 95% CI: 1.21 7.75) Maintenance Therapy Comparison Non-significant trends ADA>IFX>CTZ Stidham et al. Aliment Pharmacol Ther. 2014 Jun;39(12):1349-62 6
Comparative Effectiveness Trials of Anti-TNF Agents in Crohn s Disease Total number of subjects required for comparative efficacy RCTs between anti-tnf agents for Induction / Maintenance of remission Infliximab Certolizumab Adalimumab Infliximab - 3272 / 558 4780 / 3076 Certolizumab 3272 / 558-104518 / 286 Adalimumab 4780 / 3076 104518 / 286 - Stidham et al. Aliment Pharmacol Ther. 2014 Jun;39(12):1349-62 Comparative Effectiveness Trials of Anti-TNF Agents in Crohn s Disease Total number of subjects required for comparative efficacy RCTs between anti-tnf agents for Induction / Maintenance of remission Infliximab Certolizumab Adalimumab Infliximab - 3272 / 558 4780 / 3076 Certolizumab 3272 / 558-104518 / 286 Adalimumab 4780 / 3076 104518 / 286 - Stidham et al. Aliment Pharmacol Ther. 2014 Jun;39(12):1349-62 7
Recapturing Response with a 2 nd Anti-TNF in Crohn s disease Adalimumab Efficacy after Loss of Response/Intolerance to Infliximab (GAIN) 325 patients loss of response/intolerance IFX ADA week 0 (160 mg) + week 2 (80 mg) Placebo week 0 and 2 Outcome: Induction of remission Week 4 Remissio on (% patients) p<0.001 Sandborn et al. Ann Intern Med. 2007 Jun 19;146(12):829-38. 8
Subgroup Analysis Adalimumab Efficacy after Loss of Response/Intolerance to Infliximab (GAIN) Variable Remission at week 4 Placebo Adalimumab Previous loss of response to IFX 8% 20% Previous intolerance to IFX 5% 22% Not receiving steroids at baseline 10% 15% Receiving steroids at baseline 4% 33% Negative IFX antibodies 8% 22% Indeterminate IFX antibodies 25% 17% Positive IFX antibodies 3% 22% Sandborn et al. Ann Intern Med. 2007 Jun 19;146(12):829-38. Certolizumab Efficacy after Loss of Response/Intolerance to Infliximab (WELCOME) 539 patients loss of response IFX CTZ week 0,2 and 4 Week 4: RSP: 43.3% REM: 25.4% Week 6: RSP: 62.0% REM: 39.3% Response week 6 CTZ q 2 weeks CTZ q 4 weeks Week 26: REM CTZ q 2 weeks: 30.4% REM CTZ q 4 weeks: 29.2% Sandborn et al. Clin Gastroenterol Hepatol. 2010 Aug;8(8):688-695 9
Anti-Integrin Therapy in Crohn s disease Vedolizumab Therapy Blocking Cell Adhesion in the Gut 10
Vedolizumab (VDZ) in Crohn s Disease Short and Long-Term Efficacy (GEMINI 2) Induction of Remission Maintenance of Remission Week 6 Week 52 p<0.02 p<0.2 p<0.001 p<0.004 p<0.02 p<0.04 Sandborn et al. N Engl J Med. 2013 Aug 22;369(8):711-21. Vedolizumab Efficacy After Previous anti-tnf Antagonist Failure in Crohn s Disease (GEMINI 3) Remission Week 6 Remission Week 10 Approx. 5% higher efficacy at week 10 with concomitant steroids. No clinical effects for concomitant immunosuppression week 6 and week 10. Sands et al. Gastroenterology. 2014 Sep;147(3):618-627 11
Summary Biologics in Crohn s Disease (CD) Overall there seem to be no significant differences between the different anti-tnf s in CD Combination therapy using infliximab and azathioprine/6-mp is superior to infliximab mono-therapy Adding Methotrexate to infliximab increases trough level and decreases antibody formation, but no effect on 1 year clinical outcome No prospective data for combination therapy adalimumab or certolizumab + azathioprine/6-mp or MTX in IBD Vedolizumab is effective in CD, but has a delayed onset of clinical efficacy, so far no data of inferiority i it of mono-therapy vs combination therapy Role for steroids with vedolizumab for induction of remission Algorithm for Induction and Maintenance of Remission in Crohn s Disease Flare with severe activity Flare with mild to moderate 1. Prednisone Relapse inflammatory activity 1. Budesonide (Entocort) Predictors of severe disease (perianal disease, young age, penetrating disease, isolated upper GI- disease) 2. (5-ASA) (?) or second flare in 12 months. Consider surgery no remission Azathioprine, 6-MP + anti-tnf agent (IFX) MTX + anti-tnf (IFX)? anti-tnf (ADA, CTZ) alone Vedolizumab (?) No remission or loss of response Induction regimen Induction and Maintenance regimen Switch anti-tnf agent or Vedolizumab 12
Anti-TNF in Ulcerative Colitis Therapeutic Success anti-tnf Therapy in UC Trial ACT-1 (IFX) ACT-2 (IFX) Ultra-1 (ADA) Ultra-2 (ADA) Ultra-2 anti- TNF naïve Pursuit (GOL) Clinical Remission Week 8 Delta Clinical Remission Week 52 or 54 Placebo anti-tnf Placebo anti-tnf Delta 15.0% 39.0% 24.0% 17.0% 35.0% 18% 6.0% 34.6% 28.6% - - 9.2% 18.5% 9.3% - - 9.3% 16.5% 7.2% 8.5% 17.3% 8.8% 11.0% 21.3% 10.3% 11.4% 22.0% 10.6% 6.3% * 18.7% * 12.4% 15.4% ** 28.6% ** 13.2% * Week 6 **Week 30 and 54 Rutgeerts et al. 2005, Reinisch et al. 2011, Sandborn et al. 2012; Sandborn et al. 2014 13
Infliximab Concentration and Clinical Outcome ACT1 and ACT2 Study Infliximab 5 mg/kg bodyweight week 0,2,6, IFX level week 8 Week 8 p=0.05 Week 30 p=0.0001 Week 54 p=0.007 21.3-33.0-2.4-1.4-3.6- <21.3 >47.9 <0.11 0.11- >8.1 <33.0 <47.9 <6.8 <1.4 >6.8 <3.6 <8.1 <2.4 Reinisch W, et al. Presented at DDW; May 20, 2012. Abstract 566. *Data presented for the 5 mg/kg groups in ACT 1 & ACT 2 Factors Influencing the Pharmacokinetics of Anti-TNF Agents Presence of antibodies to drug increases clearance Lack of concomitant immunosuppression favors antibody formation High BMI increases clearance Probably only relevant for fixed dosed sc anti-tnf TNF levels High baseline TNF may increase clearance Albumin Low albumin predictor of failure Fecal Excretion of IFX High fecal secretion may be a predictor of failure Ordas et al. 2012; Brandse et al. DDW 2013 14
Infliximab, Azathioprine or Combination UC SUCCESS Trial: Week 16 Results Patients naïve to anti-tnf and AZA or >3 months stop of AZA before trial Patients (%) p<0.02 p<0.03 p<0.02 p<0.001 p<0.001 p<0.03 Remission: Steroid-free + Mayo <2, Mucosal Healing: endoscopy 0 or 1 Panaccione et al Gastroenterology. 2014 Feb;146(2):392-400. Anti-TNF Agents: Induction and Maintenance of Remission in Ulcerative Colitis Network Meta-analysis Overall Anti-TNF for Induction and Maintenance vs. Placebo Induction Remission RR 2.45, 95% CI: 1.72-3.47 Maintenance of Remission RR: 2.00, 95% CI: 1.52-2.62 Induction therapy Comparison Infliximab (IFX) with non-significant trends for superiority over golimumab (GOL) and adalimumab (ADA) Maintenance Therapy Comparison Non-significant trends IFX >ADA/GOL Stidham et al. Aliment Pharmacol Ther. 2014 Apr;39(7):660-71. 15
Comparative Effectiveness Trails of Anti-TNF Agents in Ulcerative Colitis Total number of subjects required for comparative efficacy RCTs between anti-tnf agents for Induction / Maintenance of remission Infliximab Golimumab Adalimumab Infliximab - 214 / 1870 174 / 204 Golimumab 214 / 1870-13562/ 420 Adalimumab 174 / 204 13562 / 420 - Stidham et al. Aliment Pharmacol Ther. 2014 Apr;39(7):660-71. Comparative Effectiveness Trails of Anti-TNF Agents in Ulcerative Colitis Total number of subjects required for comparative efficacy RCTs between anti-tnf agents for Induction / Maintenance of remission Infliximab Golimumab Adalimumab Infliximab - 214 / 1870 174 / 204 Golimumab 214 / 1870-13562/ 420 Adalimumab 174 / 204 13562 / 420 - PRACTICAL SIZE; SHOULD BE PERFORMED Stidham et al. Aliment Pharmacol Ther. 2014 Apr;39(7):660-71. 16
Anti-Integrin in Ulcerative Colitis Vedolizumab (VDZ)in UC Clinical Response and Remission Week 6 Depending on Prior anti-tnf Exposure (GEMINI 1) n=145 n=206 Delta: 18.4% Delta: 6.6% Delta: 26.8% Delta: 16.5% Patients (%) Feagan et al N Engl J Med. 2013 Aug 22;369(8):699-710. 17
Vedolizumab (VDZ) in UC Clinical Remission, Corticosteroidfree Remission and Mucosal Healing Week 52 (GEMINI 1) 895 patient included -373 patients responded at week 6 (42%) and were randomized Patients (%) p<0.0001 0001 p<0.05 05 p<0.0001 0001 p<0.0001 p<0.0001 p<0.0001 Feagan et al N Engl J Med. 2013 Aug 22;369(8):699-710. Therapeutic Pyramid in Ulcerative Colitis Infliximab, Adalimumab, Golimumab, Vedolizumab Cyclosporine (severe inpatient UC as bridge to other maintenance therapy) Azathioprine, 6-MP Vedolizumab (?) Steroids, Budesonide (Uceris) 5-ASA s 18
Severe Ulcerative Colitis Accelerated Infliximab Regimen for Severe Acute UC Retrospective analysis of 50 patients (35 standard and 15 accelerated protocol) Standard regimen of 5 mg/kg at 0,2,6 weeks compared to accelerated (5 mg/kg for 3 doses over a median of 24 days) p=0.039 Gibson DJ 2015 19
Accelerated Infliximab Regimen for Severe Acute UC Changes in CRP Proportion colectomy-free Gibson DJ 2015 Algorithm for Severe Ulcerative Colitis Long MD 2009 20
Algorithm for Severe Ulcerative Colitis Factors to consider that may influence the decision for accelerated infliximab dosing: Clinical severity CRP Albumin Long MD 2009 Summary Biologics in Ulcerative Colitis (UC) Infliximab with highest remission/response rates of the anti-tnfs Infliximab + azathioprine/6-mp is superior to infliximab monotherapy, but there are no data for adalimumab or golimumab combination therapy Trough levels play a role in the efficacy of anti-tnf agents in UC Vedolizumab is similarly effective when compared to anti-tnf agents, but may have a more favorable side effect profile? should vedolizumab be combined with azathioprine/6-mp or MTX to warrant long term efficacy In severe UC, accelerated dosing algorithms may improve shortterm colectomy rates, but prospective RCT s are needed 21
Acknowledgements Hans H. Herfarth MD, PhD 22