Severe IBD: What to Do When Anti- TNFs Don t Work?

Severe IBD: What to Do When Anti- TNFs Don t Work? David T. Rubin, MD, FACG Professor of Medicine Co-Director, Inflammatory Bowel Disease Center Interim Chief, Section of Gastroenterology, Hepatology and Nutrition @IBDMD Learning Objectives At the conclusion of this presentation, learners will: 1. Incorporate the emerging understanding regarding pathogenesis of loss of response in patients on anti-tnf therapy. 2. Develop an approach to the pro-active assessment of monitoring anti-tnf therapy of IBD. 3. Understand the current literature about anti-integrin therapy (such as natalizumab or vedolizumab) in patients with IBD. 1

Anti-TNF Therapies for Inflammatory Bowel Disease CD CD UC UC CD UC Modified from van Schouwenburg, P. A. et al. (2013) Immunogenicity of anti-tnf biologic therapies for rheumatoid arthritis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.4 Induction Treatment with anti-tnfα Agents 100 80 Clinical remission in anti-tnfα naïve patients (ITT) (CDAI 150) (for Targan study CDAI < 150) REMISSION AT 4 WEEKS 1,2,3 Targan 1 ** Schreiber 2 ** CLASSIC I 3 PRECiSE 1 2 Patients(%) 60 40 20 0 4.0 * NS NS * * * NS NS * * 48.2* 36.5* 25.0* 25.0* 28.6* 26.7* 18.2* 18.1 24.3 20.9* 82 8.2 12.2 10.3 1. Targan et al. N Engl J Med 1997;337:1029-1035. 2. UCB Data on File. 3. Hanauer et al. Gastroenterology 2006;130:323-333. 2

0 David T. Rubin, MD, FACG Maintenance Treatment with anti-tnf- α in CD Moderate to Severely Active IBD Most Failing Immune modulators Long Duration of Disease ACCENT I 1 Infliximab CDAI 70 & 25% reduction 5mg/kg q8 54 weeks 100% 100% CHARM 2 Adalimumab CDAI 70 40mg eow 56 weeks 100% PRECiSE 2&3 3,4 Cert pegol CDAI 100 & HBI 400mg q4 80 weeks 52% 38% 54% 43% 63% 54%* 44%* 0 0 0% 0% 0% 6 12 18 6 12 18 Months Months IFX Placebo ADA Placebo 1. Hanauer et al. Lancet 2002;359:1541-49. 2. Colombel et al. Gastroenterology 2007;132:52-65. 3. Schreiber et al. Gut 2006;55(Suppl V):A131 4. Lichtenstein et al. Gastroenterology 2007;132(Suppl 2):A502 (Abstract T1264) 6 12 18 Months certolizumab pegol certolizumab pegol open label Placebo Efficacy of Adalimumab for Induction of Remission in UC Fraction of Pts (5) 100 80 60 40 20 0 4 doses of ADA then endpoints measured at week 8 P = NS P = NS *P <.05 vs. PBO 44.6 51.5 54.6 41.5 37.7 46.9 * 18.5 9.2 10 Remission Response Mucosal Healing PBO (N = 130) ADA 80/40/40/40 (N = 130) ADA 160/80/40/40 (N = 130) The intent-to-treat (ITT) population included only the 390 patients randomized after the protocol amendment. Reinisch 6 W, et al. Gut. 2011;60(6):780 787. 3

Golimumab for the Induction of Moderate to Severe UC: PURSUIT Golimumab: A fully human monoclonal antibody against TNF-α 100 80 60 40 Phase 3: Clinical Response and Remission at Week 6 response remission *P<0.0001 vs placebo 51.8* 55.0* 29.7 20 0 Placebo (n=256) 6.3 200 mg 100 mg (n=257) 18.7* 17.8* 400 mg 200 mg (n=258) Sandborn WJ, et al. Gastroenterology. 2013 doi:pii: S0016-5085(13)00846-9 epub ahead of print. Why Do Patients With IBD Not Respond To Their Medications? Primary Nonresponse Drug/mechanism just doesn t work Wrong diagnosis Infection Ischemia Crohn s disease Wrong dose Not enough Too much? Other pk issues Wrong delivery Rationale Allergy/intolerance Secondary Nonresponse Change in dose (by you) Change in delivery Change in physiology Does disease change over time? Intentional nonadherence Episodic dosing strategy Denial Fear of therapy Unintentional nonadherence Can t afford medication Inconvenient dosing regimen 4

Why Do Patients With IBD Not Respond To Their Medications? Primary Nonresponse Drug/mechanism just doesn t work Wrong diagnosis Infection Ischemia Crohn s disease Wrong dose Not enough Too much? Other pk issues Wrong delivery Rationale Allergy/intolerance Secondary Nonresponse Change in dose (by you) Change in delivery Change in physiology Does disease change over time? Intentional nonadherence Episodic dosing strategy Denial Fear of therapy Unintentional nonadherence Can t afford medication Inconvenient dosing regimen Factors Affecting the Pharmacokinetics of Monoclonal Antibodies Presence of ADAs Concomitant use of IS High baseline TNF-α Low albumin High baseline CRP Body size Gender Impact on Pharmacokinetics Decreases serum mabs Threefold-increased d clearance Worse clinical outcomes Reduces formation Increases serum mabs Decreases mab clearance Better clinical outcomes May decrease mabs by increasing clearance Increases clearance Worse clinical outcomes Increases clearance High BMI may increase clearance Males have higher clearance Ordas I et al. Clin Pharmacol Ther. 2012;91:635. mab, monoclonal antibody; ADA, antidrug antibody 5

Rapid IFX clearance: Mechanism of Non Response in UC Kevans D, et al. Presented at DDW; May 19, 2012. Fecal Loss of Infliximab (IFX) is a Cause of Lack of Response in Severe Colitis 11 pts with colitis (8 UC, 3 CD) Compared to responders, non-responders to IFX had: Higher fecal IFX concentration at day 1 (P=0.02) Lower serum IFX concentration at day 14 (P=0.03) Brandse JF, et al. Presented at DDW, May 18, 2013. Abstract 157. 6

The Challenge of Immunogenicity All biologic therapies, regardless of humanization, induce immunogenicity Immunogenicity may result in hypersensitivity reactions and loss of response to therapy Subtherapeutic drug concentrations lead to lack of efficacy Methods to reduce immunogenicity: Maintenance therapy with drug Loading dose of drug Concomitant timmune-modulatory therapy Emerging: Appreciation for distinction between low titer and high titer antibodies Treatment to overcome low titer antibodies. Immunogenicity of TNF Antagonists with and without Concomitant Immune Modulators (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% Golimumab 7 (RA) No data 13.1% 4.3% 1 Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2 Sandborn et al. DDW 2007 Poster and abstract T1273; 3 Sandborn WJ, et al. N Engl J Med. 2007; 4 Schreiber S, et al. N Engl J Med. 2007; 5 Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6 Sandborn WJ, et al. Gut. 2007. 7 Keystone et al. J Rheumatol. 2013 May 15. [Epub ahead of print] 7

Immunogenicity of TNF Antagonists with and without Concomitant Immune Modulators (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% Golimumab 7 (RA) No data 13.1% 4.3% 1 Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2 Sandborn et al. DDW 2007 Poster and abstract T1273; 3 Sandborn WJ, et al. N Engl J Med. 2007; 4 Schreiber S, et al. N Engl J Med. 2007; 5 Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6 Sandborn WJ, et al. Gut. 2007. 7 Keystone et al. J Rheumatol. 2013 May 15. [Epub ahead of print] Who is at risk for anti-drug antibodies? The patient receiving episodic therapy Intentional ti Unintentional: break in therapy due to coverage issues or complication Pseudo-episodic therapy Sub-therapeutic serum drug levels 1 The patient with drug clearance between doses The patient who developed anti-drug antibodies previously 1 Vermeire S et al. Gut. 2007;56(9);1226. 8

Switching to Another Biologic Therapy What to choose and when to choose it? Evidence only exists in one direction (infliximab first), assumption is the opposite is true Primary non-responder: anti-tnfα loading dose with no response: Where is the drug going? try a different mechanism (not a different anti-tnfα therapy!) Primary responder now relapsing Assess for inflammation If suspect immunogenicity, switching to second anti-tnf is reasonable 1-3 If not immunogenicity, consider a different mechanism of treatment 1. Sandborn, et al. Ann Int Med, 2007 2. Panaccione R, et al. DDW 2008: #920 3. Rutgeerts PJ, et al. DDW 2008: #494 Interpretation of Infliximab Levels and Antibodies to Infliximab in a Patient Losing Response Infliximab i Level Antibodies to Treatment Infliximab recommendation Elevated Absent Switch treatment mechanism Elevated Present Unclear, consider switching to another TNF-inhibitor Not elevated Absent Adjust dose, interval of infliximab Not elevated Present Switch to another TNF-inhibitor Afif, et al. Am J Gastroenterol. 2010 ;105(5):1133-9. 9

Switching Between TNF Inhibitors: Rheumatoid Arthritis Experience Response to a second inhibitor is lower relative to first 1 Response to a second inhibitor will be comparable if initial discontinuation was due to adverse events 1, 2 Patients who do not respond to 2 TNF inhibitors are not lk likely l to respond to a third 2 1. Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29 2. Solau-Gervais et al. Rheumatology. 2006;epub ahead of print. Non-Anti-TNF Mechanisms of Management for the Patient Failing anti-tnf Therapy Confirm Inflammation First Crohn s Disease Natalizumab Methotrexate Surgery Including staged approaches or diversion for induction of remission Bowel rest Less evidence: Mycophenolate Tacrolimus Ulcerative Colitis Cyclosporine Tacrolimus Surgery Don t Forget about Clinical Trials! 10

Leukocyte Trafficking Inhibition leukocyte Brain Bone marrow integrins natalizumab α 4 β 1 α 4 β 7 Gut natalizumab Vedolizumab, rhumab-beta7 addressins PF-00547659 VCAM-1 MadCAM-1 endothelium Updated Utilization and Safety Results of Natalizumab in CD and MS (TOUCH, CD INFORM, TYGRIS & Pregnancy Registry Studies) 118,100 patients have received globally (post- marketing) as of 6/30/2013 Predominantly MS patients PML (Progressive Multifocal Leukoencephalopathy) Rare but serious 410 cases reported globally as of 01-Oct- 2013; 23% have died Longer duration and prior immunosuppressant use increases risk Risk for patients treated 24-36 months similar to rates seen in clinical trials Limited safety data beyond 4 yrs of treatment No known treatment or prevention interventions for PML https://medinfo.elan.com (accessed 12-Dec-2011); PML Incidence according to Elan Pharmaceuticals at 04- Nov-2013. 11

What happens to the patients who receive natalizumab in the current post-tnf paradigm? Chicago Experience Sakuraba et al. Inflamm Bowel Dis 2013; ;19(3):621-6. Recommendations for JCV Antibody Testing Testing prior to treatment with natalizumab If positive, consider retesting. If confirmed, option is treatment with natalizumab for 9-12 months If negative, may treat with natalizumab, retest every 6 months If converts to positive, stop therapy The benefit and safety of a drug holiday and restarting after resetting the exposure has not been tested in Crohn s disease Vedolizumab (expected approval Q2 2014) does not have PML associated with it. 12

Vedolizumab for Ulcerative Colitis Primary Endpoints (GEMINI I) Patients (%) 100 80 60 40 20 0 Week 6 P<0.0001 25.5 47.1 Clinical response (Primary endpoint) Placebo, n=149 VDZ, n=225 Patients (%) 100 80 60 40 20 0 Feagan BG et al. N Engl J Med. 2013 Aug 22;369(8):699-710. Week 52 15.9 P<0.0001 41.8 44.8 Clinical remission (Primary endpoint) P values are vs placebo. All patients were Week 6 responders P<0.0001 Placebo, n=126 VDZ Q8, n=122 VDZ Q4, n=125 Vedolizumab for Crohn s Disease Primary Endpoints (Gemini II and III) Primary Efficacy Endpoint Placebo Clinical remission at Week 6 (GEMINI II) Clinical remission at Week 6 in anti- TNF failures (GEMINI III) Enhanced clinical response at Week 6 (GEMINI II) VDZ VDZ Q8 VDZ Q4 P Value/ Induction Weeks Weeks 95% CI a 7% 15% -- -- <0.025 12% 15% NS 26% 31% -- -- NS Clinical remission at Week 52 22% -- 39% 36% Clinical remission at Week 52 in anti-tnf failures 13% -- 28% 27% <0.001 <0.0101 3.0, 27.5 2.0, 26.9 NS=not significant. a 95% CI for difference from placebo. Although these endpoints were prespecified, P values are not provided because multiple testing adjustments were not made. Sandborn WJ et al. N Engl J Med. 2013 Aug 22;369(8):711-21. 13

Clinical Assessment of Disease Control Routine inquiry regarding stability of disease control (stable maintenance between doses) Strict adherence to maintenance regimen Ongoing laboratory assessment of clinical stability Increasing utilization of surrogate markers of inflammatory activity it (fecal calprotectin) ti Future Strategies: Smarter Treatment Selection and Therapeutic Monitoring Selecting patients more likely to respond to anti-tnf panca negative? Specific polymorphisms? Fecal protein assessment? Therapeutic monitoring Can allow dose adjustment prior to loss of response to drug and clinical relapse Identifies es patients ts at high risk of subsequent ADA and loss of response 1 May allow for dose reduction of anti-tnf therapy Less drug, less direct costs Possibly avoiding AEs associated with high therapeutic exposure (?) 1 Vermeire S et al. Gut. 2007;56(9);1226. 14

Summary: What to do when the patient loses response to anti-tnf therapy in IBD Optimize use in the first place: choose the right patients, treat early, monitor carefully Confirm inflammation Distinguish between primary and secondary loss of response Use therapeutic monitoring to assist with assessment Understand emerging and new therapies Don t forget surgery! 15