Optimal Use of Immunomodulators and Biologics

Transcription

1 3/17/214 Optimal Use of Immunomodulators and Biologics Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, U.S.A. Loftus Disclosures (last 12 months) Research support Abbott Labs UCB Pharma Bristol-Myers Squibb Shire Genentech Janssen Biotech Amgen Pfizer Braintree Labs Millennium-Takeda Santarus GlaxoSmithKline Robarts Clinical Trials Consultant Abbott Labs UCB Pharma Janssen Biotech Takeda 1

2 3/17/214 Overview Existing treatment paradigms Thiopurine Anti-TNF agents Evolving paradigms Role of AZA monotherapy? Treat earlier in the course of Crohn s Use objective evidence of inflammation to base treatment decisions Use objective evidence to follow up on treatment changes Use drug monitoring when available 21 MFMER slide-3 Existing Treatment Paradigms 21 MFMER slide-4 2

3 Induction Maint Patients (%) 3/17/214 Management of Mild to Moderate UC Oral 5-ASAs Mesalamine g/d Balsalazide 6.75 g/d Sulfasalazine 4 6 g/d ± Rectal 5-ASA 1 st -Line Extensive (pancolitis) Oral steroid IV steroid Infliximab, Adalimumab 2 nd - Line 3 rd -Line 5-ASA, AZA/6-MP, IFX/ADA Kornbluth A, Sachar D. Am J Gastroenterol 21;15: Ordas I, Eckmann L, et al. Lancet 212;38: Azathioprine for Steroid-Dependent, Active UC Steroid-Free Clinical/Endoscopic Remission After 6 Months 6 53% % P=.6 5-ASA 3.2 g per day (in 3 divided doses ) AZA 2 mg/kg/d Defined as clinical remission (Powell-Tuck Index Score of ) and endoscopic remission (Baron Index Score 1) plus steroid discontinuation. Patients treated with concurrent tapering dose of steroids..8 g at breakfast and lunch and 1.6 g at dinner. Ardizzone S et al. Gut 26;55: % AE rate in AZA group 6% had to discontinue AZA 3

4 Percent of Patients Percent of Patients 3/17/214 Infliximab for UC: ACT 1 and ACT 2 Clinical Remission Placebo IFX 5 mg/kg IFX 1 mg/kg Weeks 3 Weeks 54 Weeks P.2 vs placebo P.3 vs placebo P =.1 vs placebo ACT 1 ACT Placebo IFX 5 mg/kg IFX 1 mg/kg Weeks 3 Weeks Rutgeerts P et al. N Engl J Med 25;353: ACT1/2 Trials: Survival Free of Colectomy Sandborn WJ et al, Gastroenterology 29;137:

5 3/17/214 UC Success: AZA vs. IFX vs. AZA+IFX for Moderate to Severe UC: Week 16 9% 8% 7% 6% 5% 4% 3% 2% 1% 24% 22% 4% 5% 77% 69% 37% P <.5 vs AZA P<.5 vs AZA and vs IFX 63% 55% % Steroid-free Response Mucosal healing remission Conclusion: IFX+AZA superior to both AZA and IFX monotherapy in inducing steroid-free remission AZA IFX AZA + IFX Panaccione R et al, DDW 211 Oral Presentation #835. Cyclosporine vs. Infliximab for Acute Severe UC 11 patients steroid refractory UC Treatment failure No response day 7 No steroid-free remission day 98 Relapse between days 7 and 98 Colectomy Death SAE: CyA 16%, IFX 25% Conclusion: CyA was not superior to IFX in acute severe UC 8% 7% 6% 5% 4% 3% 2% 1% % Treatment Failure, % 54% Infliximab 6% Cyclosporine Laharie D, et al. Lancet 212;38:

6 3/17/214 Adalimumab for Moderate to Severe UC: Induction/Maintenance Trial (n=494) Week 8 Endpoints Week 52 Endpoints 6% 5% 4% 3% 2% 1% % 16.5% 9.3% 5.4% 41.1% 34.6% 31.7% Placebo ADA 6% 5% 4% 3% 2% 1% % 3.2% 25.% 17.3% 18.3% 15.4% 8.5% Placebo ADA Sandborn WJ et al, Gastroenterology 212;142: Golimumab (GLM) for Moderate to Severe Ulcerative Colitis, PURSUIT Studies Induction of Clinical Response Maintenance of Clinical Response Among Responders P <.1 vs placebo Sandborn WJ et al, Gastroenterology 213 (online early). Doi:1.153/j.gastro Sandborn WJ et al, Gastroenterology 213 (online early). Doi:1.153/j.gastro

7 Induction Maint 3/17/214 Management of Crohn s Disease Prednisone, Budesonide AZA/6MP/MTX Anti-TNF (Infliximab, Adalimumab, Certolizumab pegol Natalizumab AZA/MTX, Anti-TNF, Natalizumab Lichtenstein GR, Hanauer SB, Sandborn WJ. Am J Gastroenterol 29;14: Baumgart DC, Sandborn WJ. Lancet 212;38: Updated Meta-Analysis of AZA/6-MP for Crohn s Disease: Benefit Is Not So Clear Induction of Remission Prevention of Relapse Khan KJ et al, Am J Gastroenterol 211;16:

8 3/17/214 Methotrexate for Crohn s Disease Methotrexate 25 mg/week IM/SC (and possibly 15 mg/week orally) is effective for inducing remission in patients with steroiddependent and steroid-refractory active CD Methotrexate mg/week IM/SC is effective for maintenance of remission and steroid sparing in CD Less lymphomagenic than thiopurines? Construct of Biologic Agents Used in Crohn s Disease Murine Chimeric Humanized Human Recombinant Receptor/Fc Fusion Protein Pegylated Humanized Human D2E7 Infliximab IgG 1 isotype CDP571 Etanercept Natalizumab (p75) Onercept (p55) IgG 4 isotype CDP87 Certolizumab IgG 4 isotype Adalimumab IgG 1 isotype 75% human 95% human 1% human 95% human 1% human 8

9 % of Patients % of Patients % of Patients % of Patients % of Patients 3/17/214 Induction of Clinical Remission at Week 4 In Crohn s Disease: Certolizumab, Adalimumab, Infliximab 1 8 Certolizumab Certolizumab Pegol 1 Pegol 2 Adalimumab 3 Infliximab 4 6 NS NS n Tx Pbo CzP 4mg Pbo CzP 4 mg Pbo 1. Schreiber et al. Gastroenterology. 25 Sep;129(3): Sandborn et al. N Engl J Med 27 p<.5 3. Hanauer et al. Gastroenterology 26;13: NS Non-significance 4. Targan et al. N Engl J Med 1997;337: ADA 8/4m g ADA 16/8 mg Pbo INF 5mg/kg Delta INF 1mg/k g Net Remission at Six Months: Certolizumab, Adalimumab, Infliximab Certolizumab Pegol PRECISE Open-label Induction Week 6 Pbo 28.6 CzP 47.9 Week 26 remission Net remission week Infliximab ACCENT I Open-label Induction Week 2 Pbo 21. IFX 39. Week 3 remission Net remission week Certolizumab Pegol PRECISE 1 4 Pbo CzP Net remission week Adalimumab - CHARM Open Label Induction Week 4 Pbo 17. ADA 4. Week 26 remission Net remission week Schreiber et al. New Engl J Med 27;357: Hanauer et al. Lancet 22;359: Colombel et al. Gastroenterology 27;132: Sandborn et al. New Engl J Med 27;357:

10 Patients (%) 3/17/214 Mucosal Healing With Adalimumab in CD (EXTEND) P=.56, NS 27.4% ADA induction (16/8 mg)/placebo ADA QOW (4 mg) P< % 2 1 ITT, intent-to-treat; NS, not significant 13.1% 8/61 17/62 /61 15/62 Week 12 ITT Week 52 ITT Primary End Point Rutgeerts P et al. Gastroenterology 212;142:112. Natalizumab (Anti-Alpha 4 Integrin) Therapy for Crohn s Disease Monoclonal antibody to alpha 4 integrin Target molecules are VCAM-1 and MAdCAM-1 Blocks lymphocyte trafficking from vascular space to tissues Effective for induction and maintenance of response and remission and steroid-sparing Villablanca EJ et al, Gastroenterology 211;14:

11 Percent 3/17/214 ENACT-2 Natalizumab in Active Crohn s Disease: Maintenance of Clinical Response (7 points) in Week 12 Responders Placebo Natalizumab 1 At Week 36 At Week 6 At Week 36 At Week 6 P.1 Response Remission Sandborn WJ et al, N Engl J Med 25; 353: Natalizumab-Related Progressive Multifocal Leukoencephalopathy Reactivation of the human JC polyoma virus Severe neurologic disability or death Has occurred in 395 patients out of approximately 118,1 treated as of August 213 All but two cases occurred in MS patients (less than 2% of natalizumab use in US is for Crohn s) FDA mandated risk management program (TOUCH) Risk stratified by JC virus serology Use restricted to patients who have failed anti-tnf therapy Must be administered as monotherapy (without other immunosuppressive agents) Communication with Biogen Idec Pharmaceuticals, 213 Kleinschmidt-DeMasters BK et al, J Neuropathol Exp Neurol 212;7:

12 Steroid-Free Remission, % 3/17/214 Evolving Treatment Paradigms Diminishing Role of Thiopurine Monotherapy? 21 MFMER slide-23 AZA Is No Better Than Placebo For Early Crohn s Disease Prospective multicenter Spanish double-blind placebo-controlled trial (n = 131) Early Crohn s (<8 weeks) with active inflammation on endoscopy or MRE Primary endpoint: steroid-free remission at 76 weeks Steroids tapered by 1 mg/week till 2 mg and then 5 mg/week SAE: AZA, 2.6% vs 11.1% in placebo group p =.48 Panes J et al, Gastroenterology 213;145: MFMER slide-24 12

13 3/17/214 AZA vs Conventional Management for Early Crohn s Disease: GETAID Prospective multicenter French randomized open-label trial (n=132) Early Crohn s (<6 mo) with risk factors for disabling disease : age<4, perianal disease, steroids within 3 months of diagnosis AZA 2.5 mg/kg/day vs conventional rx (give AZA only for steroid dependency, chronic active disease with flares, poor steroid response, or severe perianal disease) Primary endpoint: %trimesters in steroid-free and anti-tnf-free remission over next 3 years Primary endpoints: AZA 67% vs. conventional management 56% (p=.69) No difference in need for surgery or steroids or anti-tnf therapy Cosnes J et al, Gastroenterology 213;145: MFMER slide-25 Evolving Treatment Paradigms Treat Earlier in the Course of Crohn s Disease 21 MFMER slide-26 13

14 (%) Proportion of Patients (%) 3/17/214 Top-Down vs Step-Up: Early Infliximab or Standard Therapy Clinical remission (CDAI <15), off corticosteroids, and no intestinal resection P.1 P=.6 P=.28 P=.797 P= Step-Up Top-Down Wk 14 Wk 26 Wk 52 Wk 78 Wk 14 N=133 D Haens G et al. Lancet 28;371:66. SONIC: Corticosteroid-Free Clinical Remission at Week 26 Primary Endpoint 1 8 p=.9 p<.1 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF, et al. N Engl J Med 21;362:

15 3/17/214 Evolving Treatment Paradigms Treatment Decisions Based on Objective Evidence 21 MFMER slide-29 CDAI Versus CDEIS During Treatment With Prednisolone Complete lack of correlation between CDAI (primarily symptom-based) and endoscopic inflammation Symptoms and signs of Crohn s are neither sensitive nor specific r =.13; p = NS Modigliani R et al, Gastroenterology 199;98:

16 3/17/214 Is It Really Loss of Response or Non- Response? Are Symptoms Due to IBD? Celiac disease Bacterial overgrowth Bile salt diarrhea Irritable bowel syndrome Hypersensitivity colitis Short bowel syndrome Carbohydrate malabsorption (lactose and fructose) Bacterial Overgrowth in Crohn s Disease (n=153) Hydrogen glucose breath test in symptomatic patients Increased stool frequency, increased flatulence or pain 25% had positive breath tests Risk factors Multiple resections Partial colonic resection Ileocolonic disease Klaus J et al, BMC Gastroenterol 29;9:61 16

17 Proportion of Patients (%) 3/17/214 The Intersection Between Disease Assessment and Application of Therapy: SONIC: Corticosteroid-Free Clinical Remission at Week 26 by Baseline Endoscopy Status p<.1 p=.3 p= p=.927 p=.372 p= p=.3 p= p= /115 5/99 68/111 11/27 12/36 12/3 6/28 16/28 13/34 Lesions (n=325) No Lesions (n=93) No Endoscopy or UTD (n=9) AZA + placebo (n=17) IFX + placebo (n=169) IFX + AZA (n=169) Unable to determine Colombel JF, et al. N Engl J Med 21;362: Paradigm Shift for Making Treatment Decisions in Patients with Inflammatory Bowel Disease OLD: Treat based on symptoms But: symptoms are insensitive and non-specific for bowel inflammation NEW: Treat based on objective markers of inflammation Serologic (CRP reduction) Endoscopic (mucosal healing) Radiographic (CTE/MRE improvement) Goal should be mucosal healing or absence/reduction in inflammation This will be the only way we can hope to alter the natural history of Crohn s disease 17

18 Proportion of CD Patients Not Resected 3/17/214 Evolving Treatment Paradigms Treatment Endpoint Based on Objective Evidence Not Symptoms 21 MFMER slide-35 Mucosal Healing After Treatment as Predictor of Subsequent Disease Course in Crohn s Disease: Norway 1. Patients with MH at 1 year Patients without MH at 1 year Time in Years After 1-Year Visit MH, mucosal healing Frøslie KF et al. Gastroenterology. 27;133:

19 Patients (%) Median CRP (mg/l) Patients In Remission (%) 3/17/214 Steroid Avoidance Had More Endoscopic Healing at 2 Years Secondary End Point of the Top-Down/Step-Up Trial P= Step-up Top-down Complete endoscopic healing at 2 years and these patients did better in the next 2 yrs! 7.8 Remission Off Steroids Simple endoscopic score 1 9 Simple endoscopic score Off Steroids, No Anti-TNF D Haens G, et al. Lancet 28;371:66. Baert FJ, et al. Gastroenterology 21;138:463. Levels of CRP Are Associated With Mucosal Healing Retrospective analysis of clinical and endoscopic outcomes from serial CRP measurements in 718 CD patients receiving infliximab P=.3 P= No Healing Partial Healing Complete Healing Jurgens M et al. Clin Gastroenterol Hepatol 211;9:

20 3/17/214 CT Enterography Healing: Equivalent to Mucosal Healing at Endoscopy? 3/25/25 1/11/26 Resolution of intramural inflammation on maintenance infliximab Bruining DH, et al. Clin Gastroenterol Hepatol 211;9: Radiographic Improvement on MR Enterography Correlates With Endoscopic Improvement: Δ MaRIA- Δ CDEIS at Week 12 r =.61 p <.1 Ordas I, et al. Gastroenterology 211;14(5 Suppl 1):S73 (DDW 211). Courtesy of Ingrid Ordas, M.D. 2

21 3/17/214 Implementing Treat to Target in IBD: Mucosal Healing as the Target Primary target: absence of mucosal ulceration Level of target may be influenced by comorbidities and drug-related risks Desired target should be maintained indefinitely Use both symptoms and objective measures of inflammation (endoscopic or radiologic) to guide treatment decisions Assess mucosal healing every 6 months till target is achieved, then every 1-2 years after, adjust according to degree of inflammation Bouguen G, et al. Clin Gastroenterol Hepatol 213 (online early). Doi:1.116/j.cgh Baseline assessment of disease activity by endoscopy paired with surrogate marker A Proposed Algorithm for Disease Monitoring in IBD Choice of initial therapy based on severity and prognosis of patient 3-6 months Re-assessment of disease activity directly or with surrogate marker No Healing Documented? Yes 6-12 months Discussion with patient treatment options Clinical follow-up that includes assessment of disease stability Clinical follow-up No If no other treatment options left Is patient willing to proceed with your recommendations? Adjust therapy Yes Slide compliments of David T. Rubin, MD 3-6 months 21

22 3/17/214 Challenges to Mucosal Healing in Crohn s Disease It can t be achieved in many/most patients Unclear how much healing is really needed to affect outcomes It is unknown what incremental healing can be achieved by dose escalation or switching therapies We don t know the appropriate time interval between changes in therapy and subsequent reassessment Can surrogates of endoscopic healing be used? Evolving Treatment Paradigms Therapeutic Drug Monitoring 21 MFMER slide-44 22

23 Frequency of Response 3/17/214 TPMT Activity in 47 New Zealand Patients Wild type Homozygous mutation Heterozygous mutation Sies C et al. NZ Med J 25;118(121): Target 6-TGN Level to Optimize Efficacy: >235 P<.1 1% 8% 78% 6% 4% 2% 41% Odds Ratio 5. for treatment response when 6-TGN > 235 % n= n= n= TGN QUARTILES n= Dubinsky MC, et al. Gastroenterology 2;118(4):

24 3/17/214 Meta-Analysis: Association Between 6-TGN Levels and Clinical Remission Author & Year Patients (Remission) 6TGN Threshold Fraction Above Threshold Remission Fraction Below Threshold Remission Odds Ratio 95% Confidence Interval Dubinsky 2 92 (3) Gupta (47) Belaiche (19) Cuffari (47) Goldenberg (15) Achkar 24 6 (24) Pooled Estimate.62 (.43-.8).36 ( ) Osterman MT, et al. Gastroenterology 26:13(4); Suboptimal 6-TGN Production Correlates With 6-MP Resistance Median change in 6-TGN p= Median change in 6-MMP p= Non-Responders Responders Non-Responders Responders N=37 N=14 N=37 N=14 Dubinsky MC et al, Gastroenterology 22;122(4):

25 % of patients 3/17/214 Allopurinol Therapy for Preferential 6-MMP Metabolism Pre-allopurinol Post-allopurinol TG 6-MMP Allopurinol 1 mg added; 6-MP/AZA dose reduced to 25% to 5% of baseline Sparrow MP, et al. Aliment Pharmacol Ther 25;22:441. Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and Endoscopic Improvement in UC Patients Remission Endoscopic Improv. P< Undetectable Detectable Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<.1) Seow CH, et al. Gut 21;59:

26 Patients with Sustained Clinical Response (%) 3/17/214 ADA Trough Above.33 µg/ml Predicts Clinical Response Log Rank: P=.1 ADA TR>.33 µg/ml, n=14 ADA TR<.33 µg/ml, n= Sustained Clinical Response (weeks) Karmiris K, et al. Gastroenterology. 29;137:1628. 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 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 mab, monoclonal antibody; ADA, antidrug antibody Ordas I, et al. Clin Pharmacol Ther 212;91:

27 3/17/214 Elevating Infliximab Concentration From Subtherapeutic Levels Is Effective in Regaining Response in HACA (-) Patients Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Subtherapeutic Infliximab Concentrations Complete/ Response to Test Partial Response (%) P value Detectable HACA Subtherapeutic concentration Increase infliximab Change anti-tnf 11/12 (92) Increase infliximab Change anti-tnf 2/6 (33) 1/6 (17) <.4 25/29 (86) <.16 HACA, human antichimeric antibody Afif W et al. Am J Gastroenterol 21;15:1133. Conclusions AZA, 6-MP and MTX are steroid-sparing agents Anti-TNF agents are effective for inducing and maintaining response/remission in Crohn s (IFX, ADA, CZP) and UC (IFX, ADA, GLM) Anti-TNF agents can reduce the need for hospitalizations and surgeries in Crohn s and UC Natalizumab is an option for Crohn s disease patients who are anti-tnf refractory, but carries a risk of PML 27

28 3/17/214 Conclusions Several new studies suggest that azathioprine therapy may not be effective as we once thought Still has an important role in improving efficacy of anti-tnf therapy Use objective markers of inflammation rather than symptoms to make treatment decisions Follow up on changes in therapy with objective markers of inflammation Use drug monitoring when available 28