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Biologics: Indications and Approaches Russell D. Cohen, MD, AGAF, FACG Professor of Medicine, Pritzker School of Medicine Director IBD Center Co-Director Advanced IBD Fellowship Disclosures • Speaker’s Bureau: – Abbvie, Entera Health, Salix Pharmaceuticals, Shire PLC • Consultant / Advisory/ Data Safety Monitoring/ Scientific Advisory Board: – Abbvie, Cellgene, Elan Pharmaceuticals, Entera Health, Hospira, Janssen (Johnson & Johnson / Centocor), Prometheus Laboratories, Salix Pharmaceuticals, Sandoz Biopharmaceuticals, Santarus, Shire pLC, Takeda, UCB Pharma IBD Biologics| 2 “The Tale of Two Families” IBD Biologics| 3 FAMILY #1: The Anti-TNF’s FDA- Approved Therapies Generic Branded Crohn’s Disease Ulcerative Colitis Adalimumab Humira® + + Certolizumab Cimzia® + Golimumab Simponi® Infliximab Remicade® + + + IBD Biologics| 4 Comparison of anti-TNF Agents Chimeric monoclonal antibody Humanized Fab’ Human recombinant fragment receptor/Fc fusion protein Human recombinant antibody Humanized monoclonal antibody VL Fab VH Receptor CDR Ck CH1 Constant 2 Fc Constant 3 Infliximab Mouse Human CDP571 Adalimumab Golimumab CDR = Complementarity-determining region PEG = Polyethylene glycol Etanercept •PEG •PEG Certolizumab pegol Hanauer, Rev Gastroenterol Disord 2004; 4 (supp 3): S18-24 IBD Biologics| 5 Benefits vs. Drawbacks: Anti-TNF’s • Benefits • Work fast. • Work very well in many patients. • Dosed only every 2 weeks – 2 months. • Contain no steroids; so have no steroid side-effects. • Long-term safety profile excellent. • Drawbacks • Given IV or by shot only. • May become allergic or ineffective if stop and then restart later. • Internet-hype over very very rare potential risk of lymphoma and potential increased risk of skin cancers The benefits far outweigh the extremely rare risks in the vast majority of patients. IBD Biologics| 6 FDA Indication: Adalimumab in Crohn’s Disease Adult & Pediatric Patients • Reducing signs and symptoms • Inducing and maintaining clinical • Moderately to severely active disease who have had an inadequate response to conventional therapy – Pediatrics: specifies “corticosteroids or immumodulators such as azathioprine, 6-mercaptopurine, or methotrexate.” Adult Patients • Reducing signs and symptoms and inducing clinical remission in patients if they have also lost response to or are intolerant to http://www.rxabbvie.com/pdf/humira.pdf Accessed 11/9/2014 infliximab IBD Biologics| 7 FDA Indication: Adalimumab in Ulcerative Colitis Adult Patients • Inducing and maintaining clinical remission • Moderately to severely active disease who have had an inadequate response to immunosuppressants • “such as corticosteroids, azathioprine, or 6-mercaptopurine (6-MP)” • “The effectiveness of adalimumab has not been established in patients who have lost response to or were intolerant to TNF blockers.” http://www.rxabbvie.com/pdf/humira.pdf Accessed 11/9/2014 IBD Biologics| 8 Adalimumab Dosing (CD and UC) • Load – Week 0: 160mg sc (syringe or pen) – Week 2: 80mg sc (syringe or pen) SC ONLY • More convenient • Less compliant? • Self-Medicating? • Maintenance – Starting @ Week 4: 40mg sc every other week. • If lose response: – Increase to qweekly dosing. IBD Biologics| 9 Adalimumab: Dosing Issues 1. Use of trough levels to optimize therapy 2. Increase dose: 40 q week or 80 q2 weeks 3. Best outcomes with combination therapy 4. ? If doses over 80mg should be used. 5. High dose loading in severe disease? IBD Biologics| 10 FDA Indication: Certolizumab in Crohn’s Disease Adult Patients • Reducing signs and symptoms • Maintaining clinical response • Moderately to severely active disease who have had an inadequate response to conventional therapy http://www.cimzia.com/assets/pdf/Prescribing_Information.pdf Accessed 11/9/2014 IBD Biologics| 11 Certolizumab Pegol Dosing (CD) SC ONLY • Load • Week 0: 400 mg sc • Week 2: 400 mg sc • Maintenance 1.Lyophylized drug: Mixed and Administered by health care professional • +/- convenient • More compliant? • Less Self-Medicating? • Preferred if Medicare 2. Prefilled syringe: • More convenient • Starting @ Week 4: 400 mg sc every 4 weeks • If lose response: – Give an extra dose of 400 mg 2 weeks after last dose IBD Biologics| 12 Certolizumab Pegol: Dosing Issues 1. Use of trough levels to optimize therapy ? (N/A) 2. Increase dose to 400 q2 weeks: effective? 3. Best outcomes with combination therapy 4. High dose loading in severe disease? 5. Choose the lyophilized version for Medicare patients (Medicare pays for injectables if administered by a health care professional) IBD Biologics| 13 FDA Indication: Golimumab in UC Adult Patients • Inducing and maintaining clinical response • Inducing clinical remission • Achieving and sustaining clinical remission in induction responders • Improving endoscopic appearance of the mucosa during induction • Moderate to severe ulcerative colitis with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy http://www.simponi.com/shared/product/simponi/prescribing-information.pdf Accessed 11/9/2014 IBD Biologics| 14 Golimumab Dosing (UC) • Load – Week 0: 200 mg sc (syringe or pen) – Week 2: 100 mg sc (syringe or pen) SC ONLY • More convenient • Less compliant? • Self-Medicating? • Maintenance – Starting @ Week 4: 100mg sc every 4 weeks. IBD Biologics| 15 Golimumab: Dosing Issues 1. Use of trough levels to optimize therapy? (N/A) 2. Increase dose? 3. Best outcomes with combination therapy (anticipated) 4. ? If doses over 200 mg should be used. 5. High dose loading in severe disease? IBD Biologics| 16 FDA Indication: Infliximab in Crohn’s Disease Adult & Pediatric Patients • Reducing signs and symptoms • Inducing and maintaining clinical • Moderately to severely active disease who have had an inadequate response to conventional therapy Adult Patients • Reducing the number of draining enterocutaneous and rectovaginal fistulas • Maintaining fistula closure http://www.remicade.com/shared/product/remicade/prescribing-information.pdf Accessed 11/9/2014 IBD Biologics| 17 FDA Indication: Infliximab in Ulcerative Colitis Adult & Pediatric Patients • Reducing signs and symptoms • Inducing and maintaining clinical remission • Moderately to severely active disease who have had an inadequate response to conventional therapy Adult Patients • Inducing and maintaining mucosal healing • Eliminating corticosteroid use http://www.remicade.com/shared/product/remicade/prescribing-information.pdf Accessed 11/9/2014 IBD Biologics| 18 Infliximab: Dosing (Crohn’s and UC) • Load: • Week 0: 5mg/kg IV • Week 2: 5mg/kg IV • Week 6: 5mg/kg IV IV ONLY • Less convenient • More compliant • Maintenance: • Starting @ Week 14: 5 mg/kg IV q 8 weeks. • If lose response: • Increase dose up to 10mg/kg or decrease dosing interval. IBD Biologics| 19 Infliximab: Dosing Issues 1. Use of trough levels to optimize therapy 2. ? If should increase dose or decrease duration between infusions 3. Best outcomes with combination therapy 4. ? If doses over 10mg/kg should be used 5. Aggressive loading in severe disease? IBD Biologics| 20 Combination Therapy: Superior Efficacy in Crohn’s Anti-Infliximab Antibodies: Mono: 14% Combo: 1% P<0.001 vs. aza P=0.022 vs. ifx P<0.001 vs. aza P=0.055 vs. ifx Columbel JF et al. N Engl J Med 2010;362:1383-95. IBD Biologics| 21 Combination Therapy: Superior Efficacy in Ulcerative Colitis Anti-Infliximab Antibodies: Mono: 14% Combo: 1% Panaccione et al. Gastroenterology 2014;146:392-400 e3 IBD Biologics| 22 Best Outcomes With Combination Therapy (Biologics + Immunosuppressant) Infliximab + Azathioprine: Crohn’s Disease (SONIC Trial) 1 Ulcerative Colitis (UC-SUCCESS Trial) 2 Is the same true for adalimumab? When should thiopurine be started? Should thiopurines be at therapeutic doses? Should biologics be at therapeutic doses? 1 2 Columbel JF et al. N Engl J Med 2010;362:1383-95. Panaccione et al. Gastroenterology 2014;146:392-400. IBD: New Therapies At Last ! | 23 FAMILY #2: The Anti-Integrin Antibodies FDA- Approved Therapies Generic Branded Crohn’s Disease Natalizumab Tysabri® + Vedolizumab Entyvio® + Ulcerative Colitis + IBD Biologics| 24 FDA Indication: Natalizumab in Crohn’s Disease Adult Crohn’s Disease: I. II. III. Inducing and Maintaining Clinical Response Inducing and Maintaining Clinical Remission Moderate – to – Severe active Crohn’s Disease I. IV. V. With evidence of inflammation Inadequate response to, or are unable to tolerate conventional CD therapies and inhibitors of TNF-α. In CD, should not be used in combination with immunosuppressants or inhibitors of TNF-α. FDA Prescribing Information : v 05/2014 IBD Biologics 25 Natalizumab: Dosing (CD) • Verify JC virus “-” • No Load • Standard Dosing Regimen IV ONLY “CD-TOUCH” Program • Less convenient • More compliant? • 300 mg IV every 4 weeks • No other immunomodulators allowed; taper prednisone • If no response or lose response: • Stop therapy IBD Biologics| 26 Natalizumab: Dosing Issues 1. Verify JC virus “-” prior to starting 2. Recheck JC virus q6-12 months - Stop therapy if converts to JC “+” 3. Verify drug working by month 6; otherwise stop. 4. Can check drug level if ? of low level / likely antibodies 5. If JC virus status “-” should one be “allowed to”: • Use concomitant immunomodulators? • Dose increase ? IBD Biologics| 27 FDA Indication: Vedolizumab in Crohn’s Disease Adult Crohn’s Disease: I. II. Moderate – to – Severe active Crohn’s Disease Inadequate response with, lost response to, or intolerant to either a. b. c. III. Anti- TNF blocker Immunomodulator Corticosteroids (or dependent) Outcomes: a. b. c. Achieving clinical response Achieving clinical remission Achieving corticosteroid-free remission FDA Prescribing Information : v 05/2014 IBD Biologics 28 FDA Indication: Vedolizumab in Ulcerative Colitis Adult Ulcerative Colitis: I. II. Moderate – to – Severe active UC Inadequate response with, lost response to, or intolerant to either a. b. c. III. Anti- TNF blocker Immunomodulator Corticosteroids (or dependent) Outcomes: a. b. c. d. Inducing and maintaining clinical response Inducing and maintaining clinical remission Improving endoscopic appearance of the mucosa Achieving corticosteroid-free remission FDA Prescribing Information : v 05/2014 IBD Biologics | 29 Vedolizumab: Dosing (Crohn’s and UC) • Load: • Week 0: 300 mg IV • Week 2: 300 mg IV • Week 6: 300 mg IV IV ONLY • Less convenient • More compliant • Maintenance: • Starting @ Week 14: 300 mg IV q 8 weeks. IBD Biologics| 30 Vedolizumab: Dosing Issues 1. Use of trough levels to optimize therapy ? (N/A) 2. Decrease time between maintenance infusions to q4 weeks if needed? 3. Best outcomes with combination therapy ? 4. Overlap with other induction agents • • • Steroids √ Calcineurin inhibitors ? Anti-TNF’s ? IBD Biologics| 31 Vedolizumab Blocks α4β7 Integrin Inflammatory Cytokines Anti-a4 a4b1 a4b7 T cell MAdCAM-1 Lanzarotto F, et al. Drugs. 2006;66(9):1179-1189. IBD Biologics | 32 Vedolizumab: Induction in UC 100% GEMINI I Primary Analysis: Week 6 75% P<0.001 50% 25% P=0.001 47.1% Vedolizumab 40.9% 25.5% P=0.001 Placebo 24.8% 16.9% 5.4% 0% Clinical Response Clinical Remission Mucosal Healing Feagan BG et al. N Engl J Med 2013;369(8):699-710),. IBD Biologics | 33 Vedolizumab: Maintenance in UC 100% GEMINI I Vedolizumab q 4w Week 52 Vedolizumab q 8w Placebo P<0.001 for either drug group vs. placebo 75% P = 0.01 v. placebo 56.6% 52.0% 50% 56.0% 44.8% 41.8% 51.6% 45.2% 31.4% 25% 23.8% 15.9% 19.8% 13.9% 0% Clinical Response Clinical Remission Steroid-Free Remission Mucosal Healing Feagan BG et al. N Engl J Med 2013;369(8):699-710),. IBD Biologics | 34 Vedolizumab: Induction in Crohn’s 100% GEMINI II Primary Analysis: Week 6 75% Vedolizumab 50% P = 0.23 31.4% 25% Placebo 25.7% P = 0.02 14.5% 6.8% 0% Clinical Response Clinical Remission Sandborn et al. N Engl J Med 2013;369(8):711-721. IBD Biologics | 35 Vedolizumab: Maintenance in Crohn’s 100% GEMINI II Vedolizumab q 4w Week 52 Vedolizumab q 8w Placebo 75% P=0.005 50% P=0.004 45.5% 43.5% 30.1% P<0.001 36.4% 39.0% P=0.04 28.8% 21.6% 25% P=0.02 31.7% 15.9% 0% Clinical Response P values vs. placebo Clinical Remission Steroid-Free Remission Feagan BG et al. N Engl J Med 2013;369(8):699-710),. IBD Biologics 36 Dosing Biologics By Trough Levels “+” • Higher Response Rates • Higher Endoscopic Healing Rates • Lower Hospitalization Rates • Lower Surgical Rates • Cost-Effective GI Meetings 2013-4 “–” • Extremely Expensive • Trouble Getting Insurance Coverage • Requires Repeat Testing • Slow Turn-Around Time • Hard to Interpret Results from Different Labs IBD: New Therapies At Last ! | 37 Ongoing Debates With Biologics 1. Earlier Use of anti-TNF’s ? 2. Monotherapy vs. Combination therapy ? 3. Withdrawal of Therapies ? Answers to These Dilemmas: Tomorrow’s Program ! IBD Biologics| 38 39