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 2IBD Biologics|

“The Tale of Two Families” 3IBD Biologics|

FAMILY #1: The Anti-TNF’s 4IBD Biologics| GenericBrandedCrohn’s DiseaseUlcerative Colitis AdalimumabHumira ® ++ CertolizumabCimzia ® + GolimumabSimponi ® + InfliximabRemicade ® ++ FDA- Approved Therapies

Comparison of anti-TNF Agents 5IBD Biologics| Hanauer, Rev Gastroenterol Disord 2004; 4 (supp 3): S18-24 Human recombinant receptor/Fc fusion protein Humanized Fab’ fragment Human recombinant antibody Humanized monoclonal antibody Chimeric monoclonal antibody CDR Fc Receptor Constant 2 Constant 3 MouseCDR = Complementarity-determining region HumanPEG = Polyethylene glycol Certolizumab pegol PEG VLVH CH1 CC Fab Infliximab CDP571Adalimumab Golimumab Etanercept

6IBD Biologics| 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 Benefits vs. Drawbacks: Anti-TNF’s The benefits far outweigh the extremely rare risks in the vast majority of patients.

FDA Indication: Adalimumab in Crohn’s Disease 7IBD Biologics| 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 infliximab Accessed 11/9/2014

FDA Indication: Adalimumab in Ulcerative Colitis 8IBD Biologics| 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.” Accessed 11/9/2014

Adalimumab Dosing (CD and UC) 9IBD Biologics| Load – Week 0: 160mg sc (syringe or pen) – Week 2: 80mg sc (syringe or pen) Maintenance – Week 4: 40mg sc every other week. If lose response: – Increase to qweekly dosing. SC ONLY More convenient Less compliant? Self-Medicating?

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? 10IBD Biologics|

FDA Indication: Certolizumab in Crohn’s Disease 11IBD Biologics| Adult Patients Reducing signs and symptoms Maintaining clinical response Moderately to severely active disease who have had an inadequate response to conventional therapy Accessed 11/9/2014

Certolizumab Pegol Dosing (CD) 12IBD Biologics| Load Week 0: 400 mg sc Week 2: 400 mg sc Maintenance Week 4: 400 mg sc every 4 weeks If lose response: – Give an extra dose of 400 mg 2 weeks after last dose SC ONLY 1.Lyophylized drug: Mixed and Administered by health care professional +/- convenient More compliant? Less Self-Medicating? Preferred if Medicare 2. Prefilled syringe: More convenient

Certolizumab Pegol: Dosing Issues 13IBD Biologics| 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)

FDA Indication: Golimumab in UC 14IBD Biologics| 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 Accessed 11/9/2014

Golimumab Dosing (UC) 15IBD Biologics| Load – Week 0: 200 mg sc (syringe or pen) – Week 2: 100 mg sc (syringe or pen) Maintenance – Week 4: 100mg sc every 4 weeks. SC ONLY More convenient Less compliant? Self-Medicating?

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? 16IBD Biologics|

FDA Indication: Infliximab in Crohn’s Disease 17IBD Biologics| 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 Accessed 11/9/2014

FDA Indication: Infliximab in Ulcerative Colitis 18IBD Biologics| 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 Accessed 11/9/2014

Infliximab: Dosing (Crohn’s and UC) 19IBD Biologics| Load: Week 0: 5mg/kg IV Week 2: 5mg/kg IV Week 6: 5mg/kg IV Maintenance: Week 14: 5 mg/kg IV q 8 weeks. If lose response: Increase dose up to 10mg/kg or decrease dosing interval. IV ONLY Less convenient More compliant

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? 20IBD Biologics|

Combination Therapy: Superior Efficacy in Crohn’s 21IBD Biologics| 21 P<0.001 vs. aza P=0.055 vs. ifx P<0.001 vs. aza P=0.022 vs. ifx Columbel JF et al. N Engl J Med 2010;362: Anti-Infliximab Antibodies: Mono: 14% Combo: 1%

Combination Therapy: Superior Efficacy in Ulcerative Colitis 22IBD Biologics| Anti-Infliximab Antibodies: Mono: 14% Combo: 1% Panaccione et al. Gastroenterology 2014;146: e3

Best Outcomes With Combination Therapy (Biologics + Immunosuppressant) 23|IBD: New Therapies At Last ! Infliximab + Azathioprine: Crohn’s Disease (SONIC Trial) 1 Ulcerative Colitis (UC-SUCCESS Trial) 2 1 Columbel JF et al. N Engl J Med 2010;362: Panaccione et al. Gastroenterology 2014;146: Is the same true for adalimumab? When should thiopurine be started? Should thiopurines be at therapeutic doses? Should biologics be at therapeutic doses?

FAMILY #2: The Anti-Integrin Antibodies 24IBD Biologics| GenericBrandedCrohn’s DiseaseUlcerative Colitis NatalizumabTysabri ® + VedolizumabEntyvio ® ++ FDA- Approved Therapies

FDA Indication: Natalizumab in Crohn’s Disease Adult Crohn’s Disease: I.Inducing and Maintaining Clinical Response II.Inducing and Maintaining Clinical Remission III.Moderate – to – Severe active Crohn’s Disease I.With evidence of inflammation IV.Inadequate response to, or are unable to tolerate conventional CD therapies and inhibitors of TNF-α. V.In CD, should not be used in combination with immunosuppressants or inhibitors of TNF-α. 25 FDA Prescribing Information : v 05/2014 IBD Biologics

Natalizumab: Dosing (CD) 26IBD Biologics| Verify JC virus “-” No Load Standard Dosing Regimen 300 mg IV every 4 weeks No other immunomodulators allowed; taper prednisone If no response or lose response: Stop therapy IV ONLY “CD-TOUCH” Program Less convenient More compliant?

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 ? 27IBD Biologics|

FDA Indication: Vedolizumab in Crohn’s Disease Adult Crohn’s Disease: I.Moderate – to – Severe active Crohn’s Disease II.Inadequate response with, lost response to, or intolerant to either a.Anti- TNF blocker b.Immunomodulator c.Corticosteroids (or dependent) III.Outcomes: a.Achieving clinical response b.Achieving clinical remission c.Achieving corticosteroid-free remission 28 FDA Prescribing Information : v 05/2014 IBD Biologics

FDA Indication: Vedolizumab in Ulcerative Colitis Adult Ulcerative Colitis: I.Moderate – to – Severe active UC II.Inadequate response with, lost response to, or intolerant to either a.Anti- TNF blocker b.Immunomodulator c.Corticosteroids (or dependent) III.Outcomes: a.Inducing and maintaining clinical response b.Inducing and maintaining clinical remission c.Improving endoscopic appearance of the mucosa d.Achieving corticosteroid-free remission 29|IBD Biologics FDA Prescribing Information : v 05/2014

Vedolizumab: Dosing (Crohn’s and UC) 30IBD Biologics| Load: Week 0: 300 mg IV Week 2: 300 mg IV Week 6: 300 mg IV Maintenance: Week 14: 300 mg IV q 8 weeks. IV ONLY Less convenient More compliant

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 ? 31IBD Biologics|

Vedolizumab Blocks α 4 β 7 Integrin 32| Lanzarotto F, et al. Drugs. 2006;66(9): Anti-  4 MAdCAM-1 4141 4747 T cell Inflammatory Cytokines IBD Biologics

Vedolizumab: Induction in UC 33| Primary Analysis: Week 6 Feagan BG et al. N Engl J Med 2013;369(8): ),. GEMINI I IBD Biologics

Vedolizumab: Maintenance in UC 34| Week 52 Feagan BG et al. N Engl J Med 2013;369(8): ),. GEMINI I IBD Biologics

Vedolizumab: Induction in Crohn’s 35| Primary Analysis: Week 6 Sandborn et al. N Engl J Med 2013;369(8): GEMINI II IBD Biologics

Vedolizumab: Maintenance in Crohn’s 36 Week 52 Feagan BG et al. N Engl J Med 2013;369(8): ),. P values vs. placebo GEMINI II IBD Biologics

Dosing Biologics By Trough Levels 37|IBD: New Therapies At Last ! “ + ” Higher Response Rates Higher Endoscopic Healing Rates Lower Hospitalization Rates Lower Surgical Rates Cost-Effective “ – ” Extremely Expensive Trouble Getting Insurance Coverage Requires Repeat Testing Slow Turn-Around Time Hard to Interpret Results from Different Labs GI Meetings

Ongoing Debates With Biologics 1.Earlier Use of anti-TNF’s ? 2.Monotherapy vs. Combination therapy ? 3.Withdrawal of Therapies ? 38IBD Biologics| Answers to These Dilemmas: Tomorrow’s Program !

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