Biologic Therapy for Inflammatory. Is Top-Down Too Top-Heavy? S. Devi Rampertab, MD, FACG, AGAF Associate Professor of Medicine University of Florida

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1 Biologic Therapy for Inflammatory Bowel Disease: Is Top-Down Too Top-Heavy? S. Devi Rampertab, MD, FACG, AGAF Associate Professor of Medicine University of Florida Learning Objectives Evaluate evidence regarding the clinical i l value of early use of biologics in the treatment paradigm for Inflammatory Bowel Disease (IBD) Discuss some of the newer biologic therapies for IBD Review the safety profile of available biologic therapies for IBD 1

2 Etiologic Theories in Inflammatory Bowel Disease (IBD) Genetic Predisposition IBD Mucosal Immune System (immunoregulatory defect) Environmental Triggers (Lumenal bacteria, infection, NSAIDs) Pathogenesis of IBD Neurath MK. Nat Rev Immunol 14; 14:

3 Goals for Treatment of IBD Evolving expectations and therapeutic strategies The expanding role of biologics Rethinking our treatment approach Surgery Biologics MTX AZA/6MP Systemic Steroids Budesonide Antibiotics 5-ASA Improve patient quality of life Induce Clinical Remission Maintain Clinical Remission Decrease surgical rates Minimize disease-related complications Current Expectations for IBD Therapy Mucosal Healing Decrease hospitalizations Minimize therapy related complications 3

4 Sustained Deep Remission Goals Response Remission Deep Remission Clinical Parameters Improved symptoms No symptoms No symptoms Mucosal Healing S U S T A I N E D Mucosal Healing Associated with: Better quality of life Fewer hospitalizations Fewer surgeries Longer time to clinical relapse Reduction in risk of dysplasia/cancer Role of Tumor Necrosis Factor (TNF) in the Pathogenesis of IBD IL: interleukin RIPK: receptor-interacting protein kinase TIMP1: tissue inhibitor of matrix metalloproteinases 1 TRAF2: TNF receptor-associated factor 2 IECs: intestinal epithelial cells MMPs: matrix metalloproteinase MLCK: myosin light chain kinase NF-κB: nuclear factor-κb Neurath MK, Nat Rev Immunol 14;14:

5 Anti-TNF Biologics Golimumab: PURSUIT-SC Induction of Remission 7 p< rcentage of patients 3 Per 3.3 p< Placebo (n=251) Golimumab /1 mg (n=253) Golimumab / mg (n=257) Sandborn et al. Gastroenterol 14;146:

6 Golimumab: PURSUIT-M Maintenance of Remission 7 p<.1 6 p=.1 Percentage of patients Placebo (n=154) Golimumab 5 mg (n=151) Golimumab 1 mg (n=151) Sandborn et al. Gastroenterol 14; 146:96-19 Golimumab: PURSUIT-M Mucosal Healing 7 6 p=.11 p=.2 Pe ercentage of patients Placebo (n=154) Golimumab 5 mg (n=151) Golimumab 1 mg (n=151) Sandborn et al. Gastroenterol 14;146:

7 Early Use of Biologics: PRECISE Patients (%) Any <1 1 - <2 2 - <5 5 CD duration (yrs) Placebo Certolizumab Sandborn et al. NEJM 7;357:239 Early Use of Biologics: CHARM Patients (%) <2 yrs 2 - <5 yrs 5 yrs Disease duration Placebo Adalimumab EOW Adalimumab qw Schreiber et al. Gastroenterol 7;132:A147 7

8 SONIC TRIAL Study of Biologic and Immunomodulator Naïve Patients in Crohn s Disease Subjects 21 years of age or older with: Moderate-to-Severe Crohn s disease (CDAI* 2 and 45) No prior exposure to biologic i agents or immunomodulators Normal TPMT At least 1 of the following criteria: Corticosteroid-dependent Being considered for second (or more) course of steroids in past year 5-ASA failures: inadequate response to mesalamine 2.4 g/d or more (or equivalent) for at least 4 weeks Budesonide failures: inadequate response to budesonide 6 mg/d or more for at least 4 weeks *Crohn s Disease Activity Index Columbel JF et al. N Engl J Med 1; 362: Definitions Corticosteroid-free remission CDAI < 15 points and have not received any dose of oral systemic corticosteroids (prednisone or equivalent) for 3 weeks and have not received budesonide at a dose greater than 6 mg/day for 3 weeks Mucosal healing Complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy Columbel JF et al. N Engl J Med 1; 362:

9 Main Extension Visitsit Week * Week 2 Week 6 Week 1 Week 14 Week 18 Week 22 Week 26* Week 3 Week 38 Week 42 Week 46 Week 5 Week 54 Infusions Azathioprine 2.5 mg/kg + placebo infusions Study Design Randomization of patients Infliximab 5 mg/kg + placebo capsules Infliximab 5 mg/kg + Azathioprine 2.5 mg/kg Primary Endpoint (Corticosteroid-free Remission at Week 26) Secondary Endpoint (Week 5) * Endoscopy performed at Weeks & 26 Corticosteroid-Free Clinical Remission at Week 26 Primary Endpoint ion of Patients (%) Proporti p=.9 p< p=.22 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Columbel JF et al. N Engl J Med 1; 362:

10 Mucosal Healing at Week 26 tion of Patients (%) Proport p<.1 p=.23 p= /19 28/93 47/17 AZA + placebo IFX + placebo IFX+ AZA Columbel JF et al. N Engl J Med 1; 362: Corticosteroid-Free Clinical Remission at Week 26 by Baseline CRP p<.1 p=.27 p= % p=.53 p= % p= % 35.2%.3% 27.6% 25/71 27/67 35/69 27/98 48/11 61/96 CRP <.8 CRP >.8 AZA + Placebo IFX + Placebo IFX + AZA Columbel JF et al. N Engl J Med 1; 362:

11 Corticosteroid-Free Clinical Remission at Week 26 by Baseline Endoscopy Status p<.1 p=.117 p= % 5.5% 3.4% p=.927 p=.372 p=.688.7%.% 33.3% 3% p=.3 p= % p= % 21.4% 35/115 5/99 68/111 11/27 12/36 12/3 6/28 13/34 16/28 Lesions (n=325) No Lesions (n=93) No Endoscopy or UTD (n=9) AZA + Placebo IFX + Placebo IFX + AZA Columbel JF et al. N Engl J Med 1; 362: Summary of Adverse Events Through Week 3 Pts with 1 AE, n (%) AZA IFX IFX Ttl Total + placebo + placebo + AZA (n=161) (n=163) (n=179) (n=53) 138 (85.7%) 139 (85.3%) 156 (87.2%) 433 (86.1%) Pts with 1 39 (24.2%) 2%) 26 (16.%) 25 (14.%) 9 (17.9%) SAE, n (%) Serious infections 8 (5.%) 4 (2.5%) 6 (3.4%) 18 (3.6%) Columbel JF et al. N Engl J Med 1; 362:

12 Conclusions of SONIC Infliximab/AZA combination > AZA alone Infliximab/AZA combination > infliximab monotherapy Infliximab monotherapy > AZA monotherapy Patients with high baseline CRP and/or ulcers at baseline colonoscopy had a particularly strong benefit from early infliximab Safety was similar in all 3 arms: there was no trend toward an increased risk of serious infections with infliximab Columbel JF et al. N Engl J Med 1; 362: UC SUCCESS Randomized, double blind trial Evaluating efficacy and safety of 16 weeks of treatment in moderate to severe UC* 231 patients, all TNF α naïve 3 arms: IFX/AZA IFX + placebo oral pills AZA + placebo IV infusions * Mayo score 6-12 Panaccione R et al. Gastroenterol 14; 146:392-12

13 UC SUCCESS Corticosteroid-free remission: - total Mayo score of 2 points or less - no individual sub-score exceeding 1 point - no corticosteroids on board at week 16 Mucosal healing - Mayo endoscopy sub-score of or 1 at week 16 Panaccione R et al. Gastroenterol 14; 146:392- UC SUCCESS: Corticosteroid-Free Remission at Week 16 6 p=.32 6 in steroid-free remisson at week p= p= Percentage of pts 1 AZA (N=76) IFX (N=77) IFX/AZA (N-78) Panaccione R et al. Gastroenterol 14; 146:392-13

14 UC SUCCESS: Mucosal Healing at Week ith mucosal healing at week p=.28 p= p= Percentage wi 3 1 AZA (N=76) IFX (N=77) IFX/AZA (N-78) Panaccione R et al. Gastroenterol 14; 146:392- Anti-TNF Safety Concerns Serious Infections Reactivation of TB, Hepatitis B Opportunistic (i.e.: Histoplasmosis) Malignancies Skin cancer NHL Hepatosplenic T cell lymphoma Hypersensitivity reactions Infusion/Injection site reaction Serum sickness/delayed hypersensitivity Exacerbation of CHF Psoriasis Demyelination Lupus-like syndrome Liver toxicity 14

15 TREAT Registry Crohn s Therapy Resource, Evaluation and Assessment Tool Prospective observational registry of patients with CD 6273 adult CD patients enrolled in TREAT -34 patients (17,712 pt-yrs) have received infliximab patients (13,251 pt-yrs) have not received infliximab Mean length of followup is 5.2 years Of patients who have received infliximab, 89.9% have received 2 infusions Lichtenstein, G. et al. Am J Gastroenterol 12; 17: Patient Characteristics Infliximab- Other treatments treated patients only ypatients p-value Number of patients Disease severity Moderate-Severe 3.6% 1.7% <.1 Severe-Fulminant 2.5%.6% <.1 Concomitant Medications Immunomodulators 52.% 32.1% <.11 Corticosteroids 47.8% 31.4% <.1 Hospitalization within 14.2% 8.8% <.1 previous year Surgery within 17.4% 13.6% <.1 previous year Lichtenstein, G et al. Am J Gastroenterol 12; 17:

16 TREAT Registry: Mortality Hazard Ratio 95% CI Use of infliximab Use of 6MP/AZA/MTX Use of prednisone * Use of narcotic * * analgesics Age * *p<.1 Lichtenstein, G et al. Am J Gastroenterol 12; 17: TREAT Registry: Serious Infections Hazard Ratio 95% CI Mod-Sev Disease * Use of infliximab * Use of 6MP/AZA/MTX Use of prednisone * Use of narcotic analgesics * *p<.1 *p=.6 *p=.2 Lichtenstein, G. et al. Am J Gastroenterol 12; 17:

17 TREAT Registry: Malignancy Hazard Ratio p Baseline Age 1.59 <.1* Use of infliximab Use of 6MP/AZA/MTX Disease Duration * Smoking * Lichtenstein, G. et al. Am J Gastroenterol 14; 19: Anti-integrin Biologics Natalizumab Binds to the α4 integrins, ubiquitous in inflammatory cells in circulation Can bind to VCAM throughout the body Associated with progressive multifocal leukoencephalopathy (PML) 17

18 Vedolizumab: Mechanism of Action Vedolizumab: Vedolizumab binding blocks α4β7 binding to MAdCAM-1 GEMINI-I: Vedolizumab in UC Randomized, double-blind, placebo- controlled Patient population: Moderate to severe UC (Mayo scores 6-12) Sigmoidoscopy sub-score of at least 2 Unsuccessful previous treatment (either lack of response or adverse side effect) with either steroids, immunomodulators or anti TNF agents Previous anti-tnf failure in at least % of patients Feagan B et al. NEJM 13; 369:

19 GEMINI-I: Vedolizumab in UC Induction Phase (6 weeks): 2 cohorts: 374 patients (placebo v vedolizumab 3 mg at Wks and patients got open label vedolizumab at Wks and 2 Maintenance phase (52 weeks): patients with response in either cohort at week 6 were randomized to one of 3 groups: Placebo vedolizumab every 4 weeks Vedolizumab every 8 weeks Feagan B et al. NEJM 13; 369: GEMINI-I: Vedolizumab in UC Induction Outcomes at Week p<.1 Percentage of pts p= p= Clinical Response Clinical Remission Mucosal Healing Placebo (n=149) Vedolizumab (n=225) Feagan B et al. NEJM 13; 369:

20 GEMINI-I: Vedolizumab in UC Maintenance Outcomes at Week 52 Pe ercentage of patients p<.1 p< p<.1 p< p<.1 p=.1 Clinical Remission (wk 52) Mucosal Healing (wk 52) Steroid-free Remission (wk 52) Placebo (n=126) Vedolizumab q 8wks (n=122) Vedolizumab q 4wks (n=125) Feagan B et al. NEJM 13; 369: GEMINI-II: Vedolizumab in CD Randomized, double-blind,,placebo- controlled Patient population: Moderate to severe CD (CDAI 2-45) Evidence of active inflammation (either high CRP, multiple ulcers on colonoscopy, or elevated fecal calprotectin, plus ulcers on radiographic imaging or capsule endoscopy Unsuccessful previous treatment (either lack of response or adverse side effect) with either steroids, immunomodulators or anti TNF agents Previous anti-tnf failure in at least 5% of patients Sandborn W et al. NEJM 13; 369:

21 GEMINI-II: Vedolizumab in CD Induction Phase (6 weeks): 2 cohorts: 368 patients (placebo v vedolizumab 3 mg at Wks and patients got open label vedolizumab at Wks and 2 Maintenance phase (52 weeks): patients with response in either cohort at week 6 were randomized to one of 3 groups: Placebo vedolizumab every 4 weeks Vedolizumab every 8 weeks Sandborn W et al. NEJM 13; 369: GEMINI-II: Vedolizumab in CD Induction Outcomes at Week p=.23 Perc centage of patients p= Clinical Remission CDAI-1 Response Placebo (n=148) Vedolizumab (n=2) Sandborn W et al. NEJM 13; 369:

22 GEMINI-II: Vedolizumab in CD Maintenance Outcomes at Week 52 7 Pe ercentage of patients p=.4 p< p=.5 p= p=.4 p= Clinical Remission CDAI-1 Response Steroid-free Remission Placebo (n=153) Vedolizumab q 8wks (n=154) Vedolizumab q 4wks (n=154) Sandborn W et al. NEJM 13; 369: Vedolizumab: Safety Rare infusion related reactions and hypersensitivity Not recommended in patients with active severe infection until the infection is controlled No cases of PML have been observed Most common adverse reactions: Nasopharyngitis* -Rash Headache -Bronchitis Arthralgia -Influenza Nausea -Back pain Upper resp tract infection -Pruritis Fatigue -Sinusitis Cough -Oropharyngeal pain 22

23 Conclusions The goal of treatment for IBD is a deep remission since there will be modification of the natural history of the disease. Earlier use of biologic therapy may be beneficial in a subset of patients with more aggressive disease. Combination therapy results in greater level of mucosal healing and greater rate of corticosteroid free remission than monotherapy with azathioprine or infliximab in patients with moderate to severe CD and UC. The anti-tnf therapies are relatively safe based on data from TREAT registry. Golimumab is efficacious in the induction and maintenance of remission in moderate-severe UC. Vedolizumab is an efficacious, safe agent that is FDA approved for moderate to severe UC and CD. 23