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Disclosures In accordance with the ACCME Standards for Commercial Support of CME, the speakers for this course have been asked to disclose to participants the existence of any financial interest and/or relationship(s) (e.g., paid speaker, employee, paid consultant on a board and/or committee for a commercial company) that would potentially affect the objectivity of his/her presentation or whose products or services may be mentioned during their presentation. The following disclosures were made: Planning Committee Member John Bayliss, VP, Business Development, Annenberg Center for Health Sciences at Eisenhower Spouse is an employee of Amgen Julie Messick, PharmD No Relevant Relationships Faculty All faculty disclosures can be found in your meeting guide. 3

This program is supported by educational grants from Janssen Biotech, Inc. Prometheus Laboratories, Inc. 4

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Case Presentation 6

Patient Case 23-yr-old male presents with 8 weeks of progressive abdominal pain and weight loss Physical exam BMI 22 T 100.6 Pulse 105 Tender with fullness in RLQ 7

Patient Case (cont.) No family history of IBD Smokes 1 ppd Labs WBC 10, Hgb 10, Hct 34 Ferritin 30 CRP 15 mg/dl CMP normal except albumin 3.1 g/l Vitamin B 12 normal, Vitamin D low 8

Patient Case (cont.) MRE: edematous ileum with mesenteric stranding and sinus tract toward sigmoid colon Colonoscopy: Focal area of ulceration in sigmoid. Deep ulcerations in cecum with deformed and ulcerated ileocecal valve 9

Personalizing Treatment for IBD: Evolving Treatment Paradigms Maria T. Abreu, MD 10

Impact of Therapy Will Depend on Degree of Structural Damage and Speed of Progression 100 Cumulative probability, % 80 60 40 20 Inflammatory Penetrating Stricturing 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patients at risk Months n= 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250. 11

AGA Clinical Pathway for Crohn s Disease: Assessing Inflammatory Status Assess inflammatory status Assess symptoms/signs Fever Abdominal pain GI bleeding Localized tenderness Weight loss Joint pain Cutaneous signs Perform clinical lab testing CBC CRP CMP Fecal calprotectin ESR Select imaging modalities (if indicated) Identify symptoms without inflammatory markers Perform endoscopy Identify symptoms with inflammatory markers* Perform CTE or MRE Consider whether treatment decisions to be based on inflammatory markers vs confirming with colonoscopy. This may depend on whether there was historically good correlation between the biomarker selected and colonoscpy in the specific patient. CMP, complete metabolic panel; CTE, computed tomography enterography; ESR, erythrocyte sedimentation rate; MRE, magnetic resonance enterography. Sandborn WJ. Gastroenterology. 2014;147:702-705. 12

AGA Clinical Pathway for Crohn s Disease: Characterizing Risk Low Risk High Risk >30 years Age at diagnosis <30 years Limited Anatomic involvement Extensive No Perianal and/or severe rectal disease Yes Superficial Ulcers Deep No Prior surgical resection Yes No Stricturing and/or penetrating behavior Yes Sandborn WJ. Gastroenterology. 2014;147:702-705. 13

AGA Clinical Pathway for Crohn s Disease: Initial Treatment Low-risk patient Moderate/high-risk patient Ileum and/or proximal colon, none to minimal symptoms Options Budesonide 9 mg/day with or without AZA Tapering course of prednisone with or without AZA Diffuse or left colon, none to minimal symptoms Options Tapering course of prednisone with or without AZA Options Anti-TNF monotherapy over no therapy or thiopurine monotherapy Anti-TNF + thiopurine over thiopurine monotherapy or anti-tnf monotherapy Methotrexate for patients who do not tolerate purine analog in combination with anti-tnf Sandborn WJ. Gastroenterology. 2014;147:702-705. 14

Clinical Remission in CD: Net Remission at 6 Months with TNF Antagonists 1. Hanauer SB et al. Lancet. 2002;359:1541-1550; 2. Colombel JF et al. Gastroenterology. 2007;132:52-62; 3. Schreiber S et al. N Engl J Med. 2007;357:239-255; 4. Sandborn WJ et al. N Engl J Med. 2007;357:228-237. 15

Improving Initial Response to Biologics Treat earlier in course (before complications) Ensure Complete response Combination therapy 16

Early Aggressive Biologic Therapy versus Conventional Management of Crohn s Disease Newly-diagnosed Crohn s disease (N=133)* No previous anti-tnf, antimetabolite, or steroids + IFX IFX + AZA + AZA/MTX + (episodic) IFX Steroids Steroids Steroids Conventional Therapy (n=66) Early Aggressive (n=67) *Within 4 years. D Haens G et al. Lancet. 2008;371(9613):660-667. 17

Complete Ulcer Disappearance Mucosal Healing at Week 104 Patients with no ulcers, % 100 80 60 40 20 0 73 n=19/26 Top-down therapy P=0.003 30 n=7/23 Step-up therapy D Haens G et al. Lancet. 2008;371(9613):660-667. 18

CHARM: Early CD Shows High Levels of Remission with Adalimumab Patients in remission, % 100 80 60 40 20 0 Week 26 P=0.002 P<0.001 59 40 41 25 17 14 < 2 years 2 to 5 years 5 years Disease duration Clinical Remission Patients in remission, % 100 80 60 40 20 Placebo All adalimumab 0 P=0.014 51 Week 56 P=0.001 P=0.001 44 35 17 11 11 n=23 n=39 n=23 n=39 n=111 n=233 n=23 n=39 n=23 n=39 n=111 n=233 < 2 years 2 to 5 years 5 years Disease duration Schreiber S, et al. Gastroenterology. 2007;132(Suppl 1):A-147. 19

Response and Remission to Certolizumab Pegol in Crohn s Disease vs. Disease Duration CDAI response, % 100 80 60 40 20 0 37 90 Clinical Response 50 75 62 36 33 57 n=35 n=19 n=22 n=20 n=55 n=45 n=98 n=131 < 1 year 1 to 2 years 2-5 years 5 years Disease duration Placebo PRECiSE Trial Sandborn WJ, et al. Am J Gastroenterol. 2006;101:S454-455. [Abstract 1109]. Schreiber S, et al. N Engl J Med. 2007;357(3):239-250. CDAI remission % 100 80 60 40 20 0 68 37 36 Certolizumab pegol Clinical Remission 55 29 < 1 year 1 to 2 years 2-5 years 5 years Disease duration 47 44 24 n=35 n=19 n=22 n=20 n=55 n=45 n=98 n=131 20

Combination Therapy in CD: The SONIC Study Patients (%) 100 80 60 40 20 0 Corticosteroid-free Clinical Remission at Week 26 1 30 P=.006 44.4 P<.001 P=.022 56.8 51/170 75/169 96/169 Azathioprine Infliximab Azathioprine + Infliximab Combination therapy with immunosuppressant and anti-tnf biologic offers improved efficacy and durability compared with anti-tnf monotherapy 2 1. Colombel JF et al. N Engl J Med. 2010;362:1383-1395. 2. Sandborn WJ. Gastroenterology. 2014;147:702-705. 21

Mucosal healing improves outcomes 22

Mucosal Healing After Therapy Predicts Improved Outcomes in Crohn s Disease 100 SES 0 SES 1 8 Patients (%) 80 60 40 20 70.8 27.3 62.5 18.2 0 Remission off steroids Remission off steroids and anti-tnf SES=Simple Endoscopic Score. Baert F et al. Gastroenterology. 2010;138:463-468. 23

Mucosal Healing Reduces Risk for Colectomy in Crohn s Disease Risk of Colectomy According to Severe Endoscopic Lesions 1 Degree of Mucosal Healing and Risk of Major Abdominal Surgery 2 Patients (%) 100 80 60 40 20 No severe endoscopic lesions Severe endoscopic lesions 31 6 8 43 31 62 Patients undergoing MAS (%) 100 80 60 40 20 14.1 14 38.4 0 1 3 8 Year of follow-up 0 Complete Partial None Degree of mucosal healing MAS=major abdominal surgery; SEL=severe endoscopic lesions (extensive and deep ulcerations on index colonoscopy) 1. Allez M et al. Am J Gastroenterol. 2002;97:947-953. 2. Schnitzler F et al. Inflamm Bowel Dis. 2009;15:1295-1301. 24

Biomarkers Correlate Well With Endoscopic But Not Clinical Activity Indices IL-6 Calprotectin Lactoferrin CDAI SES-CD hscrp + + + NS + IL-6 + + NS + Calprotectin + + + Lactoferrin + + CDAI NS + indicates significant correlation coefficients (P<.05); NS, nonsignicant correlations. When stratified by extent, correlation coefficients were highest for colonic disease CDAI=Crohn s disease activity index; CRP=C-reactive protein; IL=interleukin; SES-CD=Simple Endoscopic Score-Crohn s Disease. Jones JL et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224. 25

Working Definitions of Deep Remission Deep remission implies resolution of inflammatory symptoms and objective signs of inflammation No bowel damage or disability Resolution of symptoms Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers) Existing bowel damage or disability Improvement of symptoms Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers) Colombel JF et al. Dig Dis. 2012;30 Suppl 3:107-111. 26

Not All Decisions in Crohn s Disease Are Preference-Sensitive Preference-Sensitive Decisions Anti-TNF monotherapy vs anti-tnf plus thiopurine therapy Top-down versus rapid step-up therapy at diagnosis Infliximab vs adalimumab vs certolizumab Ileocolonic resection vs augmenting therapy for persistent non-stricturing CD Anti-integrin vs 2 nd or 3 rd anti-tnf Non-Preference-Sensitive Decisions TB testing prior to initiating anti-tnf therapy Appropriate vaccinations for immunosuppressed patients Siegel CA. Gut. 2012;61:459-465. 27

Helping Patients See The Odds Risk of Lymphoma Associated with Immune Suppression (9 per 10,000 patient-years) Risk of Serious Infections in the SONIC Trial Siegel CA. Aliment Pharmacol Ther. 2011;33:23-32. 28

Patient Case (cont.) He is started on combination adalimumab and azathioprine but develops nausea and vomiting 3 weeks after starting azathioprine He improves after stopping azathioprine After 12 weeks of therapy he begins to develop recurrence of abdominal pain and night sweats CRP is 8 g/l 29

Managing Loss of Response to Anti-TNF Therapies Edward V. Loftus, Jr., MD 30

How to Maintain Remissions with Biologics Prospective Therapeutic Monitoring 31

Therapeutic Windows with Biologics Peak Concentration (µg/ml) 100 10 1 Trough 0 2 6 14 22 Time (weeks) 32

Implications of Low Trough Levels Disease recurs No longer maintenance but re-treatment Development of anti-drug antibodies Eventual loss of response 33

What Factors Influence the Pharmacokinetics of TNF Antagonists? Y Decreases drug clearance Concomitant immunosuppressives CRP=C-reactive protein Ordàs I et al Clin Gastroenterol Hepatol. 2012;10:1079-1087. Increases drug clearance Anti-drug antibodies Low serum albumin High baseline CRP High baseline TNF concentration High body mass index Male sex 34

Detectable Levels of Infliximab Are Associated with Better Outcomes Patients (%) 100 80 60 40 20 0 Clinical Outcomes By Infliximab Trough Level 6 P<0.001 82 Undetectable P<0.001 76 2.0 µg/ml 32 33 P<0.001 Clinical remission Normal CRP Endoscopic improvement 88 Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-54. 35

Clinical Remission Without Corticosteroids by Trough IFX Concentration at Week 26: SONIC Patients (%) 100 80 60 40 20 0 Corticosteroid-free Remission at Week 26 73 74 72 59 57 19/32 13/23 43/59 36/49 31/43 0 >0-1 >1-3 >3-6 >6 IFX concentration (µg/ml) at Week 30 Colombel JF, et al. N Engl J Med. 2010. 36

Post-induction Infliximab Levels Predict Clinical Outcome at Week 54 Patients, % 100 80 60 40 20 17.7 P=0.0042 Week 14 serum IFX level <3.5 µg/ml 3.5 µg/ml 39.2 82.3 60.8 0 Sustained response (n=96) No sustained response (n=51) Cornillie F et al., Gut. 2014;63: 1721-7 37

Infliximab Trough Between Weeks 14 and 22 Predicts Sustained Response in Crohn s Disease Retrospective adult cohort 84 patients IFX trough level measured at 14 or 22 weeks Sustained clinical response IFX Trough level > 3 µg/ml Increase in ATI IFX Trough level < 3 µg/ml Bortlik M, et al. J Crohns Colitis. 2013;7:736-743. Cumulative probability of sustaining in clinical response 0.0 0.2 0.4 0.6 0.8 1.0 P-value (logrank): <0.001 IFX level >3 µg/ml <3 µg/ml 0 5 10 15 20 25 30 35 Time from IFX start (months) 38

Active Monitoring of Anti-TNF Levels May Ensure Durability of Response Prospectively optimized IFX trough concentrations to a target range of 5-10 µg/ml 100 Probability on Infliximab 80 60 40 20 Vaughn B, et al. Inflamm Bowel Dis. 2014;20:1996-2003. 0 0 P=.0006 100 200 300 400 500 600 700 Weeks Optimized Not Optimized 39

Assessing Loss of Response Reassess disease activity Measure drug level and anti-drug antibodies If possible? 40

Assessing Loss of Response Confirmed Active Inflammation Subtherapeutic concentration and positive ADA Therapeutic drug concentration or detectable trough level Subtherapeutic concentration or undetectable trough level Change to another anti-tnf agent Increase dose frequency If persistent disease Change to treatment with different MOA (non-anti-tnf agent) or Consider adding immunosuppressant (if monotherapy) ADA, anti-drug antibodies. Afif W et al. Am J Gastroenterol. 2010;105:1133-1139. 41

Increasing Dose of Infliximab in the Presence of ATI Formation is Inferior to Changing Anti-TNF Complete/partial response, % 100 80 60 40 20 0 Patients with detectable ATI (n=35) 92 P<0.004 Complete/Partial Response 17 20 n=11/12 n=1/6 0 n=11/12 n=1/6 Anti-TNF changed Complete/partial response, % 100 80 60 40 Patients with sub-therapeutic IFX concentrations (n=69) 33 P<0.016 Infliximab increased 86 Afif W et al. Am J Gastroenterol. 2010;105:1133-1139. 42

Adalimumab & ATA Levels at LOR Correlate With Response to Dose Intensification Adalimumab Levels at the Time of LOR in Patients Who Subsequently Responded to Dose Intensification Compared with Those Who Did Not ATA Levels at the Time of LOR in Patients Who Subsequently Responded to Dose Intensification Compared with Those Who Did Not mcg/ml mcg/ml-eq LOR, loss of response. Yanai et al. Clin Gastroenterol Hepatol. 2015;13:522 530 43

Patient Case Adalimumab trough level is undetectable Anti-drug antibodies are positive What would you do next? 44

The First Biologic is the Best Opportunity Longer disease duration Progressive transmural changes Refractory disease 45

4-Week Remission Rate with Adalimumab By Prior Anti-TNF Exposure Patients in remission, % 100 80 60 40 20 0 Clinical Remission (CDAI 150) at Week 4 Placebo Adalimumab 160 mg (Wk 0)/80 mg(wk 2) 12 P<0.001 36 Anti-TNF-naïve (CLASSIC-I) 7 P<0.001 21 n=74 n=76 n=166 n=159 Infliximab failure/intolerance (GAIN) Adapted from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed 0708/09. Sandborn WJ, et al. Ann Intern Med. 2007;146(12):829-838. 46

Certolizumab Pegol: Week 26 Clinical Remission by Prior Anti-TNF Exposure Patients in remission, % 100 80 60 40 20 0 Clinical Remission (CDAI 150) in PRECiSE 2 Certolizumab pegol (3 injections) + placebo Certolizumab pegol 400 mg 33.3 P<0.001 52.8 No prior anti-tnf 13.7 P=0.008 32.7 n=159 n=163 n=51 n=52 Prior anti-tnf (infliximab) Schreiber S, et al. N Engl J Med. 2007;357(3):239-250. Columbel JF, et al. Presented at UEGW 47

Vedolizumab in Crohn s Disease: Clinical Remission at Week 6 and 10 100 Clinical Remission at Week 6 100 Clinical Remission at Week 10 Patients, % 80 60 40 20 P=.05 19.1 12.1 12.1 15.2 12 31.4 Patients, % 80 60 40 20 P=.001 P<.001 26.6 28.7 12.1 13 16 35.3 0 Overall population Failure Naïve TNF antagonist experience 0 Overall population Failure Naïve TNF antagonist experience Placebo Vedolizumab Q8W PBO=placebo; VDZ=vedolizumab Sands BE et al. Gastroenterology. 2014;147:618-627. 48

Effect of Concomitant Azathioprine or Methotrexate on Anti-drug Antibodies ATI IFX levels Patient 1 Patient 3 Concentration (mcg/ml) 7 6 5 4 3 2 1 Start MTX 0 0 10 20 30 40 50 Concentration (mcg/ml) 25 20 15 10 5 0 Start AZA 0 10 20 30 40 50 60 Weeks Weeks Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447. 49

Patient Case He was treated with infliximab 5mg/kg induction and maintenance and methotrexate 15 mg orally He did well for 6 months but then had recurrence of pain, fever and diarrhea Colonoscopy demonstrated a fistula in the sigmoid and persistent deep ulcers in the cecum and a strictured ileocecal valve. Infliximab levels were 9 and there were no anti-drug antibodies What would you do next? 50

The IBD Pipeline IL-Inhibitors Ustekinumab Multiple anti-il-23 inhibitors Downstream signaling blockade Tofacitinib Ozanimod Mongersen Anti-adhesion molecules Alicaforsen AMG181 Anti-MAdCAM Etrolizumab Adapted from Amiot A, Peyrin-Biroulet L. Ther Adv Gastroenterol. 2015;8(2):66-82.c 51

Ustekinumab for Crohn s Disease p40 IL-12 p35 ustekinumab NK or T cell membrane No IL-12 or IL-23 Intracellular signal p19 IL-23 p40 IL-12 and IL-23 are key cytokines in the pathogenic immune cascade of CD Ustekinumab is a fully human IgG1k monoclonal antibody that binds the p40 subunit of Interleukins-12 & 23 Prevents IL-12 and IL-23 from binding IL-12Rβ1 Inhibits IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production Approved for moderate to severe psoriasis and psoriatic arthritis Feagan B, et al. UEGW 2015. 52

UNITI-2 Trial Ustekinumab in Anti-TNF-Naïve CD Patients Patients, % 100 80 60 40 20 0 28.7 Clinical Response at Week 6 ( 100 point CDAI reduction) P<0.001 P<0.001 P<0.001 51.7 55.5 53.6 n=209 n=209 n=209 n=418 Placebo 130 mg ~6 mg/kg* Combined Ustekinumab *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight 55 kg), 390 mg (weight >55 mg and 85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Feagan BG et al. UEGW 2015. 53

UNITI-1 Trial Ustekinumab in CD Patients Failing Anti-TNF Therapy Subjects, % 50 P=0.002 40 30 20 10 0 p=0.001 *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight 55 kg), 390 mg (weight >55 mg and 85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Sandborn WJ, et al. CCFA 2015. 21.5 Clinical Response at Week 6 ( 100 point CDAI reduction) P=0.003 34.3 33.7 n=247 n=245 n=249 Placebo 130 mg ~6 mg/kg* Ustekinumab 54

UNITI-2 Ustekinumab General Safety Summary SAEs were uncommon and, except for Crohn s disease, anal abscess, and small bowel obstruction, no individual SAE was reported in >1 subject in any group No deaths, malignancies, or MACE through Week 8 Proportions of subjects with infections similar across all ustekinumab and placebo groups No cases of TB and no opportunistic infections in ustekinumab-treated subjects Adverse events during or within an hour of infusion were infrequent, and did not occur at a higher rate in ustekinumab groups vs. placebo None were serious, and no anaphylaxis events were reported Feagan B et al. UEGW 2015. 55

Mongersen (GED-0301): Phase 2 Trial in Steroid-dependent or -resistant CD Clinical Remission at Week 12 P<0.001 P<0.001 Patients, % 100 80 60 40 20 0 9.5 12.2 Placebo (n=42) P<0.001 10 mg/day (n=41) P<0.001 55 40 mg/day (n=40) 65.1 160 mg/day (n=43) Monteleone G et al. N Engl J Med. 2015;372:1104-1113. Mongersen 56

Summary Early aggressive treatment according to prognosis vs symptoms Treatment decisions based on objective measures Prevent loss of response Assess loss of response and mechanisms Share decisions with patients 57

Panel Discussion 58