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2 Join the conversation at #IBDNEWSDDW 2

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5 Disclosures All faculty, staff, and reviewers involved in the planning, review, or presentation of continuing education activities sponsored/provided by Purdue University College of Pharmacy are required to disclose to the audience any relevant commercial financial affiliations related to the content of the presentation or enduring material. Full disclosure of all commercial relationships must be made in writing to the audience prior to the activity. All additional planning committee members, staff, and reviewers of the Gi Health Foundation and Purdue University College of Pharmacy have no relationships to disclose. Planning Committee Member Julie Messick No Relevant Relationships Faculty All faculty disclosures can be found in your meeting guide. 5

6 This program is supported by educational grants from American Regent and Janssen Biotech, Inc. 6

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8 Welcome and Introduction Stephen B. Hanauer, MD 8

9 DDW IBD Therapeutics News Biosimilars Therapeutic drug monitoring New agents Ustekinumab, tofacitinib, ozanimod, anti-il 23, anti-mmp-9 Fecal transplant 9

10 Case Presentation: Mild to Moderate IBD Gary R. Lichtenstein, MD 10

11 Patient Case HISTORY MEDICATION LABS PROGRESS NOTES OTHER HPI PMH 32-year-old woman with a longstanding history of GI issues Abdominal pain dating back to late teens (17 years old) when she presented for emergent appendectomy; c/o irregular bowel habits since then Symptoms largely resolved during pregnancy 2 years ago Postpartum, developed watery diarrhea, 3-4 times daily associated with periumbilical abdominal pain postprandially Nonerosive GERD Prior perianal fistula age 15 yrs with no recurrence S/P fistulotomy FH No family history of IBD SH Smokes 1 ppd cigarettes x 5 years 11

12 Patient Case HISTORY MEDICATION LABS PROGRESS NOTES OTHER Lansoprazole 30 mg once daily Ibuprofen prn for dysmenorrhea 12

13 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Ferritin 20 ng/ml CMP normal except albumin 3.8 g/dl CRP 3 mg/l (normal) Fecal calprotectin 338 mcg/g Vitamin B ng/ml (normal) Vitamin D 15 ng/ml (low) 10.0/mm 3 11 g/dl 500 x10 3 /μl 33% 13

14 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Colonoscopic Findings Small AVM in the sigmoid colon Otherwise normal examination 1 cm of terminal ileum visualized; normal in appearance Biopsies in colon and ileum taken No evidence of acute inflammation or ulceration No crypt distortion No granulomas 14

15 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER MRI Enterography Diffuse abnormality of the distal and terminal ileum with wall thickening and narrowing of the lumen 15

16 Audience Response Question: What would you recommend next for this 32 yo female with inflammatory ileal activity on MRE, abnormal labs, but unremarkable colonoscopy? A. Retrograde Double Balloon Enteroscopy with biopsy B. Start anti-tnf therapy C. Oral steroid tapering and start immunomodulators D. Wireless capsule endoscopy E. Start anti-tnf + Immunomodulator therapy 16

17 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Retrograde double balloon enteroscopy Non-caseating granulomas are present and histology consistent with Crohn s disease 17

18 Patient Follow-Up: Initial Therapy PROGRESS NOTES HISTORY MEDICATION LABS OTHER Due to symptoms, MRE findings, and elevated calprotectin, and negative stool studies, patient started on oral EC budesonide 9 mg x 8 weeks Symptom relief within a week and rapid resolution of diarrhea Patient started on oral FeSO mg QD 18

19 Understanding Iron Deficiency in Crohn s Disease Gary R. Lichtenstein, MD 19

20 Causes of Anemia in Inflammatory Bowel Disease (IBD) Common 1 Occasional 1 Iron deficiency Anemia of chronic disease Vitamin B 12 deficiency Folate deficiency Drug-induced (sulfasalazine, thiopurines) Most common form of anemia in IBD 1,2 Commonly caused by intestinal blood loss, malnutrition, and impaired iron uptake 1,2 Rare 1 Hemolysis Myelodysplastic syndrome Aplasia (often drug-induced) Innate hemoglobinopathies or disorders of erythropoiesis 1. Gasche C, et al. Inflamm Bowel Dis. 2007;13: Kulnigg S, Gasche C. Aliment Pharmacol Ther. 2006;24:

21 Normal Distribution of Iron in Adults Andrews NC. N Engl J Med. 1999;341:

22 Hepcidin is a Critical Regulator of Iron Homeostasis and is Increased in Inflammation 25-aa peptide Principal regulator of iron absorption and distribution to tissues Synthesized predominantly in hepatocytes Binds to ferroportin, causes internalization and degradation Hepcidin increased in inflammatory states Nemeth E, Ganz T. Acta Haematol. 2009;122:

23 Hepcidin: The Master Regulator of Iron Absorption Fe 2+ Ferroportin Nemeth E, Ganz T. Acta Haematol. 2009;122:

24 Hepcidin: The Master Regulator of Iron Absorption Ferroportin Hepcidin Nemeth E, Ganz T. Acta Haematol. 2009;122:

25 Hepcidin: The Master Regulator of Iron Absorption Hepcidin Iron export through ferroportin Hepcidin Ferroportin degradation: Iron locked in cell Ferroportin Hepcidin Nemeth E, Ganz T. Acta Haematol. 2009;122:

26 Hepcidin Levels Correlate With Presence of IBD and Disease Activity Patients with IBD and healthy controls (N=202) Median hepcidin levels higher in UC and CD patients vs healthy controls (P<0.0001) Serum hepcidin positively correlated with disease activity in UC (r=0.36, P=0.009) and C-reactive protein [CRP (r=0.29, P=0.004)] Serum hepcidin negatively correlated with ferritin (P=0.0008) Oustamanolakis P et al. Eur J Gastroenterol Hepatol. 2011;23:

27 Laboratory Workup of Anemia Initial evaluation CBC with differential Serum ferritin Transferrin saturation CRP Creatinine Reticulocyte count If cause of anemia not identified Vitamin B 12 Methylmalonic acid Folic acid Haptoglobin Lactate dehydrogenase Bone marrow aspirate CBC=Complete blood count; Hb=hemoglobin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume Gasche C, et al. Inflamm Bowel Dis. 2007;13:

28 Normal Distribution of Iron in Adults Andrews NC. N Engl J Med. 1999;341:

29 Oral Iron in IBD Considered standard because of established safety profile, lower cost, ease of administration May be useful in patients with inactive IBD Most widely used oral iron supplements contain ferrous iron Optimal dose not established Goldberg N. Clin Exp Gastroenterol. 2013;6:

30 Limitations of Oral Iron A significant fraction of ingested iron remains unabsorbed 1 Intolerance due to GI side effects results in discontinuation of up to 20% of patients 2 Nausea Vomiting Diarrhea Abdominal pain Constipation Melena-like stools 1.Goldberg N. Clin Exp Gastroenterol. 2013;6:61-70; 2. Lindgren et al. Scand J Gastroenterol. 2009;44:

31 Personalizing Treatment for IBD: Evolving Treatment Paradigms Maria T. Abreu, MD 31

32 Patient Follow-Up: 2 Weeks Later PROGRESS NOTES HISTORY MEDICATION LABS OTHER Worsening postprandial abdominal pain noted, no fevers Stopped smoking cigarettes Receiving Vitamin D 50,000 units /week PE: Fullness in RLQ mild tenderness, no guarding 32

33 Patient Follow-up: 2 Weeks Later HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER 11.0/mm 3 11 g/dl 623 x10 3 /μl 30% Ferritin 25 ng/ml (increased from previous value) CMP normal except albumin 3.1 g/dl CRP 12 mg/l Fecal calprotectin 423 μ/g 33

34 Discussion Question What would you recommend for treatment at this time? A. Admit patient for parenteral steroids B. Start anti-tnf therapy C. Oral steroid tapering and start immunomodulators D. Oral steroid tapering and start immunomodulators + anti-tnf E. Start anti-tnf + immunomodulator therapy 34

35 Impact of Therapy Will Depend on Degree of Structural Damage and Speed of Progression Cumulative probability, % Inflammatory Penetrating Stricturing Patients at risk Months n= Cosnes J et al. Inflamm Bowel Dis. 2002;8:

36 Treating IBD Beyond Symptoms: Rationale for a Clear Management Strategy Personalized management for IBD will depend on Disease severity at presentation Clinical and biologic prognostic factors Achievement of clinical and biologic remission Maintenance of clinical and biologic remission Patient adherence Therapeutic monitoring Pharmacoeconomics 36

37 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:

38 AGA Clinical Pathway for Crohn s Disease: Initial Treatment Low-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 Moderate/high-risk patient 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:

39 Patients (%) Clinical Remission in CD: Net Remission at 6 Months with TNF Antagonists Infliximab Adalimumab Certolizumab pegol Open-label induction week 2 ACCENT I 1 Net remission Week Week 30 remission Open-label induction week 4 CHARM Week 26 remission Net remission Week Open-label induction week 4 PRECiSE Week 26 remission Net remission Week PRECiSE 1 4 Net remission Week Placebo Active treatment 1. Hanauer SB et al. Lancet. 2002;359: ; 2. Colombel JF et al. Gastroenterology. 2007;132:52-62; 3. Schreiber S et al. N Engl J Med. 2007;357: ; 4. Sandborn WJ et al. N Engl J Med. 2007;357:

40 Is A Treat-to-Target Approach Feasible in IBD? Symptoms QoL Labs CRP Calprotectin? Mucosal healing Hospitalizations Surgery Biologic (Deep remission) Histologic remission Disease modification 40

41 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:

42 Improving Initial Response to Biologics 42

43 Remission at 1 year (%) The Earlier the Intervention in Crohn s Disease the More Effective the Therapy 80 SUTD REACH 2 CHARM 6 subanalysis SONIC 3 CHARM 4 ACCENT I 5 20 Durations shown are median values D Haens G, et al. Lancet 2008;371: Hyams J, et al. Gastroenterology 2007;132(3): Colombel JF, et al. N Engl J Med 2010;362; Disease duration (years) 4. Colombel JF, et al. Gastroenterology 2007;132: Hanauer S, et al. Lancet 2002;359: Schreiber S, et al. Gastroenterol 2007;132(4 Suppl 2):A

44 Early Aggressive Biologic Therapy versus Conventional Management of Crohn s Disease Patients with no ulcers, % Complete ulcer disappearance at Week P= D Haens G et al. Lancet. 2008;371(9613): n=19/26 Top-down Therapy (IFX + AZA) n=7/23 Step-up therapy 44

45 Patients (%) Mucosal Healing After Therapy Predicts Improved Outcomes in Crohn s Disease 100 SES 0 SES Remission off steroids 18.2 Remission off steroids and anti-tnf SES=Simple Endoscopic Score. Baert F et al. Gastroenterology. 2010;138:

46 Patients (%) Combination Therapy in CD: The SONIC Study Corticosteroid-free Clinical Remission at Week P=.006 P< P= /170 75/169 96/169 Azathioprine Infliximab Azathioprine + Infliximab 1. Colombel JF et al. N Engl J Med. 2010;362: Sandborn WJ. Gastroenterology. 2014;147:

47 Patients (%) Patients undergoing MAS (%) 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 No severe endoscopic lesions Severe endoscopic lesions 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: Schnitzler F et al. Inflamm Bowel Dis. 2009;15:

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49 Case Presentation: Moderate to Severe IBD David G. Binion, MD 49

50 Patient Case 2 HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER 23-year-old male HPI 8 weeks of progressive abdominal pain and weight loss Physical BMI 22 mg/kg 2 T 100.6º Pulse 105 Tender with fullness in RLQ Family/Social History No family history of IBD Smokes 1 ppd cigarettes 50

51 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER 10.0/mm 3 9 g/dl 30% 520 x10 3 /μl 23-year-old male Ferritin 15 ng/ml CMP normal except albumin 3.1 g/dl CRP 25 mg/l (high) Vitamin B 12 normal Vitamin D low 51

52 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Colonoscopic Findings Focal area of ulceration in sigmoid. Deep ulcerations in cecum with deformed and ulcerated ileocecal valve MRE Edematous ileum with mesenteric stranding and sinus tract toward sigmoid colon 52

53 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:

54 Biomarkers Correlate Well With Endoscopic But Not Clinical Activity Indices IL-6 Calprotectin Lactoferrin CDAI SES-CD hscrp NS + IL NS + Calprotectin Lactoferrin + + CDAI NS + indicates significant correlation coefficients (P<.05); NS, nonsignificant 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:

55 Managing Iron Deficiency in Moderate to Severe Crohn s Disease David G. Binion, MD 55

56 Prevalence and Characteristics of Anemia in a Large US Inflammatory Bowel Disease Cohort: A 5-Year Prospective Study Prevalence (%) 5-Year Prevalence of Anemia Anemia* Severe anemia Overall IBD (N=1826) CD (n=1,077) UC (n=744) *Hb <13 g/dl in men, Hb <12 g/dl in nonpregnant women; Hb 10 g/dl Koutroubakis IE, et al. J Clin Gastroenterol Oct 17 [Epub ahead of print]. 56

57 Anemia Duration May Serve as a Biomarker for IBD Severity Number P< Phone calls ED visits GI department visits No anemia (n=137) Healthcare Utilization P< P< Anemia for 1 2 years (n=140) 12 P< Hospitalizations Anemia for 3 years (n=133) Koutroubakis IE, et al. Clin Gastroenterol Hepatol. 2015;13(10):

58 Why IV Iron in IBD? Active disease results in malabsorption of iron GI intolerance may be magnified in patients with IBD Significant anemia may require more potent treatment 58

59 Intravenous Iron Products: Approved Indications in the United States Iron dextran Sodium ferric gluconate complex Iron sucrose Ferumoxytol Ferric carboxymaltose Treatment of patients with iron deficiency when oral administration is unsatisfactory or impossible Treatment of iron deficiency anemia in adult and in pediatrics ( 6 years of age) with CKD receiving hemodialysis who are receiving supplemental epoetin therapy Treatment of iron deficiency anemia in adult and pediatric patients 2 years of age or older with CKD Treatment of iron deficiency anemia in adult patients with CKD Treatment of IDA in adults Who have intolerance to oral iron or have had unsatisfactory response to oral iron Who have non-dialysis dependent CKD 1. Venofer (iron sucrose injection) (prescribing information]. American Regent, Inc., Shirley, NY; Dexferrum (iron dextran injection) [prescribing information]. American Regent, Inc., Shirley, NY; Injectafer (ferric carboxymaltose injection) [prescribing information]. American Regent, Inc., Shirley, NY; Feraheme (ferumoxytol injection) [prescribing information]. AMAG Pharmaceuticals, Inc., Waltham, MA;

60 Intravenous Iron Products: Approved Indications in the United States Iron dextran Sodium ferric gluconate complex Iron sucrose Ferumoxytol Ferric carboxymaltose Treatment of patients with iron deficiency when oral administration is unsatisfactory or impossible Treatment of iron deficiency anemia in adult and in pediatrics ( 6 years of age) with CKD receiving hemodialysis who are receiving supplemental epoetin therapy Treatment of iron deficiency anemia in adult and pediatric patients 2 years of age or older with CKD Treatment of iron deficiency anemia in adult patients with CKD Treatment of IDA in adults Who have intolerance to oral iron or have had unsatisfactory response to oral iron Who have non-dialysis dependent CKD 1. Venofer (iron sucrose injection) (prescribing information]. American Regent, Inc., Shirley, NY; Dexferrum (iron dextran injection) [prescribing information]. American Regent, Inc., Shirley, NY; Injectafer (ferric carboxymaltose injection) [prescribing information]. American Regent, Inc., Shirley, NY; Feraheme (ferumoxytol injection) [prescribing information]. AMAG Pharmaceuticals, Inc., Waltham, MA;

61 Responders, % Response to Intravenous vs Oral Iron P= % Ferric carboxymaltose (n=136) Oral iron (n=60) P= % Week 1.5% vs 7.9% AE-related discontinuation Kulnigg et al. Am J Gastroenterol 2008;103:

62 Potential Algorithm for Diagnosing and Managing IDA in IBD Hb <12 g/dl (women) or <13 g/dl (men) Serum ferritin <100 ng/ml Hb >10 g/dl CRP normal CRP elevated Hb <10 g/dl Oral Iron 30 to 50 mg per day Intolerance Noncompliance Inefficacy IV iron ( mg) Serum ferritin <100 ng/ml IV iron ( mg) IV Iron (500 mg) Adapted from Stein J, et al. Nat Rev Gastroenterol Hepatol. 2010;7:

63 Summary: IV Iron IV iron may be an appropriate first-line therapy in many patients with GI disease, including those with IBD More rapid and complete repletion of iron stores Avoids gastrointestinal side effects of oral iron supplementation Two IV iron formulations are approved for general treatment of IDA in the United States Iron dextran Ferric carboxymaltose Adverse events with IV iron can be managed 63

64 Managing Loss of Response to Anti-TNF Therapies Edward V. Loftus, Jr., MD 64

65 Patient Follow-Up: First 6 Months of Treatment HISTORY MEDICATION LABS OTHER Induction prednisone attempted but flare with tapering He is started on combination infliximab and azathioprine but develops nausea and vomiting 3 weeks after starting azathioprine He improves after stopping azathioprine, achieves clinical remission, and CRP normalizes Treated with 2 infusions of ferric carboxymaltose and hemoglobin normalizes After 6 months of therapy he begins to develop recurrence of abdominal pain and night sweats CRP is 8 mg/l (high) PROGRESS NOTES 65

66 Loss of-response Rate Loss of Response to Infliximab in Crohn s Disease: Health-Care Claims Data 100% 80% 1 year, ~50% 2 years, 77% Health-care claims database ( ) Selected patients with CD receiving infliximab maintenance therapy with an initial response 60% 40% 20% Loss of response Loss of response inferred from: Upward dose adjustment New drug therapy for CD CD-related emergency room or inpatient visits 0% Wu EQ et al. Value Health. 2008;11: Days from Index Date Annual total health-care and CD-related costs estimated and adjusted for inflation to 2005 US dollars 66

67 How to Maintain Remission with Biologics 67

68 Concentration (µg/ml) Therapeutic Windows with Biologics Peak Trough Time (weeks) 68

69 Implications of Low Trough Levels Disease recurs No longer maintenance but re-treatment Development of anti-drug antibodies Eventual loss of response 69

70 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: Increases drug clearance Anti-drug antibodies Low serum albumin High baseline CRP High baseline TNF concentration High body mass index Male sex 70

71 Patients (%) Detectable Levels of Infliximab Are Associated with Better Outcomes Clinical Outcomes By Infliximab Trough Level 6 P< Undetectable P< µg/ml P<0.001 Clinical remission Normal CRP Endoscopic improvement 88 Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:

72 Post-induction Infliximab Levels Predict Clinical Outcome at Week 54 Patients, % ACCENT I P= Week 14 serum IFX level <3.5 µg/ml 3.5 µg/ml Sustained response (n=96) No sustained response (n=51) Cornillie F et al. Gut. 2014;63:

73 Cumulative probability of sustaining in clinical response 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 P-value (logrank): <0.001 IFX level >3 μg/ml <3 μg/ml Time from IFX start (months) Bortlik M, et al. J Crohns Colitis. 2013;7:

74 Probability on Infliximab 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 P=.0006 Optimized Not Optimized Vaughn B et al. Inflamm Bowel Dis. 2014;20: Weeks 74

75 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:

76 Complete/partial response, % Complete/partial response, % Increasing Dose of Infliximab in the Presence of ATI Formation is Inferior to Changing Anti-TNF Complete/Partial Response Patients with detectable ATI (n=35) Patients with subtherapeutic IFX concentrations (n=69) P<0.004 P< n=11/12 n=1/6 0 n=2/6 n=25/ Anti-TNF changed Infliximab increased Afif W et al. Am J Gastroenterol. 2010;105:

77 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Infliximab trough level is undetectable Anti-drug antibodies are positive 10.0/mm g/dl 33% 390 x10 3 /μl What would you do next? 77

78 The First Biologic is the Best Opportunity 78

79 Patients in remission, % 4-Week Remission Rate with Adalimumab By Prior Anti-TNF Exposure Clinical Remission (CDAI 150) at Week Placebo Adalimumab 160 mg (Wk 0)/ 80 mg (Wk 2) 12 P< Anti-TNF-naïve (CLASSIC-I) 7 P< n=74 n=76 n=166 n=159 Infliximab failure/intolerance (GAIN) Adapted from Accessed 0708/09. Sandborn WJ et al. Ann Intern Med. 2007;146(12):

80 Patients, % Patients, % Vedolizumab in Crohn s Disease: Clinical Remission at Week 6 and Clinical Remission at Week Clinical Remission at Week P= P<.001 P= Overall population Failure Naïve TNF antagonist experience 0 Overall population Failure Naïve TNF antagonist experience Placebo Vedolizumab Q8W Sands BE et al. Gastroenterology. 2014;147:

81 Concentration (mcg/ml) Concentration (mcg/ml) Effect of Concomitant Azathioprine or Methotrexate on Anti-drug Antibodies ATI IFX levels Patient 1 Patient Start MTX Start AZA Weeks Weeks Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:

82 Patient One-Year Follow-Up PROGRESS NOTES HISTORY MEDICATION LABS OTHER He was treated with adalimumab induction and maintenance and methotrexate 15 mg orally After 3 months, he has worsening pain, fever and diarrhea C. difficile is negative What would you do next? Colonoscopy demonstrated persistent deep ulcers in the sigmoid, cecum and terminal ileum Adalimumab levels were 9 µg/ml and there were no anti-drug antibodies 82

83 Unmet Needs in IBD: Novel Therapeutics 83

84 The IBD Pipeline IL-Inhibitors Ustekinumab Multiple anti-il-23 inhibitors IL-6 inhibitors Anti-adhesion molecules Alicaforsen Anti-MAdCAM Etrolizumab Downstream signaling blockade Tofacitinib Ozanimod Mongersen MMP-9 inhibitor GS-5745 Fecal transplants MMP, matrix metalloproteinase. Note: Several of these agents are currently approved for other indications. Adapted from Amiot A, Peyrin-Biroulet L. Ther Adv Gastroenterol. 2015;8(2):

85 Ustekinumab for Crohn s Disease Ustekinumab is a fully human IgG1k monoclonal antibody that binds the p40 subunit of IL-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 No IL-12 or IL-23 intracellular signal Approved for moderate to severe psoriasis and psoriatic arthritis Leung Y and Pannacione R. Gastroenterol Clin N Am. 2014;43(3):

86 Patients, % Patients, % Ustekinumab in CD: Clinical Response at Week 6 ( 100 point CDAI Reduction) UNITI-1 1 Patients Failing Anti-TNF Therapy 21.5 P=0.002 P= UNITI-2 2 Anti-TNF Naïve Patients P<0.001 P<0.001 P< n=247 n=245 n=249 0 n=209 n=209 n=209 n=418 Placebo 130 mg ~6 mg/kg* 0 Placebo 130 mg ~6 mg/kg* Combined Ustekinumab 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. 1. Sandborn WJ, et al. CCFA Feagan BG et al. UEGW

87 Patients, % Ustekinumab Maintenance IM-UNITI Placebo (n=131) Ustenkinumab 90 mg Q12W (n=129) Ustekinumab 90 mg Q8W (n=128) P<0.01 P< P<0.05 P< P<0.01 * * * 20 0 Clinical remission (CDAI <150) *Nominally significant Sandborn WJ, et al. DDW Clinical response ( 100-point reduction in CDIA or being in clinical remission) Steroid-free remission Sustained clinical remission (clinical remission at Week 36, 40, and 44) 87

88 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 or malignancies 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 SAE, serious adverse event. Feagan B et al. UEGW

89 Patients, % Mongersen (GED-0301): Phase 2 Trial in Steroid-dependent or -resistant CD Clinical Remission at Week 12 P<0.001 P< P<0.001 P< Placebo (n=42) 10 mg/day (n=41) 40 mg/day (n=40) 160 mg/day (n=43) Monteleone G et al. N Engl J Med. 2015;372: Mongersen 89

90 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 90

91 Thank you to our educational supporters American Regent and Janssen Biotech, Inc. 91