Selection and use of the non-anti- TNF biological therapies: Who? When? How?

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1 Selection and use of the non-anti- TNF biological therapies: Who? When? How? Asher Kornbluth, MD Clinical Professor of Medicine The Henry D. Janowitz Division of Gastroenterology The Icahn School of Medicine New York, New York

2 Non Anti-TNF Biologics: Who, When, How As first line therapy: UC Crohn s disease As 2 nd line therapy: UC Crohn s disease In combination with a thiopurine

3 Non Anti- TNF Biologics: Is There a Need?

4 ACT 1 Clinical Remission with Infliximab in UC Proportion of Patients (%) *p < p= at Week * 32.0 Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab Rutgeerts P et al. NEJM. 2005;353(23):30-44.

5 ACT 1 Sustained Remission in UC at Week 8, 30 and Proportion of Patients (%) *p = * 20.5* 0 Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab Rutgeerts P et al. NEJM. 2005;353(23):30-44.

6 How effective is treatment with anti-tnf therapy in CD? (infliximab, adalimumab, certolizumab) Within a few weeks of starting treatment of an anti-tnf drug 40% do not have improvement in their symptoms 60% do have improvement in their symptoms Continued anti-tnf or placebo For those who improve, after 1 year of either continued treatment with the anti-tnf medication or placebo, this is what happens: Anti-TNF Placebo How many people were free from symptoms and off of prednisone? 29% 7%

7 Vedolizumab in UC and Crohn s disease: An alpha 4, Beta 7 Anti- Integrin Antibody

8 Artist s rendition

9 Vedolizumab in UC: Study Design Induction Weeks 0 6 Maintenance Week 6 52 Cohort 1 Blinded Induction Randomization n=374 (3:2 VDZ:PBO) NO Placebo n=149 Vedolizumab n=225 NO Placebo n=149 Vedolizumab every 4 wks n=373 Screening and Enrollment (Days -21 to -1) Cohort 1 Enrollment Complete? # Week 6: Achieved primary endpoint? YES Cohort 2* Open Label Induction Treatment n=521 Vedolizumab n=521 VDZ dose = 300 mg IV at weeks 0 and 2 for induction phase # Filled first with no more than 50% prior exposure to anti-tnf *Filled second for patients previously exposed to anti-tnf; Opened for anti-tnf naïve patients after completion of Cohort 1 enrollment Reduction in complete Mayo score of 3 points and 30% from baseline with an accompanying decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore of 1 point) Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved YES Maintenance Randomization (1:1:1) Forced Corticosteroid Tapering Placebo n=126 Vedolizumab every 4 wks n=125 Vedolizumab every 8 wks n=122 Feagan B, et al. DDW2012

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12 Vedolizumab 300 mg Q8 weeks (n=70)

13 VDX ( n=220)dz VDZ VDZ (n=747) VDZ Open label VDZ q 4 weeks (non-itt)

14 Vedolizumab in Crohn s disease in anti-tnf exposed vs Anti- TNF Naïve Patients: Increased Remissions Between Weeks 6 and 10

15 Vedolizumab 300 mg Q8 weeks (n=154) Vedolizumab 300 mg Q8 weeks (n=154)

16 Vedolizumab 300 mg Q8 weeks (n=82)

17 Vedolizumab is Effective for Fistula Closure in CD: Post-Hoc Analysis of GEMINI 2 57 (12%) patients* with 1 draining fistula at study entry By Week 14 28% closure rate (VDZ) vs 11% (placebo) At Week 52 Treatment difference maintained through Week 52 (31% vs 11%) *72% patients had perianal fistulae; 4/57 patients had 3 fistulae. Feagan 17 B et al. Presented at DDW; May 16, Abstract Sa1261.

18 Vedolizumab in UC: Adverse Events Through Week 52 Placebo* N=126 Maintenance ITT Population VDZ Q8Wks N=122 VDZ Q4Wks N=125 Safety Population Placebo* N=275 VDZ N=620 Any adverse event (AE), % Drug-related AEs, % AE resulting in discontinuation, % Serious AEs, % Serious infection AEs, % Deaths, n (%) (<1%) *Includes patients who never received VDZ (n=149) and patients who received 2 VDZ induction doses followed by Pbo maintenance (n=126) Feagan B, et al. DDW2012

19 Infections With Vedolizumab and Placebo in UC and CD Trials Patients treated with Vedolizumab are at increased risk for developing infections

20 Adverse reactions in 3% of Vedolizumab-treated patients and 1% higher than in placebo (UC Trials I & II 3 and CD Trials I & III 3 Vedolizumab b

21 Vedolizumab Safety Issues No baseline TB testing required No baseline measurement of hepatitis B No baseline JC antibody measurement required

22 Should Vedolizumab Be Used With Thiopurines? In vedo trials 11% of patients developed antivedo antibodies on consecutive measurements None of these patients maintained a response No patients on thiopurines developed antibodies No increased toxicity with combination of vedolizumab and thiopurines? Infections Lymphoma HSTCL

23 Ustekinumab, an Anti- Interleukin 12 and 23 Antibody in Crohn s disease

24 Proportion of Subjects (%) Ustekinumab in Crohn s disease, Primary Endpoint: Clinical Response Week 6 CERTIFI Number of Subjects in 100 point Clinical Response a,b at Week 6; Randomized Subjects in Induction Phase p=0.021 p=0.057 p=0.005 p=0.005 N=132 N=131 N=132 N=131 N=394 Ustekinumab

25 Proportion of Subjects (%) Ustekinumab in Crohn s disease, Major Secondary Endpoint: Clinical Remission at Week 22 Number of Subjects in Clinical Remission a,b at Week 22; Subjects Randomized as Responders to UST Induction CERTIFI p= /73 30/72 a Subjects who discontinued study agent due to lack of efficacy, had a prohibited CD-related surgery, or had prohibited concomitant medication changes after Week 8 are considered not to be in clinical remission, regardless of their CDAI score b Subjects who had insufficient data to calculate the CDAI score are considered not to be in clinical remission

26 Open Label Ustekinumab is Effective in CD Refractory to Conventional and Anti-TNF Therapy 26 Wils P et al. Presented at DDW; May 18, Abstract 595.

27 Non- Anti-TNF Biologics: Take Home Messages Still significant unmet need in both UC and Crohn s disease even in the age of effective anti-tnf therapy Vedolizumab effective in UC for induction and maintenance Slow onset of action in Crohn s disease, effective maintenance Excellent safety profile Positioning as first line therapy still in evolution More likely in UC With steroid jump start in Crohn s disease?