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
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
Non Anti- TNF Biologics: Is There a Need?
ACT 1 Clinical Remission with Infliximab in UC Proportion of Patients (%) 100 90 80 70 60 50 40 30 20 10 0 *p < 0.001 p=0.002 14.9 at Week 8 38.8* 32.0 Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab Rutgeerts P et al. NEJM. 2005;353(23):30-44.
ACT 1 Sustained Remission in UC at Week 8, 30 and 54 100 Proportion of Patients (%) 90 80 70 60 50 40 30 20 10 *p = 0.002 6.6 19.8 * 20.5* 0 Placebo 5 mg/kg Infliximab 10 mg/kg Infliximab Rutgeerts P et al. NEJM. 2005;353(23):30-44.
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%
Vedolizumab in UC and Crohn s disease: An alpha 4, Beta 7 Anti- Integrin Antibody
Artist s rendition
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
Vedolizumab 300 mg Q8 weeks (n=70)
VDX ( n=220)dz VDZ VDZ (n=747) VDZ Open label VDZ q 4 weeks (non-itt)
Vedolizumab in Crohn s disease in anti-tnf exposed vs Anti- TNF Naïve Patients: Increased Remissions Between Weeks 6 and 10
Vedolizumab 300 mg Q8 weeks (n=154) Vedolizumab 300 mg Q8 weeks (n=154)
Vedolizumab 300 mg Q8 weeks (n=82)
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, 2015. Abstract Sa1261.
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), % 84 82 81 80 80 Drug-related AEs, % 32 30 30 28 32 AE resulting in discontinuation, % 12 6 5 11 6 Serious AEs, % 16 8 9 13 12 Serious infection AEs, % 3 2 2 3 2 Deaths, n (%) 0 0 0 0 1 (<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
Infections With Vedolizumab and Placebo in UC and CD Trials Patients treated with Vedolizumab are at increased risk for developing infections
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
Vedolizumab Safety Issues No baseline TB testing required No baseline measurement of hepatitis B No baseline JC antibody measurement required
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
Ustekinumab, an Anti- Interleukin 12 and 23 Antibody in Crohn s disease
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
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=0.029 20/73 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
Open Label Ustekinumab is Effective in CD Refractory to Conventional and Anti-TNF Therapy 26 Wils P et al. Presented at DDW; May 18, 2015. Abstract 595.
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?