Gionata Fiorino VEDOLIZUMAB E IBD. Un nuovo target terapeutico

Transcription

1 Gionata Fiorino VEDOLIZUMAB E IBD Un nuovo target terapeutico

2 Anti cell adhesion molecules Danese S, NEJM 2011

3 6 Steps leukocyte recruitment Fiorino G. et al. 2010

4 Vedolizumab Blocks Fewer Biological Pathways than Natalizumab MadCAM-1 Source: Soler, 2009 and TYSABRI prescribing information. BB-012

5 Vedolizumab Induction and Maintenance Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo Controlled, Double Blind, Multicenter Phase 3 Trial Brian G. Feagan, Paul Rutgeerts, Bruce E. Sands, William Sandborn, Jean Frederic Colombel, Stephen Hanauer, Gert Van Assche, Jeffrey Axler, Hyo Jong Kim, Silvio i Danese, Irving Fox, Catherine Cth Milch, Serap Sankoh, Tim Wyant, Jing Xu, and Asit Parikh

6 Pi Primary and Secondary Outcomes Induction Primary: clinical response at 6 weeks Secondary: clinical remission at 6 weeks; mucosal healing at 6 weeks Maintenance Primary: clinical remission at 52 weeks Secondary: durability of clinical response; durability of clinical remission; mucosal healing at 52 weeks; corticosteroid free remission at 52 weeks Definitions: Clinical response = reduction in complete Mayo score of 3 points and 30% + decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore of 1 point Clinical remission = complete Mayo score of 2 points and no individual subscore >1 point Mucosal healing = Mayo endoscopic subscore of 1 point Durability = endpoint met at both weeks 6 and 52

7 C13006 Induction Phase Week 0 Week 6 10 C13006 and C13007 Study Schema Sh Maintenance Phase Week 6 Week 52 Cohort 1 Blinded induction randomization (2:3) Placebo Vedolizumab Placebo No No VDZ Q 4 wks Screening and enrollment (Days 21 to 1) Cohort 1 Enrollment complete? Yes Week 6: Does patient meet defined criteria for response? Placebo Cohort 2 Open label induction treatment Vedolizumab Yes Maintenance randomization (1:1:1) VDZ Q 4 wks VDZ Q 8 wks a The number of patients within each treatment group is an estimate based upon the expected response rate.

8 Disposition iti of Patients, Pti t ITT Populations 8

9 3 Clinical i l Response, Remission, i Mucosal lh Healing at 6 Weeks P< Induction ITT Population P= % P= % CI: Δ 21.7 Δ 11.5 Δ , , , 25.9

10 Clinical Response and Remission at 6 Weeks: Prior Anti TNFα Failure vs No Anti TNFα Exposure Induction ITT Population Patients with Prior Anti TNF Failure Patients Without Anti TNF Exposure (n = 145) (n = 206) % 95% CI: Δ , 32.9 Δ , 22.8 Δ , 39.9 Δ , 30.2

11 2 Pi Primary and Secondary Outcomes Through h 52 Weeks Maintenance ITT Population *** *** *** *** *** *** *** * % ** ** n: Δ26.1 Δ29.1 Δ32.8 Δ28.5 Δ32.0 Δ36.3 Δ11.8 Δ15.3 Δ17.6 Δ31.4 *P<0.05 **P<0.01 ***P<

12 Clinical Remission, Durable Clinical Response at 52 Weeks: Prior Anti TNFα Failure vs No Anti TNFα Exposure Patients with Prior Anti TNF Failure (n = 121) Maintenance ITT Population Patients Without Anti TNF Exposure (n = 224) % 95% CI Q8Wks: 95% CI Q4Wks: Clinical Remission Durable Clinical Response Clinical Remission Durable Clinical Response Δ31.9 Δ29.7 Δ30.7 Δ26.7 Δ26.8 Δ29.0 Δ38.7 Δ , , , , , , , , 44.6

13 C13006: Mean Vedolizumab Serum Concentrations at Weeks 6, 14, 22, 38 and 46 Observed 4

14 Adverse Events Through h Week k52 Maintenance ITT Population Safety Population Placebo N=126 VDZ Q8Wks N=122 VDZ Q4Wks N=125 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)

15 7 Exposure Adjusted Adverse Events Affecting >5% of VDZ Patients Through Week 52, Safety Population Preferred Term Pbo Rate (N=275) VDZ Rate (N=620) Relative Risk 95% CI Headache , Ulcerative colitis , Nasopharyngitis , Upper respiratory tract infection , Arthralgia , Nausea , Abdominal pain , Anaemia , Fatigue , Cough , Influenza , Any serious AE , Any infection ,

16 Summary and Conclusion Refractory population: approximately one third with anti TNFα failure Compared with placebo: Significantly greater proportion of VDZ treated patients achieved clinical response, remission, and mucosal healing at 6 weeks Significantly greater proportion of VDZ treated patients achieved clinical remission, mucosal healing, and corticosteroid free remission at 52 weeks and durable response and remission (6 and 52 weeks) Similar rates of AEs, serious AEs, and serious infections between VDZ and placebo groups; low rate of sensitization/avas Conclusion: Vdli Vedolizumab bis more effective than placebo as induction and maintenance therapy in patients with moderate to severely active ulcerative colitis (anti TNF exposed and naïve patients) 16

17 Vedolizumab GEMINI CD Efficacy Results C13007 and C13011

18 VedolizumabDevelopment in Crohn s Disease: Key Trial Aspects C13007 Double blind 6 week PLC controlled induction Responders on Vedo randomized to maintenance on 2 dosing regimens of Vedo or PLC Open label induction to enrich maintenance arms 46 week maintenance Limited Anti TNF prior exposure to 50% (not necessarily failure) C13011 Classical double blind 10 week PLC controlled, 2 arms induction Endpoints at weeks 6 and 10 Primarily anti TNF failure patients

19 Pi Primary Endpoints C13007 Simultaneous testing of twoprimary Week 6 endpoints (Hochberg method) Clinical remission (CDAI 150) and Enhanced Clinical Response (CDAI decrease 100 points) at week 6 Test both endpoints simultaneously at p 0.05 If one endpoint negative: test the other endpoint at p The Hochberg approach controls family wise type I error rate at 0.05 (two sided) Remission at Week 6 in TNFα failure patients

20 9 Study Overview: C13007 Total, N=1117 Induction Phase Week 0 Week 6 Maintenance Phase Week 6 Week 52 Cohort 1 Blinded induction randomization Placebo N=148 (2:3) N=370 Vedolizumab N=220 No No Placebo N=148 VDZ Q4 wks N=412 a Screening and enrollment (Days 21 to 1) Cohort 1 Enrollment complete? Week 6: Does patient meet defined d criteria for response? * Yes Cohort 2 Open label induction treatment N=747 Vedolizumab N=747 Yes Maintenance randomization (1:1:1) N=461 Placebo N=153 a VDZ Q4 wks VDZ Q8 wks N=154 a

21 Inclusion Cit Criteriai C13007 Moderately to severely active CD as determined by a CDAI score of 220 to 450 (see Section 15.1) within 7 days prior to the first dose of study drug and 1 of the following: CRP level >2.87 mg/l during the Screening period OR Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each >0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent withcd CD, within 4 months prior to randomization OR Fecal calprotectin >250 µg/g stool during the Screening period in conjunction with CT evidence of fixed stenosis or small bowel stenosis with prestenotic dilation should not be included.) C13011 Moderately to severely active CD as determined by a CDAI score of 220 to 400 (see Section 15.1) within 7 days before enrollment and 1 of the following: CRP level > 2.87 mg/l during the Screening period, OR Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each > 0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous cm of intestine) consistent with CD, within 4 months enterography, MR enterography, contrast enhanced small bowel radiography, or wireless capsule endoscopy revealing Crohn s ulcerations (aphthae not sufficient), within 4 months prior to screening. (Patients with before enrollment, OR Fecal calprotectin >250 µg/g stool during the Screening period in conjunction with computed tomography (CT) enterography, magnetic resonance (MR) enterography, contrast enhanced small bowel radiography, or wireless capsule endoscopy revealing Crohn s ulcerations (aphthae not sufficient), within 4 months before screening. (Patients with evidence of fixed stenosis or small bowel stenosis with prestenotic dilation should not be included.)

22 C13007 Disposition of Patients, ITT Population, Cohort 1 and 2 Randomized d N=368 Placebo N=148 VDZ (I) N=220 VDZ (2) N=747 Completed N=137 (93%) Completed N=199 (90%) Completed N=674 (90%) Discontinued N(%) (7%) (10%) 73 (10%) Adverse Event Lack of Efficacy Consent Withdrawn

23 Results: Primarily Clinical Remission

24 Clinical Remission (95% CI) by Treatment Group at Week 6 ITT C13007 C13011 p=0.02 p=0.048

25 Clinical Remission (95% CI) by Treatment Group at Week 6 Anti TNF Failure and Anti TNF Naive ITT p= C13007 C13011 C13007 C13011 N=70, N=105 N=157, N=158 N=78, N=115 N=50, N=51

26 C13011: Percent of Patients Achieving Clinical Remission Over Time p=0.048 p <0.0001

27 C13007 Vdli Vedolizumab bin Crohn s Disease: Maintenance Results

28 Disposition of Patients, Maintenance Phase, ITT Population Randomized N=461 Placebo N=153 VDZ Q8 Wks N=154 VDZ Q4 Wks N=154 Completed N=64 (42%) Completed N=73 (47%) Completed N=82 (52%) Discontinued Na (%) (58%) (53%) (47%) Adverse Event Lack of Efficacy Other* *Includes protocol violation, withdrawn consent, loss to follow-up, and other reasons.

29 5 Primary and Secondary Outcomes Through 52 Weeks ITT Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0 Δ15.9 Δ12.9 *P<0.05; **P<0.01 CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.

30 8 C13007: Mean Vedolizumab Serum Concentrations at Weeks 6, 14, 22, 38 and 46 Observed

31 CLINICAL POSITIONING OF CURRENT BIOLOGICS UC Anti TNF Anti integrin Induction / maintenance UC / / Steroid refractory fulminant UC Steroid refractory UC (post hoc) Early UC / Late UC (post hoc) Sft Safety in UC Favourable efficacy and/or safety profile Less favourable profile CD, Crohn s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis Danese S, Panés J. Gastroenterology 2014; Epub 14 September (DOI: /j.gastro ). 31

32 CLINICAL POSITIONING OF CURRENT 1 BIOLOGICS UC CD Anti TNF Anti integrin Induction / maintenance UC / / Steroid refractory fulminant UC Steroid refractory UC (post hoc) Early UC / Late UC (post hoc) Safety in UC Induction / maintenance luminal CD / / Perianal fistulising CD Infliximab Early luminal / Late luminal CD (post hoc) / / Favourable efficacy and/or safety profile Less favourable profile CD, Crohn s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis Danese S, Panés J. Gastroenterology 2014; Epub 14 September (DOI: /j.gastro ). 32

33 Grazie

34 CLINICAL POSITIONING OF CURRENT 1 BIOLOGICS OG UC CD Anti TNF Anti integrin Induction / maintenance UC / / Steroid refractory fulminant UC Steroid refractory UC (post hoc) Early UC / Late UC (post hoc) Safety in UC Induction / maintenance luminal lcd / / Perianal fistulising CD Infliximab Early luminal / Late luminal CD (post / / hoc) Favourable efficacy and/or safety profile Less favourable profile CD, Crohn s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis Danese S, Panés J. Gastroenterology 2014; Epub 14 September (DOI: /j.gastro ). 34

35 2 UC: Primary and Secondary Outcomes Through 52 Weeks Maintenance ITT Population *** *** *** *** *** *** *** * % ** ** n: Δ26.1 Δ29.1 Δ32.8 Δ28.5 Δ32.0 Δ36.3 Δ11.8 Δ15.3 Δ17.6 Δ31.4 *P<0.05 **P<0.01 ***P<0.0001

36 3 P< UC Induction ITT Population P= % P= % CI: Δ 21.7 Δ 11.5 Δ , , , 25.9

37 4 C13006: Mean Vedolizumab Serum Concentrations at Weeks 6, 14, 22, 38 and 46 Observed

38 5 CD Primary and Secondary Outcomes Through 52 Weeks ITT Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ15.9 Δ12.9 *P<0.05; **P<0.01 CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved. Δ7.2 Δ2.0

39 6 Steps leukocyte recruitment Fiorino G. et al. 2010

40 7 Exposure Adjusted Adverse Events Affecting>5% of VDZ Patients Through Week 52, Safety Population Preferred Term Pbo Rate (N=275) VDZ Rate (N=620) Relative Risk 95% CI Headache , Ulcerative colitis , Nasopharyngitis , Upper respiratory tract infection , Ath Arthralgia li , Nausea , Abdominal pain , Anaemia , Fatigue , Cough , Influenza , Any serious AE , Any infection ,

41 C13007: Mean Vedolizumab Serum 8 Concentrations ti at Weeks 6, 14, 22, 38 and 46 Observed

42 9 Study Overview: C13007 Total, N=1117 Induction Phase Week 0 Week 6 Maintenance Phase Week 6 Week 52 Cohort 1 Placebo Placebo Blinded N=148 N=148 induction randomization (2:3) N=370 Vedolizumab N=220 VDZ Q4 wks No No N=412 a Screening and enrollment (Days 21 to 1) Cohort 1 Enrollment complete? Yes Week 6: Does patient meet defined criteria for response? * Placebo N=153 a Cohort 2 Open label induction treatment N=747 Vedolizumab N=747 Yes Maintenance randomization (1:1:1) N=461 VDZ Q4 wks VDZ Q8 wks N=154 a

43 C13006 and C13007 Study 10 Schema Induction Phase Maintenance Phase Week 0 Week 6 Week 6 Week 52 Cohort 1 Placebo Placebo Blinded induction randomization (2:3) Vedolizumab No No VDZ Q 4 wks Screening and enrollment (Days 21 to 1) Cohort 1 Enrollment complete? Yes Week 6: Does patient meet defined criteria for response? Placebo Cohort 2 Open label induction treatment Vedolizumab Yes Maintenance randomization (1:1:1) VDZ Q 4 wks VDZ Q 8 wks a The number of patients within each treatment group is an estimate based upon the expected response rate.