Biologic Therapy for Ulcerative Colitis in 2015

Transcription

1 5/6/215 Biologic Therapy for Ulcerative Colitis in 215 John K. Marshall MD MSc FRCPC AGAF Division of Gastroenterology McMaster University Bressler B, Marshall JK, et al. Gastroenterology 215;148: No prior CAG guidelines for non-hospitalized UC Evolving strategies: Disease monitoring Treatment monitoring New therapies Bressler B, Marshall JK, et al. Gastroenterology 215;148:

2 5/6/215 Goals of Care: Inflammatory Bowel Disease Normalize Quality of Life Limit Disability Heal the Mucosa Prevent Surgery Avoid Steroids Relieve Symptoms CAG Ulcerative Colitis Clinical Practice Guidelines The goal of therapy in treating ulcerative colitis is a durable, steroid-free complete* remission. * Both clinical and endoscopic Bressler B, Marshall JK, et al. Gastroenterology 215;148: Defining Outcomes in UC: 215 Symptomatic response: Meaningful improvement in symptoms as judged by both the patient and physician in the absence of remission Not a desirable final outcome but useful to assess early response Symptomatic remission: Normal stool frequency ( 3/day) and no blood in the stool Endoscopic healing: Normal mucosa, vascular blurring, or chronic changes (e.g. inflammatory polyps, scarring) without friability Complete remission: Both symptomatic remission and endoscopic healing Recommended therapeutic target Bressler B, Marshall JK, et al. Gastroenterology 215;148:

3 5/6/215 Comprehensive IBD Assessment Disease Activity Symptoms Objective markers Disease Impact Frequency of hospitalization Need for surgery Ability to work Participation in leisure Response to medications Risk Profile Older age Elevated CRP/ESR Extent of disease Need for steroids Hospitalization Bressler B, Marshall JK, et al. Gastroenterology 215;148: New Therapeutic Target: Leukocyte Trafficking Vedolizumab (anti α4β7) Natalizumab (anti α4) RhuMab-beta7 PF (anti MADCAM) Rutgeerts P. Gastroenterology 29;136: Vedolizumab Mechanism of Action Endothelial cell MAdCAM-1 Vedolizumab: α4 subunit β7 subuni t A humanized monoclonal antibody (mab) that binds exclusively to α4β7 integrin and blocks the interaction of α4β7 with MAdCAM-1, which is primarily localized to blood vessels within intestinal mucosa and gut-associated lymphoid tissue α4 subunit The MOA of vedolizumab works to reduce inflammation in the GI tract β7 subunit Memory T lymphocyte Artist s Rendition Entyvio (vedolizumab) Product Monograph: Takeda Canada Inc. Jan. 25,

4 Patients, % Patients, % 5/6/215 Screening and Enrollment Days 21 to 1 Induction Wks 6 (N=895) Maintenance Wks 6 52 (N=73) Cohort 1 Blinded Induction (n=374) Randomized VDZ:PBO=3:2 Stratified:+/- GC or +/- IS or +/- prior anti-tnfα Cohort 2 Open-label Induction (n=521) PBO n=149 VDZ n=225 Yes VDZ n=521 No Response at week 6? Maintenance (n=373) Randomized 1:1:1 Stratified: by cohort, +/- GC, +/- IS, +/- prior anti-tnfα PBO/PBO n=149 VDZ/PBO n=126 VDZ Q8W n=122 VDZ Q4W* n=125 VDZ Q4W open-label + ITT Population Induction Efficacy ITT Population Maintenance Efficacy GC=glucocorticoid; IS=immunosuppressant; ITT=intent-to-treat; Q4W=every 4 weeks; Q8W=every 8 weeks; TNF=tumour necrosis factor Feagan BG. N Engl J Med 213;369: PBO (n=149) VDZ (n=225) GEMINI I: Vedolizumab UC Week 6 of Induction Phase Primary Outcome p <.1 47 Induction ITT population Secondary Outcomes p < p < Mean % (95% CI) VDZ vs. PBO 5 Clinical Response Clinical Remission Improvement of Endoscopic Appearance of the Mucosa 21.7 (11.6, 31.7) 11.5 (4.7, 18.3) 16.1 (6.4, 25.9) Feagan BG. N Engl J Med 213;369: Week 52 of Maintenance Phase Primary Outcome: Maintenance ITT Population VDZ/PBO (n=126) VDZ Q8W (n=122) Adjusted difference, percentage points (95% CI) VDZ Q8W vs. PBO p < Clinical Remission 26.1 (14.9, 37.2) Feagan BG. N Engl J Med 213;369:

5 Patients, % Patients, % 5/6/215 Week 52 of Maintenance Phase p <.1 Secondary Outcomes: Maintenance ITT Population VDZ/PBO (n=126) VDZ Q8W (n=122) p < p < Durable Clinical Response Improvement of Endoscopic Appearance of Mucosa Durable Clinical Remission Mean % (95% CI) VDZ Q8W vs. PBO 32.8 (2.8, 44.7) 32. (2.3, 43.8) 11.8 (3.1, 2.5) Feagan BG. N Engl J Med 213;369: Week 52 of Maintenance Phase Prior TNFα Antagonist Failure Outcomes at Week Patients With Prior TNFα Antagonist Failure (n=81) PBO VDZ Q8W 5 37 Clinical Remission Maintenance ITT Population 16 Durable Clinical Response Patients With No Prior TNFα Antagonist Therapy (n=151) Results are based on pre-defined exploratory analyses 19 Clinical Remission Durable Clinical Response Feagan BG. N Engl J Med 213;369: Key Safety Results Clinical trial adverse events in GEMINI I Placebo, % (N=149) Vedolizumab, % (N=62) Adverse events 77 8 Serious adverse events Discontinued due to adverse events 11 6 Adverse reactions reported in 5% of vedolizumab-treated patients in GEMINI I Placebo a, n (%) (N=149) Vedolizumab b, n (%) (N=62) Headache 13 (9) 8 (13) Nasopharyngitis 11 (7) 8 (13) Arthralgia 1 (7) 56 (9) Upper respiratory tract infection 8 (5) 52 (8) Cough 7 (5) 36 (6) Abdominal pain 8 (5) 35 (6) Fatigue 5 (3) 33 (5) Influenza 3 (2) 3 (5) a Patients who received placebo during the entire trial b Patients received vedolizumab on Week and 2 and continued to receive vedolizumab every 8 weeks or every 4 weeks for up to 52 weeks 5

6 Geometric Mean Serum Anti-HBsAb Concentration, IU/L Geometric Mean IgG Titer, Thousands (%CV) 5/6/215 Infections Placebo (N=149) Combined Vedolizumab (N=62) Infection rate 31% 42% Serious infection rate 3% 2% Infections consisted primarily of: Nasopharyngitis, URTI, influenza Most patients did not require discontinuation of vedolizumab No significant increase in serious infections over time Exposure-adjusted relative risk for serious infections with vedolizumab vs. placebo was.56 (95% CI:.22, 1.44) Vedolizumab has no known systemic immunosuppressive activity No cases of PML reported in vedolizumab clinical trials Entyvio (vedolizumab) Product Monograph: Takeda Canada Inc. Jan.25, 215 Feagan BG. N Engl J Med 213;369: & Supplementary Appendix Infusion-Related Reactions (IRR) Rate of IRRs Vedolizumab 5%, placebo <1% Most frequent IRRs in patients treated with vedolizumab: arthralgia, fatigue, headache, pruritus, tinnitus, urticaria, vomiting, infusion site irritation Majority of IRRs Mild or moderate intensity Within first 2 hours Generally resolved with no or minimal intervention <1% of IRRs resulted in discontinuation of study treatment Entyvio (vedolizumab) Product Monograph: Takeda Canada Inc. Jan. 25, 215. VDZ Immune Response Study: Response to Systemic and Oral Vaccine Concentration of Anti-HBsAb Over Time (ITT) Serum Anti-Cholera IgG Titer Over Time 15 PBO 14 VDZ Seroconversion (HBsAb 1 IU/L) Days Days Wyant T. Gut 215;64:

7 5/6/215 Toronto Consensus Guidelines: Vedolizumab for Ulcerative Colitis In patients with moderate-to-severe active UC who fail corticosteroids or thiopurines, or anti-tnf therapies, we recommend vedolizumab to induce complete corticosteroid-free remission. GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree 7%; agree 26%; disagree 4%. In patients with primary failure to an anti-tnf therapy, we recommend switching to vedolizumab over switching to another anti-tnf therapy to induce complete corticosteroid-free remission. GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree 48%; agree 43%; uncertain 9%. In patients with secondary failure to an anti-tnf therapy, we recommend switching to another anti-tnf therapy or vedolizumab based on TDM results to induce complete corticosteroid-free remission. GRADE: Strong recommendation, very low-quality evidence. Vote: strongly agree 43%; agree 57%. Bressler B, Marshall JK, et al. Gastroenterology 215;148: Management of Moderate-Severe UC: The Toronto Consensus Bressler B, Marshall JK, et al. Gastroenterology 215;148: Management of Steroid-Refractory UC: The Toronto Consensus Bressler B, Marshall JK, et al. Gastroenterology 215;148:

8 5/6/215 Summary CAG Consensus Guidelines for Ambulatory UC Goals of care (steroid-free complete remission) Comprehensive approach to patient evaluation Treatment algorithms role(s) of biologic therapy Two classes of biologic therapy for UC: Anti-TNFα therapies: Adalimumab, Golimumab, Infliximab Anti-integrin therapies: Vedolizumab Unanswered questions: Real-world experience Sequencing of biologics Combination therapy Therapeutic drug monitoring Thank You 8

9 5/6/215 Clinical Response and Remission by Week 6 VDZ Trough Quartile Feagan BG. N Engl J Med 213;369: Clinical Remission by Week 52 VDZ Trough Quartile Feagan BG. N Engl J Med 213;369: