Alexandra James

Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists

BACKGROUND & AIMS: The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin &agr;4&bgr;7, were demonstrated in multicenter, phase 3, randomized, placebo‐controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohns disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti–tumor necrosis factor‐&agr; (TNF) antagonists. METHODS: We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations. RESULTS: At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4–40.4; RR, 2.0; 95% CI, 1.3–3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8–33.5; RR, 1.9; 95% CI, 1.1–3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9–41.1; RR, 2.5; 95% CI, 1.5–4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8–46.1; RR, 6.6; 95% CI, 1.7–26.5). No differences in adverse events were observed among groups. CONCLUSIONS: Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy.

Background: Vedolizumab is a gut-selective &agr;4&bgr;7 integrin antagonist for the treatment of moderately to severely active Crohns disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-&agr;) antagonist therapy (TNF-naïve) or who had discontinued TNF-&agr; antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). Methods: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ⩽150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. Results: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-&agr; antagonist failure or the number of prior TNF-&agr; antagonists failed. Safety profiles were similar in both subpopulations. Conclusions: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-&agr; antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.

Effects of vedolizumab on health-related quality of life in patients with ulcerative colitis: results from the randomised GEMINI 1 trial

Health‐related quality of life (HRQL) is often diminished in patients with ulcerative colitis.

Sustained Clinical Remission With Vedolizumab in Patients With Moderate-to-Severe Ulcerative Colitis

Abstract Background Sustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6. Methods Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52. Results The proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage-point difference (∆) 12.6%; 95% confidence interval [CI], 5.2–20.0]; RBS: 47.3% vs 28.9% [∆18.4%; 95% CI, 10.1–26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab-treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; ∆39.8%; 95% CI, 22.7–56.9; RBS: 56.7% vs 20.9%; ∆35.7%; 95% CI, 22.3–49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist-naive and antagonist-failure patients. Conclusion Compared with placebo, 35%–40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.

PTH-052 Efficacy of Vedolizumab with and Without Continued Immunosuppressant Use in Gemini 1 and Gemini 2

Introduction In GEMINI 1 and GEMINI 2, vedolizumab (VDZ) was safe and effective in patients (pts) with ulcerative colitis (UC) or Crohn’s disease (CD), respectively, on stable doses of immunosuppressants (IS).1,2 The effect of discontinuing IS in pts who responded to VDZ induction therapy in these studies has not been characterised. Methods Pts who responded to VDZ at week (wk) 6 were re-randomised to placebo (VDZ/PBO) or VDZ every 4 or 8 wks (VDZ/VDZ Q4W or Q8W) for 46 wks. At United States (US) sites, re-randomised pts discontinued IS use at wk 6. At non-US sites, pts could continue IS use. Efficacy, VDZ serum concentration, and immunogenicity data (via an enzyme-linked immunosorbent assay) were evaluated post hoc in pts with baseline IS use stratified by region. Results At wk 52, rates of clinical remission and response (Table), mucosal healing (UC), durable clinical remission, and corticosteroid-free remission were numerically higher with VDZ, mostly irrespective of IS use. The US and non-US sites had similar numbers of patients who were positive for anti-VDZ antibodies during VD maintenance therapy (Table). Mean trough concentrations were similar between US and non- US pts at wk 46.Abstract PTH-052 Table 1 Maintenance VDZ with and without continued IS use UC CD US (Discontinued IS) Non-US (Continued IS) US (Discontinued IS) Non-US (Continued IS) VDZ/PBO n = 10; VDZ/VDZ n = 18 VDZ/PBO n = 41; VDZ/VDZ n = 70 VDZ/PBO n = 5; VDZ/VDZ n = 9 VDZ/PBO n  =   44; VDZ/VDZ n = 94 Efficacy endpoints % Difference from PBO (95% CI) at wk 52 Clinical remissiona 28.9 (-10.5, 63.3) 25.2 (8.0, 42.4) 4.4 (-49.6, 54.7) 17.3 (0.4, 34.1) Clinical responseb 18.9 (-20.8, 54.7) 35.0 (17.1, 52.9) 15.6 (-39.9, 63.8) 17.7 (0.2, 35.3) Immunogenicity No. of pts with ≥1 positive sample VDZ/PBO 3 1 1 4 VDZ/VDZ 1 2 0 0 a UC: complete Mayo score of ≤2 and no individual subscore > 1. CD: CD Activity Index (CDAI) score ≤150. b UC: durable clinical response is a reduction in complete Mayo score of ≥3 and ≥30% from wk 0 with a decrease in rectal bleeding subscore (RBS) of ≥1 or absolute RBS of ≤1 at wks 6 and 52. CD: enhanced clinical response is a ≥100-point reduction in CDAI score from wk 0. Conclusion Discontinuing IS did not appear to substantially affect efficacy of VDZ maintenance therapy. Interpretation of these post hoc analyses is limited by potential IS discontinuation in non-US pts and the relatively small sample sizes. References 1 Feagan BG, et al. N Engl J Med. 2013;369:699-710; NCT00783718. 2 Sandborn WJ, et al. N Engl J Med. 2013;369:711-721; NCT00783692. Disclosure of Interest B. Feagan Grant/research support from: Abbott/AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma, Consultant for: Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Warner-Chilcott, Wyeth, Zealand, Zyngenia, Speaker bureau with: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Conflict with: Directorship as CEO and Senior Scientific Director, Robarts Clinical Trials Inc, Western University, London, Ontario, C. Siegel Grant/research support from: AbbVie, Janssen, Salix, Takeda, UCB, Consultant for: AbbVie, Amgen, Janssen, Lilly, Pfizer, Takeda, UCB, Speaker bureau with: AbbVie, Janssen, Takeda, G. Melmed Grant/research support from: Prometheus Labs, Consultant for: AbbVie, Celgene, Genentech, Given Imaging, Janssen, Luitpold, Takeda, UCB, K. Isaacs Grant/research support from: AbbVie, Given Imaging, Janssen, Luitpold, Pfizer, Takeda, and UCB, K. Lasch Employee of: Takeda Pharmaceuticals U.S.A., Inc., Deerfield, IL, USA, M. Rosario Employee of: Takeda Pharmaceuticals U.S.A., Inc., Deerfield, IL, USA, A. James Employee of: Takeda Development Centre Europe Ltd, London, UK, B. Abhyankar Employee of: Takeda Development Centre Europe Ltd, London, UK