Chen, Jingjing

Abstract Background Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Methods Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1–46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. Results No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Conclusions Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

Abstract Background Vedolizumab (VDZ) is a gut-selective α 4β 7 integrin monoclonal antibody approved for IV administration for moderate to severe ulcerative colitis (UC). The phase 3 VISIBLE 1 study evaluated SC VDZ for UC maintenance therapy. After 2 IV doses, 56.1% patients had a clinical response at week 6; among patients who received a third induction infusion, clinical response rates were 79.7%. In this post hoc analysis, we examined baseline characteristics as predictors of clinical response to IV induction with VDZ. Methods In the VISIBLE 1 study (NCT02611830; EudraCT 2015-000480-14), patients (patients) received IV VDZ 300 mg at Weeks 0 and 2. At Week 6, clinical responders were randomised to maintenance SC therapy; nonresponders were given a third IV dose and reassessed at Week 14. As endoscopy was only available at Week 6, the clinical response at Week 6 was defined as ≥3 points and ≥30% reduction in complete Mayo score from Week 0 and at Week 14 as a ≥2 points and ≥25% reduction in partial Mayo score from Week 0. Both definitions also included an accompanying decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1. Results Overall, 383 patients received ≥1 dose of IV VDZ. Of these, 56.1% responded at Week 6 after 2 VDZ doses. Of the 143 patients who received 3 IV doses, 79.7% responded at Week 14. No clinically meaningful differences in baseline demographic and disease characteristics were observed between patients who responded after 2 or 3 IV doses (Table). Differences in disease location and partial Mayo score (< or ≥6) were observed between the responders and nonresponders in the 3 IV dose group. Baseline characteristics were evaluated descriptively to assess predictors of clinical response after 2 or 3 IV VDZ doses. Conclusion Clinical response was achieved by most patients after either 2 or 3 IV VDZ infusions in the VISIBLE 1 trial. Post hoc analyses revealed no clinically meaningful differences in baseline characteristics or disease characteristics that could serve as predictors of response following 2 or 3 VDZ infusions. Further real-world experience may elucidate potential predictors of response to VDZ.

Abstract Background Patients with ulcerative colitis (UC) experience substantial impairment in quality of life (QOL). Patient QOL endpoints are important measures of treatment outcome. We evaluated the effects of intravenous vedolizumab vs. adalimumab on QOL in VARSITY, the first head-to-head trial comparing the efficacy and safety of biologics in patients with moderately to severely active UC. Methods VARSITY was a phase 3b, double-blind, double-dummy, randomised trial (NCT02497469; EudraCT 2015-000939-33). QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ) at baseline, Week (Week) 30, and Week 52. Endpoints included clinically meaningful IBDQ improvement (defined as an increase in total score of ≥16 points from baseline to Week 52), IBDQ remission (defined as a total score of >170 points at Week 52) and change from baseline in IBDQ-specific domain scores (bowel symptoms, systemic symptoms, emotional function, and social function) at Week 30 and Week 52. Serum C-reactive protein (CRP) and faecal calprotectin (FCP) were also assessed as indicators of disease activity. Results Among randomised patients, 383 (vedolizumab) and 386 (adalimumab) patients received ≥1 dose of study drug (N=769). At Week 52, clinically meaningful IBDQ improvement was observed in 52.0% (vedolizumab) vs. 42.2% (adalimumab) of patients (treatment difference 9.7%; 95% confidence interval [CI], 2.7% to 16.7%), while IBDQ remission was achieved by 50.1% (vedolizumab) vs. 40.4% (adalimumab) of patients (treatment difference 9.6%; 95% CI, 2.8% to 16.5%). Mean (standard deviation [SD]) changes in IBDQ total score from baseline for observed cases favoured vedolizumab over adalimumab (Week 30: 61.3 [39.8] vs. 52.6 [42.8]; Week 52: 66.1 [41.8] vs. 60.4 [42.2]; Figure 1). IBDQ subscores showed similar favourable trends for vedolizumab (Figure 2). At Week 52, mean (SD) changes from baseline in CRP for patients treated with vedolizumab vs. adalimumab were –50.9 (174.8) nmol/l vs. –37.2 (169.2) nmol/l and for FCP were –2187.3 (7440.4) µg/g vs. –1846.6 (4560.6) µg/g (Figure 3). Among patients with FCP >250 µg/g at baseline, the proportion of patients achieving FCP ≤250 µg/g was 33.9% vs. 24.5% at Week 30 and 35.2% vs. 28.9% at Week 52 for patients treated with vedolizumab vs. adalimumab, respectively. Conclusion Based on IBDQ total score and subscores, more patients with UC treated with vedolizumab than with adalimumab achieved clinically meaningful improvement and clinical remission. Reduced inflammation, as indicated by improvements in CRP and FCP, was consistent with improvements in QOL.

INTRODUCTION: Histologic remission is associated with superior long-term clinical outcomes in ulcerative colitis (UC). VARSITY, the first head-to-head comparison of biologic agents in UC (NCT02497469; EudraCT 2015-000939-33), showed superior clinical remission and endoscopic improvement at Week 52 with vedolizumab (VDZ), a gut-selective, humanized, α 4 β 7 integrin monoclonal antibody, vs adalimumab (ADA), a systemic, human, anti-tumor necrosis factor (anti-TNF) monoclonal antibody. 1 Both VDZ and ADA were generally safe and well-tolerated. 1 This analysis compared histologic improvements with VDZ vs ADA in VARSITY. METHODS: Patients with moderately to severely active UC were randomized 1:1 to active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections or placebo IV/active ADA SC (160/80/40 mg). Prespecified histologic exploratory endpoints included histologic remission (Geboes score < 2 or Robarts Histopathology Index [RHI] score < 3) and minimal histologic disease activity (Geboes score < 3.2 or RHI score < 5) at Week 14 and Week 52. Histologic remission was also assessed based on previous anti-TNF use. RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Median (range) duration of exposure was 477 (127, 630) days for VDZ and 420 (71, 454) days for ADA. Mean (standard deviation) baseline histologic disease activity was similar between groups (Geboes: VDZ, 15.0 [4.92]; ADA, 15.1 [5.03]; RHI: VDZ, 19.5 [8.74]; ADA, 19.6 [8.89]). Histologic remission induced by VDZ at Week 52 was greater than with ADA in the overall (Geboes or RHI), anti-TNF naïve (Geboes or RHI), and anti-TNF failure (RHI only) groups (Table 1). Histologic remission at Week 14 favored VDZ over ADA, with larger differentiation when using RHI (Table 1). VDZ also outperformed ADA in achieving minimal histologic disease activity at Weeks 14 and 52 (Table 1). CONCLUSION: VARSITY showed that use of VDZ, compared with ADA, achieved higher rates of histologic remission and minimal histologic disease activity at Weeks 14 and 52 in patients with moderately to severely active UC. These data support the use of VDZ over ADA in UC.

INTRODUCTION: VARSITY is the first head-to-head trial comparing the efficacy and safety of 2 biologic therapies, vedolizumab (VDZ) and adalimumab (ADA), in patients with moderately to severely active ulcerative colitis (UC). We previously reported significantly higher rates of clinical remission (31.3% vs 22.5%; P = 0.0061) and endoscopic improvement (39.7% vs 27.7%; P = 0.0005) at Week (Wk) 52 with VDZ vs ADA. 1 METHODS: VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study (NCT02497469; EudraCT 2015-000939-33). Here we report the predefined, exploratory endpoints of early clinical response and clinical remission (defined in the Table 1) within the first 14 wks, as well as durable clinical remission (patients in clinical remission at Wk 14 and Wk 52). RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Baseline characteristics were comparable between the 2 groups. A trend for separation in clinical response started to emerge at Wk 6 favoring VDZ vs ADA. Clinical response at Wk 14 favored VDZ vs ADA (257 [67.1%] vs 177 [45.9%]; treatment difference 21.2%). More patients achieved clinical remission at Wk 14 on VDZ vs ADA (102 [26.6%] vs 82 [21.2%]; treatment difference 5.3%). Patients on VDZ achieved higher rates of durable clinical remission (70 [18.3%] vs 46 [11.9%]); laboratory results correlated with these findings. Post hoc analyses showed a larger mean (standard deviation) change of C-reactive protein (CRP) from baseline to Wk 14 (−32.88 [155.77] nmol/L VDZ vs −3.35 [260.81] nmol/L ADA) and to Wk 52 (−50.87 [174.76] nmol/L VDZ vs −37.21 [169.17] nmol/L ADA) in favor of VDZ. Greater mean declines in fecal calprotectin (FCP) levels were seen in patients on VDZ compared with ADA (Wk 14: −1,551.3 [6,236.70] mg/kg VDZ vs −1,167.6 [4,647.67] mg/kg ADA; Wk 52: −2,187.3 [7,440.42] mg/kg VDZ vs −1,846.6 [4,560.55] mg/kg ADA). CONCLUSION: Patients on VDZ had numerically higher rates of both clinical response and clinical remission by Wk 14 compared with ADA. Patients on VDZ also achieved higher rates of durable clinical remission compared with ADA. CRP and FCP results correlated with these findings. These data on early clinical response and clinical remission, as well as durable remission, further support the use of VDZ over ADA in patients with moderately to severely active UC.