On May 20, 2014, the US Food and Drug Administration (FDA) approved vedolizumab (Entyvio®) for moderately to severely active UC and moderately to severely active CD. Vedolizumab (Entyvio®) is indicated for inducing and maintaining clinical response, inducing and maintaining clinical remission, improving the endoscopic appearance of the mucosa, and achieving corticosteroid-free remission in adult individuals with moderately to severely active ulcerative colitis. Vedolizumab (Entyvio®) is also indicated for achieving clinical response, achieving clinical remission, and achieving corticosteroid-free remission in adult individuals with moderately to severely active CD.
Vedolizumab (Entyvio®) is a humanized monoclonal antibody that binds to a specific integrin protein found on white blood cells and prevents the integrin's ability to bind with a cell adhesion molecule found on gastrointestinal blood vessels. This inhibition prevents the memory T-cells from migrating into inflamed gastrointestinal parenchymal tissue and helps to minimize the chronic inflammation, which is a hallmark symptom of UC and CD.
The effectiveness of vedolizumab (Entyvio®) for active UC was evaluated using two integrated randomized, double-blind, placebo-controlled trials. For the induction therapy trial, 374 individuals randomly received vedolizumab (Entyvio®) or placebo intravenously at weeks 0 and 2. Clinical response was assessed using the Mayo Clinic score*. For the maintenance therapy trial, at week 6, the individuals who had a clinical response to vedolizumab (Entyvio®) were randomly assigned to one of three therapies: to continue vedolizumab (Entyvio®) treatment every 4 weeks, continue vedolizumab (Entyvio®) treatment every 8 weeks, or to switch to a placebo for up to 52 weeks. The response rate at the end of the induction therapy trial (week 6) was 47.1 percent for vedolizumab (Entyvio®) group versus 25.5 percent for the placebo-controlled group. At the conclusion of the maintenance therapy trial (week 52), clinical remission was reached in 41.8 percent of individuals who received vedolizumab (Entyvio®) every 8 weeks and 44.8 percent of individuals who received vedolizumab (Entyvio®) every 4 weeks compared to 15.9 percent of the placebo-controlled group.
For active CD the effectiveness of vedolizumab (Entyvio®) was evaluated using two integrated randomized, parallel-group, double-blind, placebo-controlled studies. In the trial of induction therapy, 368 individuals randomly received vedolizumab (Entyvio®) or placebo at weeks 0 and 2. Clinical response to the therapy was determined using the Crohn's Disease Activity Index. The maintenance therapy trial was composed of individuals who had a clinical response to vedolizumab (Entyvio®) in the double-blind group, and individuals who had a clinical response in the open-label parallel-group. From these two groups, 461 therapy-responsive individuals were randomly assigned to continue vedolizumab (Entyvio®) treatment every 4 weeks, to continue vedolizumab (Entyvio®) treatment every 8 weeks, or to switch to a placebo for up to 52 weeks. At week 6, 31.4 percent of the vedolizumab (Entyvio®) group had a clinical response to therapy compared to 25.7 percent in the placebo-controlled group. In the vedolizumab (Entyvio®) group, 14.5 percent were in clinical remission at week 6 versus 6.8 percent in clinical remission in the placebo-controlled group. At the end of week 52, clinical remission was reached in 39.0 percent of individuals who received vedolizumab (Entyvio®) every 8 weeks and in 36.4 percent of individuals who received vedolizumab (Entyvio®) every 4 weeks compared to 21.6 percent of the placebo-controlled group.
*The Mayo Score is a combined endoscopic and clinical scale used to assess the severity of UC. The Mayo Score is a composite of subscores from four categories, including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy or colonoscopy, and physician’s global assessment, with a total score ranging from 0 to 12. Within the endoscopic component of the Mayo Score, a score of 0 is given for normal mucosa or inactive UC, while a score of 1 is given for mild disease with evidence of mild friability, reduced vascular pattern, and mucosal erythema. A score of 2 is indicative of moderate disease with friability, erosions, complete loss of vascular pattern, and significant erythema, and a score of 3 indicates ulceration and spontaneous bleeding. Mucosal healing has been defined as a Mayo endoscopic subscore of 0 or 1 in major trials of biological therapies in UC.
VEDOLIZUMAB (ENTYVIO®) VERSUS ADALIMUMAB (HUMIRA®) FOR MODERATE-TO-SEVERE ULCERATIVE COLITIS
The American Gastroenterological Association (AGA) clinical practice guidelines on the management of moderate to severe UC recommends treating adult individuals with moderate to severe UC with infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or ustekinumab for the induction and maintenance of remission.
On September 28, 2012, the FDA approved adalimumab (Humira®) for the treatment of moderate-to-severe UC in adult individuals. The safety and effectiveness of adalimumab (Humira®) for UC were evaluated in two clinical studies (UC-I and UC-II). Both studies enrolled a total of 908 individuals who were tumor necrosis factor (TNF)--inhibitor naļve and individuals who lost response to or were intolerant to TNF-inhibitor. Forty percent of the population in the UC-II study previously used another TNF-inhibitor. The studies were designed to measure the percentage of individuals whose Mayo score decreased to 2 or less, with no individual subscore of more than 1 after 8 weeks of treatment. Individuals who obtained such reductions in the Mayo score were determined to have achieved clinical remission. Induction of clinical remission (defined as Mayo score of less than or equal to 2 with no individual subscores more than 1) at week 8 was evaluated in both studies. Clinical remission was evaluated at week 52, and sustained clinical remission (defined as clinical remission at both weeks 8 and 52) were evaluated in Study UC-II. Results from both studies showed that a greater percentage of the individuals treated with adalimumab (Humira®) compared to individuals treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the individuals treated with adalimumab (Humira®) compared to individuals treated with placebo achieved sustained clinical remission (clinical remission at both weeks 8 and 52). In Study UC-II, 17.3 percent (43/248) in the adalimumab (Humira®) group were in clinical remission at week 52 compared to 8.5 percent (21/246) in the placebo group (treatment difference: 8.8 percent; 95 percent confidence interval (CI): [2.8 percent, 14.5 percent]; p < 0.05). The effectiveness of adalimumab (Humira®) has not been established in individuals with UC who have lost response to or were intolerant to TNF inhibitors.
Efficacy and safety of vedolizumab (Entyvio®) compared to adalimumab (Humira®) in individuals with UC were investigated in the randomized, head-to-head VARSITY trial in adult individuals with moderately to severely active UC. Previous exposure to a TNF inhibitor, other than adalimumab (Humira®), was allowed in up to 25 percent of individuals. The individuals were assigned to receive infusions of 300 mg of vedolizumab (Entyvio®) on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab (Humira®), with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). A total of 769 individuals underwent randomization and received at least one dose of vedolizumab (Entyvio®) (383 individuals) or adalimumab (Humira®) (386 individuals). At week 52, clinical remission was observed in a higher percentage of individuals in the vedolizumab (Entyvio®) group than in the adalimumab (Humira®) group (31.3 percent vs. 22.5 percent; difference, 8.8 percentage points; 95 percent confidence interval [CI], 2.5 to 15.0; P=0.006), as was endoscopic improvement (39.7 percent vs. 27.7 percent; difference, 11.9 percentage points; 95 percent CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6 percent of the individuals in the vedolizumab (Entyvio®) group and in 21.8 percent in the adalimumab (Humira®) group (difference, −9.3 percentage points; 95 percent CI, −18.9 to 0.4). In this trial, vedolizumab (Entyvio®) showed superiority to adalimumab (Humira®) with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission.
Sands et al (2019) pointed additional limitations of the Varsity study: Inclusion of the individuals, who had not had a response to a TNF inhibitor. Guidelines recommend the use of a different class given the reduced efficacy of a second TNF inhibitor. No dose escalation was allowed, but real-world data show that dosages are increased more often within the first year in individuals who receive adalimumab (Humira®) (in 55 to 65 percent of individuals) than in individuals who receive vedolizumab (Entyvio®) (in 21 percent); thus, the dose of adalimumab (Humira®) might have been too low. A treatment goal in UC is corticosteroid-free clinical remission, and this outcome was not achieved more often with vedolizumab (Entyvio®) than with adalimumab (Humira®), which did not correlate with outcomes GEMINI 1 trial. The aim of this trial was to assess the comparative efficacy of vedolizumab (Entyvio®) and adalimumab (Humira®) for the treatment of UC, but because of the trial design and outcomes, the conclusions that can be drawn for clinical practice are limited.
Laurent Peyrin-Biroulet et al (2019) performed systematic review and meta-analysis of 10 eligible cohorts that investigated the incidence rate of loss of the response to vedolizumab (Entyvio®) maintenance therapy and whether a dose escalation restores response to this drug.
In the analyzed data, most individuals had received prior treatment with a TNF antagonist. The pooled incidence rates of loss of the response were 47.9 per 100 person-years of follow up (95 percent CI, 26.3‒87.0; I2 = 74 percent**) among individuals with CD and 39.8 per 100 person-years of follow up (95 percent CI, 35.0‒45.3; I2 = 0 percent) among individuals with UC. Dose escalation restored response to the drug in 53.8 percent of secondary non-responders (95 percent CI, 21.8 percent‒82.9 percent; I2 = 77 percent). The authors concluded that dose escalation restores responsiveness to more than half of studied population, but suggested that further studies are warranted to assist clinical decision making.
**I2 statistic describes the percentage variation across studies that is due to heterogeneity rather than chance; the authors used the cutoffs of < 30 percent, 30-59 percent, 60-75 percent and > 75 percent to suggest low, moderate, substantial, and considerable heterogeneity, respectively.
Stefan Schreiber et al (2018) analyzed literature of the dose escalation in the management of IBD. The eight studies that where included (n = 8) reported that 4–60 percent of individuals with secondary loss of response to biologics in the clinical individuals required dose escalation up to week 54, lower rates reported in biologic-naive individuals (n = 2; range 0–20 percent). However, the highest rates of dose escalation (47–60 percent) were observed in more complex, treatment-refractory UC and CD individuals. Those individuals were included as part of a compassionate-use program and thus are unlikely to be representative of the general IBD population that was treated with biologics. In two studies, dose-escalation rates were lower with vedolizumab (Entyvio®) than with anti-TNF agents. Of the few studies reporting dose-escalation outcomes (N = 4), at least one-third of individuals were able to recapture response. In this analysis, the authors did not provide definitive conclusion.
Loftus EV Jr et al (2016) provided interim analysis of long-term safety GEMINI (LTS) study for every 4 weeks dosing and long-term efficacy of vedolizumab (Entyvio®) for UC. Individuals from the C13004 and GEMINI 1 studies and a cohort of vedolizumab (Entyvio®)-naļve individuals received open-label vedolizumab (Entyvio®) every 4 weeks. Interim data were collected from May 22, 2009 to June 27, 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life [HRQL], were assessed for up to 152 weeks of cumulative treatment in the efficacy population. Among individuals who responded to vedolizumab (Entyvio®) induction and had data available, 88 percent (n = 120/136) were in remission after 104 weeks of exposure (96 percent [n = 70/73] after 152 weeks). Among individuals who withdrew from every-8-week vedolizumab (Entyvio®) maintenance in GEMINI 1 [n = 32] before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41 percent and 28 percent, respectively, after 52 weeks, an increase from 19 percent and 6 percent, respectively, from before the dose increase.
Additionally, population pharmacokinetics modelling using data collected during GEMINI 1 showed that among individuals who were receiving vedolizumab (Entyvio®) every 8 weeks during maintenance, those who withdrew early had numerically lower predicted vedolizumab (Entyvio®) serum concentrations at week 52 [30.5 µg/ml; range, 15.7–98.9] than those who completed the study [36.9 µg/ml; range, 18.1–138.2] despite the same dosing frequency. A greater inflammatory burden may hypothetically lead to increased drug clearance and reduced serum drug concentration, as has been observed for TNF inhibitors. Future prospective studies that show the dose–response relationship of vedolizumab (Entyvio®) are warranted to investigate the clinical impact of adjusting dosing frequency in some populations of individuals. The authors did not state a firm conclusion: "The clinical benefits of vedolizumab (Entyvio®) continued with long-term treatment regardless of prior TNF inhibitor exposure. Increased dosing frequency might improve outcomes in individuals who lose response to conventional 8-weekly dosing."
An ongoing, phase-4, open-lable, multi-center study, Evaluate Vedolizumab Intravenous (IV) Dose Optimization on Treatment Outcomes in Nonresponders with Moderately to Severely Active Ulcerative Colitis (ENTERPRET), is currently investigating the efficacy and safety of vedolizumab (Entyvio®) dose optimization on mucosal healing compared with the standard vedolizumab (Entyvio®) dosing regimen over a 30-week treatment period in individuals with moderately to severely active UC and high vedolizumab (Entyvio®) clearance, based on a week 5 predefined serum vedolizumab (Entyvio®) concentration threshold of less than (<) 50 microgram per milliliter (mcg/mL) and on week 6 non-responders based on partial Mayo score. All randomized subjects will receive vedolizumab (Entyvio®) IV either 300 mg or 600 mg every 4 or 8 weeks. This trial is unpublished and has not been peer-reviewed. Finalized data is not available to make concise clinical decision at the present time.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
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