Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract of unknown etiology. IBD has two major categories: ulcerative colitis (UC) and Crohn's disease (CD). The most common symptoms in UC and CD are diarrhea, rectal bleeding, urgency to have bowel movements, abdominal cramps, pain, fever, and weight loss. Although UC and CD have similar clinical presentations, they differ in the body areas affected. UC primarily causes inflammation of the mucosal lining and is generally limited to the colon and rectum, whereas CD affects the entire digestive system and can produce ulcers that extend deep into the intestinal wall.
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 UC. 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.
PEER-REVIEWED LITERATURE
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 the 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 naïve 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 ≤2 with no individual subscores >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.
The 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, 0–12, with higher scores indicating more severe disease] and no subscore >1 [range, 0–3] 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 CI, 2.5–15.0; P=0.006), as was endoscopic improvement (39.7 percent vs. 27.7 percent; difference, 11.9 percentage points; 95 percent CI, 5.3–18.5; 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, −18.9–0.4). 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 out 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 in the 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.
DOSE ESCALATION
Laurent Peyrin-Biroulet et al. (2019) performed a 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 they 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 less than 30 percent, 30–59 percent, 60–75 percent, and >75 percent to suggest low, moderate, substantial, and considerable heterogeneity, respectively.
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 to 60 percent of individuals with secondary loss of response to biologics in the clinical individuals required dose escalation up to week 54; lower rates were reported in biologic-naïve individuals (n=2; range, 0–20 percent). However, the highest rates of dose escalation (47–60 percent) were observed in individuals with more complex, treatment-refractory UC and CD. 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 a 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)-naïve 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."
A phase-4, open-label, multicenter study, Evaluated 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 µg/mL and on week 6 nonresponders based on partial Mayo score. All randomized subjects received vedolizumab (Entyvio) IV either 300 mg or 600 mg every 4 or 8 weeks. In conclusion, in individuals with early nonresponse and high drug clearance, vedolizumab dose optimization was not required. A proportion of individuals benefited from continuation treatment without effect of the dose received.
PEER-REVIEWED LITERATURE IN PEDIATRIC POPULATION
A retrospective Multicenter Experience of Vedolizumab Effectiveness in Pediatric Inflammatory Bowel Disease review studied 52 individuals: 58% with CD and 42% with UC. Median age at the initiation was 14.9 (range, 7–17) years. Ninety percent of participants had failed more than one anti-tumor necrosis factor (TNF) agent. At week 14, remission rates were for UC and CD respectively, 76% and 42% (P<0.05). Eighty percent of anti-TNF–naïve individuals experienced remission at week 14. At week 22, anti-TNF–naïve individuals had higher remission rates than TNF-exposed patients (100% vs. 45%; P=0.04). There were no infusion reactions or serious adverse events/infections. In conclusion, results suggest that vedolizumab is efficacious and safe in pediatric individuals with IBD, with UC individuals experiencing earlier and higher rates of remission than CD individuals. Individuals without anti-TNF exposure experienced higher remission rates than those with anti-TNF exposure. Controlled clinical trial data are needed to confirm these observations.
An observational Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease prospective cohort study examined a pediatric population with refractory IBD in whom had anti-TNF therapy had failed and subsequently initiated vedolizumab therapy. Twenty-one individuals participated: 16 with CD received vedolizumab. Clinical response was observed in six of 19 (31.6%) of the evaluable subjects at week 6 and in 11 of 19 (57.9%) by week 22. Before induction, 15 of 21 (71.4%) individuals were treated with systemic corticosteroids. Steroid-free remission was seen in one of 20 (5.0%) individuals at 6 weeks, three of 20 (15.0%) at 14 weeks, and four of 20 (20.0%) at 22 weeks. There was statistically significant improvement in serum albumin and hematocrit; however, C-reactive protein increased by week 22 (P<0.05). There were no infusion reactions. Vedolizumab was discontinued in two individuals because of severe colitis, requiring surgical intervention. In conclusion, there is limited experience with vedolizumab therapy in pediatric IBD. This study is limited by small sample size, and larger prospective studies are warranted.
The retrospective study, Vedolizumab in Pediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Pediatric IBD Porto Group of ESPGHAN, investigated short-term effectiveness and safety of vedolizumab in a European multicenter pediatric IBD cohort. The pediatric population was between ages 2 and 18 years treated with vedolizumab. Primary outcome was Week 14 corticosteroid-free remission [CFR].
In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range, 14–38; range 6–116]); 41 [64%] cases of UC/IBD unclassified [UC/IBD-U] and 23 [36%] with CD). All were previously treated with anti-TNF (28% primary failure, 53% secondary failure). Week 14 CFR was 37% in UC, and 14% in CD [P=0.06]. CFR by last follow-up was 39% in UC and 24% in CD (P=0.24). Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate (42% vs 35%; P=0.35 at Week 22). There were three minor drug-related adverse events. Only three of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). In conclusion, vedolizumab was safe and effective in this cohort of pediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC. This study showed promising data that vedolizumab is safe and effective in pediatric UC, and to a lesser extent also in CD. The currently enrolling prospective multicenter VEDOKIDS cohort study investigated role of vedolizumab in pediatric IBD.
VEDOKIDS was a pediatric, multicenter, prospective cohort study that report the 14-week outcomes as the first analyses of the planned 3-year follow-up of the VEDOKIDS cohort. Individuals enrolled were of age range 0 to 18 years with IBD who received vedolizumab and were followed up at baseline and at 2, 6, and 14 weeks without standardization of dosing or criteria for escalation. The primary outcome was steroid-free and exclusive enteral nutrition-free remission at 14 weeks, analyzed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT02862132.
This study enrolled 142 children (76 [54%] girls and 66 [46%] boys; mean age 13.6 years [SD 3.6]) were enrolled. Sixty-five (46%) children had CD, 68 (48%) had UC, and nine (6%) had unclassified IBD (those with unclassified IBD were analyzed with the UC group). Thirty-two (42% [95% CI, 30–54]) of 77 children with UC and 21 (32% [23–45]) of 65 children with CD were in steroid-free and exclusive enteral nutrition-free remission at 14 weeks. Median drug concentrations at week 14 were higher in children with UC than in those with CD (11.5 μg/mL [IQR 5.5–18.1] vs 5.9 μg/mL [3.0–12.7]; P=0.006). In children who weighed less than 30 kg, the optimal drug concentration associated with steroid-free and exclusive enteral nutrition-free clinical remission was 7 μg/mL at week 14 (area under the curve 0.69 [95% CI, 0.41–0.98]), corresponding to a dose of 200 mg/m2 body surface area or 10 mg/kg. Thirty-two (23%) of 142 children reported at least one adverse event, the most common were headache (five [4%]), myalgia (four [3%]), and fever (three [2%]). None of the adverse events were classified as severe, and only two (1%) patients discontinued treatment due to adverse events. Vedolizumab showed safety and effectiveness at inducing remission in children with IBD at 14 weeks, especially those with UC. Vedolizumab may be considered in children when other approved drug interventions for IBD are unsuccessful. In children who weigh less than 30 kg, vedolizumab was dosed by the child's body surface area (200 mg/m2) or weight (10 mg/kg). Considerable delay is expected until the pediatric phase 3 trial results for vedolizumab are available; early, real-life data are required to provide evidence for the common off-label use of vedolizumab in children.
