Takeda's Gut-Selective Anti-Inflammatory Drug Entyvio Subcutaneous Formulation Demonstrates Success in Phase III Trial for Moderately to Severely Active Crohn’s Disease

February 17, 2020 News /Bio ValleyBIOON/ -- Takeda recently at the 2020 European Crohn's and Colitis Organisation (ECCO) annual meeting held in Vienna, AustriaMeetingThe Phase III VISIBLE 2 study evaluating the subcutaneous (SC) formulation of Entyvio (vedolizumab) for the treatment of Crohn's disease (CD) was published.Clinical Trialresults.

This was a randomized, double-blind, placebo-controlled study conducted in adult patients with moderately to severely active Crohn’s disease (CD) to evaluate the efficacy and safety of Entyvio SC for maintenance therapy. A total of 644 patients were enrolled in the study; all patients had previously received corticosteroids, immunomodulators, orTumorInsufficient response, loss of response, or intolerance to tumor necrosis factor-alpha (TNF-α) antagonists. In the study, all patients received two open-label induction doses of Entyvio 300 mg intravenously (IV) at Week 0 and Week 2. Patients who achieved a clinical response by Week 6 (n=410) were randomized into two groups to receive either Entyvio 108 mg subcutaneously (SC) or placebo subcutaneously every two weeks from Week 6 to Week 50.

In this study, clinical response was defined as a decrease in the Crohn’s Disease Activity Index (CDAI) score of ≥70 points from baseline (Week 0). The primary endpoint was clinical remission, defined as a CDAI score ≤150 at Week 52. Secondary endpoints included: (1) enhanced clinical response, defined as a decrease in the CDAI score of ≥100 points from baseline (Week 0); (2) corticosteroid-free remission, defined as discontinuation of oral corticosteroids in patients who were receiving oral corticosteroids at baseline and achieving clinical remission (CDAI score ≤150) at Week 52; and (3) the proportion of anti-TNFα-naïve patients achieving clinical remission (CDAI score ≤150) at Week 52.

The results showed that the study met its primary endpoint: at Week 52, a significantly higher proportion of patients in the Entyvio SC treatment group achieved clinical remission compared with the placebo group (48.0% [n=132/275] vs. 34.4% [n=46/134], p=0.008). Results for secondary endpoints showed that at Week 52, the rate of enhanced clinical response was higher in the Entyvio SC treatment group than in the placebo group (52.0% [n=143/275] vs. 44.8% [n=60/134]). As the differences between treatment groups were not statistically significant, no further statistical testing was performed on the remaining secondary endpoints. Among patients receiving corticosteroid therapy at baseline, the corticosteroid-free clinical remission rate was 45.3% (n=43/95) in the Entyvio SC treatment group and 18.2% (n=8/44) in the placebo group. The study enrolled both anti-TNFα-naïve (biologic-naïve) and anti-TNFα-experienced (previously treated) patients. Among anti-TNFα-naïve patients, the clinical remission rates at Week 52 were 48.6% (n=52/107) in the Entyvio SC treatment group and 42.9% (n=27/63) in the placebo group.

In this study, the safety profile of Entyvio SC was consistent with the known safety profile of Entyvio IV in patients with Crohn’s disease (CD). In both treatment groups, serious infections, second-line therapies, and hepatic injury occurred in ≤5% of patients. Anti-vedolizumab antibodies were detected in 2.5% of patients in the Entyvio SC group, approximately half of which were neutralizing antibodies. Injection-site reactions were reported in less than 3% of patients in the Entyvio SC treatment group.

Dr. Séverine Vermeire, Head of the Department of Chronic Diseases and Metabolism at KU Leuven and Honorary Member of ECCO, stated: “The VISIBLE 2 study demonstrated that Entyvio SC helps patients with moderately to severely active Crohn’s disease achieve clinical remission at Week 52 following an initial clinical response to intravenous Entyvio induction therapy. These findings suggest that the gut-selective subcutaneous formulation of Entyvio offers a new treatment option for patients who may prefer self-administration outside of a hospital setting.”

Dr. William Sandborn, Director of the Inflammatory Bowel Disease Center at the University of California, stated, “These data suggest that the subcutaneous formulation of Entyvio appears to have a similar safety profile to the intravenous formulation. If approved, subcutaneous Entyvio, together with the intravenous formulation, could provide patients with more treatment options, helping to meet their individual needs and preferences.”

Entyvio is a gut-selective biologic agent whose active pharmaceutical ingredient is vedolizumab, a humanized monoclonal antibody that specifically antagonizes α4β7 integrin, thereby inhibiting the binding of α4β7 integrin to the gut mucosal cell adhesion molecule MAdCAM-1. MAdCAM-1 is selectively expressed in the gastrointestinal vasculature and lymph nodes. α4β7 integrin is expressed on a subset of circulating leukocytes, which have been shown to play a critical role in mediating inflammation in Crohn’s disease (CD) and ulcerative colitis (UC). By inhibiting α4β7 integrin, vedolizumab may restrict the ability of certain leukocytes to infiltrate intestinal tissue.

Entyvio intravenous (IV) formulation was approved for marketing in the United States and the European Union in May 2014. This product has been approved in more than 60 countries worldwide for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD).

Currently, Takeda is developing the subcutaneous (SC) formulation of Entyvio, which includes prefilled syringes and prefilled injection pens, and has submitted it for regulatory review to multiple major regulatory authorities worldwide. If approved, Entyvio will become the only maintenance therapy offering both intravenous (IV) and subcutaneous (SC) formulations for ulcerative colitis (UC) and Crohn’s disease (CD).

It is worth noting that in December 2019, the U.S. FDA issued a Complete Response Letter (CRL) regarding the Biologics License Application (BLA) for Entyvio SC, refusing to approve the formulation. However, in the CRL,FDAIssues Raised and Key Points Supporting the BLAClinical TrialsThe data and conclusions of the VISIBLE-1 study are unrelated. Takeda firmly believes that Entyvio SC formulation will bring potential benefits to patients with moderate-to-severe UC. The company remains committed to working withFDACollaboration, meeting the unmet needs of patients through this important route of administration and enhancing patient experience based on their treatment preferences and lifestyle. (Bioon.com)

Original Source: Investigational Subcutaneous Formulation of Vedolizumab Achieves Clinical Remission at Week 52 in Patients with Moderately to Severely Active Crohn’s Disease