Vedolizumab for Crohn’s Disease

Results of a phase 3, randomized, parallel-group, double-blind, placebo-controlled, multicenter trial show that patients with active Crohn’s disease treated with induction vedolizumab were more likely to have clinical remission at 6 weeks compared with patients receiving placebo, but not more likely to have a Crohn’s Disease Activity Index (CDAI) response [N Engl J Med. 2013;369(8):711-721].

In a second analysis that looked at maintenance therapy with vedolizumab, the study found that the rates of clinical remission at week 52 among the patients who responded to vedolizumab were significantly higher in patients who received maintenance vedolizumab every 8 or 4 weeks compared with patients receiving placebo.

Undertaken to assess the efficacy of vedolizumab both as induction therapy and maintenance therapy in patients with moderate-to-severe Crohn’s disease, the study enrolled 1115 patients between December 2008 and May 2012 from 286 medical centers in 39 countries. Patients enrolled in the study were 18 to 80 years of age, had active Crohn’s disease for at least 3 months with a CDAI score of 220 to 450, and had either a serum C-reactive protein level >2.87 mg per liter, ≥3 large ulcers or ≥10 aphthous ulcers detected by colonoscopy, or >250 µg per gram of stool in fecal calprotectin concentrations. Patients were excluded from the study if previously treated with vedolizumab, natalizumab, efalizumab, or rituximab, or had a stoma, >3 small-bowel resections, short-bowel syndrome, extensive colonic resection, intestinal stricture, abdominal abscess, active or latent tuberculosis, or cancer.

The study first looked at the efficacy of vedolizumab as induction therapy in 368 patients randomized to receive vedolizumab 300 mg (n=220) or placebo (n=148) at weeks 0 and 2 (cohort 1) and followed for 6 weeks. A further group of 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 1) to fulfill sample-size requirements for the maintenance trial. Patients with a clinical response (defined as ≥70-point decrease in the CDAI score) to vedolizumab at week 6 were randomly assigned in a maintenance trial to receive vedolizumab every 8 weeks, every 4 weeks, or placebo for 52 weeks.

The primary end points of the induction trial were clinical remission (defined as CDAI score of <150 points) and CDAI-100 response (≥100-point decrease in the CDAI score) at week 6. The primary end point of the maintenance trial was clinical remission at week 52. Secondary end points included CDAI-100 response, glucocorticoid-free remission (clinical remission without glucocorticoid therapy at week 52), and durable clinical remission (clinical remission at >80% of study visits at week 52).

In the induction trial, the study found that significantly more patients treated with vedolizumab compared with placebo in cohort 1 had a clinical remission at week 6 (14.5% vs 6.8%, P=.02). However, no significant difference was found in CDAI-100 response (31.4% vs 25.7%, respectively; P=.23).

Overall, 416 patients in cohorts 1 and 2 had a response to induction therapy with vedolizumab and were randomized to maintenance therapy. At 52 weeks, significantly more patients receiving maintenance vedolizumab for 8 weeks maintained clinical remission compared to placebo (39.0% vs 21.6%, P<.001) as did those receiving vedolizumab for 4 weeks (36.4% vs 21.6%, P=.004).

Although the study found a significantly greater proportion of patients who received vedolizumab every 8 or 4 weeks had a CDAI-100 response and glucocorticoid-free remission compared with placebo, there was no difference between the vedolizumab groups and placebo in durable clinical remission.

Compared with placebo, vedolizumab was associated with a higher rate of serious adverse events (15.3% vs 24.4%), infections (40.2% vs 44.1%), and serious infections (3.0% vs 5.5%) as well as a higher frequency of nasopharyngitis. Headaches and abdominal pain were less frequent with vedolizumab.

Left unanswered by the study was which specific patients with Crohn’s disease would benefit the most from treatment with vedolizumab, as well as the efficacy of combining vedolizumab with immunosuppressive agents.