Vedolizumab (Entyvio, Takeda Pharmaceuticals America, Deerfield, IL) is a humanized monoclonal antibody to α-4 β-7 integrin, which is expressed on lymphocytes and is the ligand to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), preferentially expressed on endothelial cells in the gut vasculature. Vedolizumab selectively interferes with lymphocyte homing in the gut, thus affording the potential for a relatively gut-selective mechanism of action, which could impact not only the efficacy of the drug but also its safety. Vedolizumab was approved by the U.S. Food and Drug Administration and the European Medications Agency for the treatment of moderate to severe ulcerative colitis and Crohn’s disease in mid-2014. Now is a good time to review the top-line clinical data, as well as pause and reflect upon the positioning of vedolizumab in our inflammatory bowel disease (IBD) treatment algorithms.
The GEMINI 1 trials were designed to study the efficacy and safety of vedolizumab for both induction of clinical response and maintenance of clinical remission in patients with active ulcerative colitis.1 For induction, patients received vedolizumab at weeks zero and two. For the primary endpoint of week six clinical response (decrease in Mayo score of at least three points with at least 30 percent decrease from baseline, at least one point decrease in rectal bleeding score, and absolute rectal bleeding subscore less than or equal to 1), 47.1 percent of vedolizumabtreated patients responded compared to only 25.5 percent in the placebo-treated patients, for a “delta” of about 22 percentage points (p less than 0.001). The week-six responders were randomized to placebo or one of two doses of vedolizumab (every four or every eight weeks). At week 52, rates of clinical remission (Mayo score less than or equal to 2 and no subscore less than 1) were 42 percent for every eight weeks infusions, 45 percent for every four weeks infusions, and only 16 percent for those on placebo, for a “delta” of between 26 and 29 percentage points (p less than 0.001 for both vedolizumab groups vs placebo). There were no significant differences in the rates of adverse events, serious adverse events, or serious infections between those treated with vedolizumab or the placebo.At the end of a year, vedolizumab therapy was associated with higher percentages of patients who were able to taper off corticosteroids and remain steroid-free for up to 180 days.2 Patients who completed GEMINI 1 were eligible to enter an open-label extension study of vedolizumab infusions every four weeks (GEMINI LTS), and a significant proportion of patients remained in clinical response (97 percent as observed, 46 percent non-responder imputation for missing data) for up to three years.3
The GEMINI 2 trials were designed to assess the efficacy and safety of vedolizumab for moderate to severe Crohn’s disease.4 The primary induction endpoints, after doses of vedolizumab at weeks zero and two, were clinical remission (Crohn’s disease activity index (score less than or equal to 150) and clinical response (CDAI score reduction greater than or equal to 100) at week 6. The remission endpoint was met (14.5 percent vs. 6.8 percent, p=0.02) but not the response endpoint (31.4 percent vs. 25.7 percent, p=0.23). Responders were randomized to one of two doses of vedolizumab (every four or eight weeks) or placebo, and the primary maintenance endpoint was clinical remission at week 52, which was significantly higher in the vedolizumab-treated patients (between 36 percent and 39 percent, compared to 22 percent with placebo, p=0.004 and p less than 0.001 respectively). Serious adverse events (24 percent vs. 15 percent) and serious infections (5.5 percent vs. 3 percent) occurred more commonly in vedolizumab-treated patients. Vedolizumab was associated with a numerically higher percentage of patients who were able to taper off corticosteroids by week 52 compared to placebo, and a higher percentage of patients were able to lower their dose of corticosteroids.5 Among the patients who completed GEMINI 2 and entered the open-label GEMINI LTS extension, clinical response was observed in a high proportion of patients for up to three years (97 percent as observed, 47 percent nonresponder imputation for missing data).6 The GEMINI 3 trial was an induction study of a Crohn’s disease cohort enriched with patients who had failed anti-TNF therapy (75 percent), and the primary endpoint was clinical remission at week 6 in the anti-TNF failures.7 The difference in primary endpoint between the vedolizumab and placebo groups was not statistically significant (15 percent vs. 12 percent, p=0.433),but the difference in this endpoint at week 10 was significantly higher in the vedolizumab-treated patients (27 percent vs. 12 percent, nominal p=0.001). Rates of adverse events (56 percent vs. 60 percent), serious adverse events (6 percent vs. 8 percent), and serious infections (less than 1 percent vs. 0 percent) were similar in the two groups.
We are beginning to see reports of “real-world” experiences with vedolizumab in clinical practice. For example, a consortium of seven academic medical centers in the U.S. recently reported their experience with vedolizumab in 212 patients with moderately to severely active Crohn’s disease.8 Despite the fact that 90 percent of these patients had been anti- TNF-exposed (often considered a sign of more refractory disease), the 1-year rates of clinical remission and mucosal healing were 35 percent and 63 percent, respectively. Risk factors for not achieving clinical remission included prior anti- TNF exposure, cigarette smoking, active perianal disease and severe disease activity.
Perhaps the attribute of vedolizumab that substantially differentiates it from the other currently approved biologics for IBD is its safety profile. An integrated safety analysis from six clinical trials of vedolizumab involving more than 2,800 patients with over 4,800 personyears of follow-up could not demonstrate increased risks for any infection or serious infection with vedolizumab.9 In particular, there were no cases of progressive multifocal leukoencephalopathy (PML) identified — this had been a potential concern because a less specific predecessor molecule, natalizumab, had been associated with the development of PML. Among ulcerative colitis patients, risk factors for serious infection included previous anti-TNF failure and opioid analgesic use. In Crohn’s disease, risk factors for serious infection included younger age, corticosteroid use and opioid use. Malignancy was observed in less than 1 percent of vedolizumab-treated patients. The rates of any infections or serious infections did not differ significantly whether or not patients were on concomitant corticosteroids or immunosuppressants at baseline (range, 3 to 5 percent of patients, or 4 to 6 cases per 100 person-years of follow-up).10 Not unexpectedly, in the real-world consortium study, the rate of serious infections was higher than that reported in clinical trial — 13 cases per 100 person/years of follow-up.8 One issue that needs to be clarified with further study is the safety of perioperative use of vedolizumab among IBD patients undergoing abdominal operations, as a preliminary report from Mayo Clinic suggested that the rate of surgical site infections might be higher than expected.11 Hopefully, further studies comparing complication rates between patients on various medications in the perioperative setting can sort out whether this increased risk is related to underlying disease severity or actually related to medication.
In ulcerative colitis, the combination of vedolizumab’s efficacy and safety is particularly notable.
In ulcerative colitis, the combination of vedolizumab’s efficacy and safety is particularly notable, and it seems clear that it could be considered as a first-line biologic in patients who are steroid-dependent or steroid-refractory. On the other hand, the fact that some of the week six endpoints in the Crohn’s disease trials with vedolizumab were not met suggests that the onset of action in Crohn’s disease may be slightly delayed. In GEMINI 2 (albeit not in GEMINI 3), serious adverse events were more common in vedolizumab-treated Crohn’s disease patients. The exact positioning of vedolizumab in the Crohn’s disease treatment algorithm remains uncertain due to its longer onset of action. Studies of induction optimization as well as endoscopic response in patients with Crohn’s disease will help clarify its role. However, these are broad generalizations, and we need to tailor the decision about initial biologic to the individual patient. For example, in a Crohn’s disease patient with a personal history of cancer or of a demyelinating condition, vedolizumab may make more sense as a first-line biologic agent. Other examples where vedolizumab may be the biologic of choice are in patients who are more risk-averse than usual or who may be at risk for serious infections (e.g., elderly patients).
Dr. Loftus has consulted for and has received research support from Takeda/Millenium, Janssen, UCB Pharma and AbbVie.
1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369(8):699-710.
2. Loftus EV Jr, Siegel CA, Panaccione R, Sandborn WJ, Smyth MD, Green A, Xu J, Abhyankar B. Corticosteroid dose reduction in ulcerative colitis patients treated with vedolizumab during the gemini 1 trial (abstract). Am J Gastroenterol 2015; 110:S790.
3. Loftus EV, Colombel JF, Previtali A, Smyth MD. Response and remission rates with up to 3 years of vedolizumab treatment in patients with ulcerative colitis (abstract). Gastroenterology 2016;150(4 Suppl):S805.
4. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369(8):711-21.
5. Loftus EV Jr, Siegel CA, Panaccione R, Sandborn WJ, Smyth MD, Green A, Xu J, Abhyankar B. Corticosteroid dose reduction with vedolizumab treatment of Crohn’s disease during the gemini 2 trial (abstract). Am J Gastroenterol 2015; 110:S789.
6. Vermeire S, Feagan BG, Mody R, Previtali A, Abhyankar B. Response and remission rates with up to 3 years of vedolizumab treatment in patients with Crohn’s disease (abstract). Gastroenterology 2016;150(4 Suppl):S803-4.
7. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014;147:618-27.
8. Dulai PS, Singh S, Jiang X, et al. The real-world effectiveness and safety of vedolizumab for moderate-severe Crohn’s disease: results from the US VICTORY Consortium. Am J Gastroenterol 2016 (online early). Doi:10.1038/ ajg.2016.236.
9. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut 2016 (online early). Doi: 10.1136/gutjnl-2015-311079.
10. Loftus E, Colombel JF, Siegel C, Lewis J, Abhyankar B, Sankoh S, Smyth M, Milch C. Safety of vedolizumab alone or with concomitant corticosteroids and/or immunosuppressants in patients with ulcerative colitis or Crohn’s disease (abstract). Am J Gastroenterol 2014;109(Suppl):S478.
11. Lightner A, Cima R, Pemberton J, et al. Does vedolizumab affect postoperative outcomes in patients undergoing abdominal operations for inflammatory bowel disease? (abstract). Inflamm Bowel Dis 2016;22(Suppl):S46-7.