Sunday, October 20, 2013


Vedolizumab - A Possible Alternative for Anti-TNF-Alpha Non-Responders

Vedolizumab (the name rolls off the tongue almost as well as adalimumab) is a monoclonal antibody (the –mab in the name refers to this class of drugs).  Monoclonal antibodies are biological agents that are clones of the same parent and that target the same epitope (the unique part of an antigen).  In this case, Vedolizumab binds to integrin α4β7 (part of the cell’s signaling system).  This provides Vedolizumab with an interesting risk-benefit possibility – the selective targeting of inflammation in the intestines (due to the targeting of α4β7 ) without binding to other areas in the body, reducing any systemic effects.(1)

Vedolizumab has gotten through two phase III trials for Crohn’s and Ulcerative Colitis as a potential new therapy, providing yet another biologic option that targets a different mechanism than the trio of anti-TNF-alpha drugs currently approved for IBD treatment.  The drug is going through a final Phase III trial to evaluate its long term safety.  The trials (dubbed GEMINI) involve 2,700 patients, and include both Crohn’s and Ulcerative Colitis patients.  They are placebo controlled and involve patients that showed lack of responsiveness to traditional treatments (including anti-TNF-alpha drugs and steroids).  The looked to the drug to both induce and maintain remission.

For induction therapy in ulcerative colitis, the following were the findings:

47.1 percent of patients receiving vedolizumab achieved clinical response compared to 25.5 percent of patients receiving placebo (p < 0.001), 16.9 percent achieved clinical remission versus 5.4 percent receiving placebo (p = 0.001), and 40.9 percent of vedolizumab-treated patients experienced mucosal healing compared to 24.8 percent of patients receiving placebo (p=0.001).

Similarly, for the maintenance of remission, the study found the following:

41.8 percent and 44.8 percent of patients receiving vedolizumab every eight and four weeks, respectively, were in clinical remission at week 52, compared to 15.9 percent of patients who received placebo (p < 0.001). 56.6 percent and 52.0 percent of patients treated with vedolizumab every eight and four weeks, respectively, achieved durable clinical response (defined by a response at both week six and week 52), compared to 23.8 percent of patients receiving placebo (p=0.01, p < 0.001, respectively).

One item of interest on the maintenance study – the dose/response curve appears to flatten (or even decline) at a monthly dosing regimen.  Initial safety results found that “no increase in rates of serious, opportunistic or enteric infections was observed with vedolizumab”.(2)

The latest publication looked at the individuals in the population suffering from Crohn’s disease.  The initial study looked at the results related to induction therapy.  The findings were as follows:

At week six, clinical remission was seen in 14.5 percent of patients randomized to vedolizumab versus 6.8 percent who received placebo (p=0.02). At six weeks, no significant difference was observed in CDAI-100 response between the vedolizumab and placebo groups (31.4 percent versus 25.7 percent, respectively [p=0.23])

The induction therapy numbers for Crohn’s disease don’t appear to be as promising as those for UC.  The higher clinical remission numbers are promising, but the CDAI-100 numbers showed minimal difference.  There are multiple reasons that could be responsible, from the randomization of the population to a longer term needed to show efficacy to a lack of efficacy for inducing maintenance.  The numbers for maintenance show some positives as well:

At week 52, remission was seen in 39.0 percent and 36.4 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 21.6 percent of the patients receiving placebo (p < 0.001, p=0.004, respectively). CDAI-100 response was seen in 43.5 percent and 45.5 percent of patients randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 30.1 percent of patients receiving placebo at week 52 (p=0.01, p=0.005 respectively). Glucocorticoid-free remission was seen in 31.7 percent and 28.8 percent of patients taking oral glucocorticoids at baseline randomized, respectively, to vedolizumab every eight weeks or every four weeks versus 15.9 percent of patients receiving placebo at week 52 (p=0.02, p=0.04, respectively).

Again, the numbers are promising but not unwaveringly so.  The safety numbers are similar, but with a few deaths that would need further investigation:

The most common adverse events reported in the 814-patient vedolizumab arm (>8.0 percent) were Crohn’s disease exacerbation, arthralgia, pyrexia, nasopharyngitis, headache, nausea and abdominal pain. The most common adverse events reported in the 301-patient placebo arm (≥8.0 percent) were Crohn’s disease exacerbation, headache, arthralgia, pyrexia, abdominal pain, nausea, and nasopharyngitis. Five deaths occurred during the study period, four among patients receiving vedolizumab (one death each from Crohn’s disease with sepsis, intentional overdose of prescription medication, myocarditis, and septic shock) and one in the placebo group (from bronchopneumonia)(3)

While the numbers look like there is potential, there is one factor that the authors note and may have artificially increased the aggregate numbers for the vedolizumab group.  Specifically, the individuals who were response in the induction phase were selected to have vedolizumab in the maintenance phase, in addition to an open label group.  The responsive group may indicate there is a particular genotype or other factor that will indicate who is responsive, or it could represent a particularly “healthy” portion of the population from the start.  Teasing out these numbers and finding the long term safety profile may require large population monitoring post-approval, but it appears that this may be a viable alternative therapy for at least a portion of the non-responsive patient population with UC and Crohn’s disease.  Approval for both indications is currently in progress in the US and Europe.

Bottom Line

·         Clinical trials with vedolizumab show promise in a high risk population of IBD patients.
·         The UC responsiveness for induction and maintenance was good.  For Crohn’s, it appears the maintenance numbers were better than induction numbers.
·         Vedolizumab is likely to be a second-line treatment (at least initially) for those with IBD that are non-responsive to anti-TNF-alpha therapies.

1.    Soler, Dulce, Tobias Chapman, Li-Li Yang, Tim Wyant, Robert Egan, and Eric R. Fedyk. "The binding specificity and selective antagonism of vedolizumab, an anti-α4β7 integrin therapeutic antibody in development for inflammatory bowel diseases." Journal of Pharmacology and Experimental Therapeutics 330, no. 3 (2009): 864-875.
2.    Feagan B, Rutgeerts P, Sands B, et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2013;369;8:699-710.

3.    Sandborn W, Feagan B, Rutgeerts P, et al. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2013;369;8:711-721.

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