Therapy of Inflammatory Bowel Disease: What to Expect in the Next Decade

David A. Leiman; Gary R. Lichtenstein


Curr Opin Gastroenterol 

In This Article

Antiadhesion Molecules

Natalizumab, a humanized IgG4 monoclonal antibody directed against the α4 integrin adhesion molecule involved in endothelial leukocyte migration, was initially approved by the Food and Drug Administration (FDA) for the treatment of multiple sclerosis,[13] but its efficacy was demonstrated in Crohn's disease for both induction and maintenance of remission.[14,15] Lingering concerns over its association with progressive multifocal leukoencephalopathy have led to a search for gut-specific antiintegrin action that would eliminate this risk. Drugs with selective effects in the α4β7 integrin and mucosal adhesion molecule (MadCAM-1) pathway were sought. The results of the subsequent GEMINI studies investigating vedolizumab for both induction and maintenance in ulcerative colitis and Crohn's disease were published in 2013.[16,17]

In the Crohn's disease study, 368 patients were randomized to vedolizumab or placebo. Disease activity was measured at week 6 by assessing the reduction of Crohn's disease activity index (CDAI). Patients on vedolizumab had a statistically significant difference in clinical remission of 14.5 versus 6.8% in placebo (P = 0.02) but no difference in CDAI-100 response or reduction in mean C-reactive protein (CRP) levels. A second cohort was given open-label vedolizumab and a total of 461 responders from both cohorts continued in the maintenance portion of the trial; patients were randomized to receive drug every 4 or 8 weeks or placebo for 52 weeks. There was statistical significance in clinical remission, CDAI-100 response, and glucocorticoid-free remission at week 52 in the every 4 or 8-week group versus placebo (P < 0.001 and 0.004, respectively).[17]

A similarly designed study was conducted for vedolizumab in ulcerative colitis; 374 patients were randomised to either drug or placebo as part of induction. The response for week 6 was measured by the Mayo score and documented mucosal healing. During induction, 47.1% of the patients on vedolizumab versus 25.5% of the patients on placebo achieved remission (P < 0.001). A second cohort of patients received open-label vedolizumab and responders from both cohorts were included in the maintenance trial that evaluated clinical remission at week 52. Patients were randomized to receive drug every 4 or 8 weeks or placebo. A total of 41.8% maintained remission when receiving medication every 8 weeks compared with 44.8% who received drug every 4 weeks; patients on placebo had maintenance of remission at a rate of 15.9%. There was a statistically significant difference in maintenance of remission between patients who received drug every 8 weeks versus placebo (P < 0.001) and those receiving drug every 4 weeks versus placebo (P < 0.001).[16] Based on these findings, the drug was approved for use in adults with moderate to severe ulcerative colitis and moderate to severe Crohn's disease when one or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor blocker medications) have not resulted in an adequate response.[18]

Another adhesion molecule blocker, AJM300, which has broad α4 integrin antagonist properties, has been tested in patients with active Crohn's disease. These data were published in a 2009 abstract, showing a significant decrease in CDAI between groups on higher doses as well as reduction in C-reactive protein.[19] Recently, the company developing AJM300 released data from a phase IIa study showing efficacy in the treatment of patients with ulcerative colitis.[20] It reports that 102 patients in 42 Japanese sites were studied to assess the primary end point of clinical response rate at 8 weeks post administration, with an intention to induce remission rates that were significantly higher in the AJM300 treatment group compared with patients receiving placebo. These preliminary studies suggest that AJM300 could provide an oral option for ulcerative colitis and Crohn's disease, though further investigative studies are needed.

Recently published data from the EUCALYPTUS trial, a phase II randomized, double-blind, placebo-controlled induction study to evaluate efficacy and safety in patients with refractory moderate-to-severe active ulcerative colitis, show promise for another molecule in the antiadhesion molecule family. Etrolizumab, which targets the β7 subunit, provides the advantage of not penetrating into the central nervous system. In EUCALYPTUS, 124 patients were randomized to two dose levels of drug (100 mg monthly subcutaneous or 300 mg monthly subcutaneous and loading dose of 420 mg subcutaneous between week 0 and 2) or placebo for three doses with demonstration of safety and efficacy.[21] Another agent, an anti-MadCAM-1 antibody (PF-00547659) showed encouraging results in a 12-week study of 80 patients with active ulcerative colitis with a primary end point for safety.[22] Antagonists of β7, such as AMG181, will also be studied more in the future. This suggests that the adhesion molecule pathway will continue to provide drug targets going forward. Many physicians anticipate that vedolizumab will gain regulatory approval for treatment of patients with ulcerative colitis soon.