POSTOPERATIVE CROHN DISEASE
Several important clinical trials were first reported during the meeting.
An anxiously awaited multicenter trial of infliximab in the setting of postoperative Crohn disease was presented by Regueiro and colleagues.[11] The PREVENT study was a global, randomized, double-blind, placebo-controlled trial enrolling patients with an "increased risk" for recurrent Crohn disease after ileocolonic resections. Patients were randomly assigned to receive infliximab 5 mg/kg or placebo every 8 weeks for nearly 4 years. No loading dose was administered. The primary endpoint was clinical recurrence before week 76. The major secondary endpoint was endoscopic recurrence scored by a central reader.
Although the primary endpoint was not achieved at week 76 or 104, there was clear evidence of less severe endoscopic findings at week 76 in patients receiving infliximab. The results were disappointing from a clinical standpoint, but it does appear that postoperative infliximab will probably delay subsequent clinical recurrences. Substantiation of clinical benefits will probably require more than several years of observation.
NEW AGENTS FOR IBD
Phase 2 results also were presented for three novel agents being developed for IBD.
Prior and ongoing studies of antibodies targeting the p40 subunit common to IL-12 and IL-23 have suggested efficacy in patients with Crohn disease who had failed treatment with anti-TNF agents. MEDI2070 is a specific IgG2 monoclonal antibody that binds to the p19 unit and specifically targets IL-23. It was evaluated in a randomized, double blind, placebo-controlled trial in patients with active Crohn disease who had failed anti-TNF antibody therapy.[12] The investigative team demonstrated statistically significant benefits in clinical response, remission, and reduction in C-reactive protein and fecal calprotectin biomarkers by 8 weeks.
Two phase 2 studies on the inhibition of MAdCAM also were presented. PF-00547659 is a fully human monoclonal antibody that binds to MAdCAM on endothelial cells. Sandborn[13] and Reinisch[14] reported the results from trials in Crohn disease (OPERA study) and ulcerative colitis (TURANDOT study), respectively. In the Crohn disease study, the primary endpoint was not met due to a higher than anticipated placebo response. However, patients with elevated C-reactive protein at baseline had better results with PF-00547659 compared with placebo. In contrast, significant differences were found between the anti-MAdCAM antibody and placebo in the TURANDOT study after 12 weeks, although clinical remission rates were relatively low (11%-17% vs 2.7% with placebo).
Another means of inhibiting lymphocyte traffic to the gut involves a blockade of the sphingosine-1-phosphate (S1P) receptors 1 and 5, which prevents lymphocytes from egressing into the blood stream and tissues. RPC 1063 (ozanimod) is an oral S1P receptor modulator that is in clinical development for multiple sclerosis and ulcerative colitis. The TOUCHSTONE study was a phase 2, 8-week induction trial assessing low- and high-dose ozanimod in 197 patients with moderate to severe ulcerative colitis.[15] Both clinical remission and response rates with both doses of ozanimod were superior to placebo. The safety profile appeared to be excellent, with the most commonly observed adverse events related to the underlying disease. These results are promising for an oral agent with a novel mechanism of action in ulcerative colitis.
Although only a small fraction of the abstracts have been reviewed, it is clear that substantial progress continues to be made as the diagnosis, course, and management of IBD continue to evolve.
