A friend of mine, who has spent 15 years dealing with the ebbs and flows of ulcerative colitis (UC), is the kind of patient who would hope her physician pays attention to the results of two RCTs published this week in NEJM. She is one of an estimated 1.4 million Americans diagnosed with UC or Crohn’s disease, the two varieties of inflammatory bowel disease (IBD). She’s been on and off the standard drugs, stopped methotrexate when she became pregnant and worries that one day her personal nightmare will come true. That nightmare would be surgery to “cure” the ulcerative colitis and leave her a “bag” lady. She’d much rather deal with individual drugs and the side effects of each drug. Now she may have the chance for new therapy and, perhaps, new side effects.
This week’s issue contains results of two RCTs, one for UC and one for Crohn’s disease, with a total enrollment of 2,010 patients. Both trials limited enrollment to IBD patients who either had no response to other therapy or had unacceptable side effects. The standard drugs used for both UC and Crohn’s include glucocorticoids, immunosuppressive medications (azathioprine and 6-mercpatopurine) or tumor necrosis factor antagonists.
In an accompanying editorial, Dr. Fabio Cominelli noted that the trials were based on one drug in a new class of monoclonal blocking antibodies, and have revolutionized the way gastroenterologists treat IBD, “significantly improving patient quality of life by reducing the need for hospitalizations and surgeries.” The prototypic biological approach in IBD is the use of monoclonal antibodies targeting the pro-inflammatory cytokine tumor necrosis factor (TNF). The new drugs also present the risk of new challenges with potential serious side effects.
Both trials were done with vedolizumab, a monoclonal antibody that blocks the entire α4β7 heterodimer. In the UC trial, patients treated with vedolizumab had a 47% clinical response at 6 weeks and up to 45% of the responding patients were in remission at a year. The comparative figures for the patients on placebo were 26% at 6 weeks and 16% at 52 weeks.
Results of the Crohn’s trial were also successful, but showed lower efficacy. Among the patients with Crohn’s disease, 31% had a clinical response at 6 weeks and up to 39% of the responders remained in remission at 52 weeks. The patients who were in the placebo group had a 26% response at 6 weeks and 22% at 52 weeks.
None of the patients treated with vedolizumab in the two trials were reported to have developed progressive multifocal leukoencephalopathy (PML). Earlier work showed that natalizumab, approved for Crohn’s disease in 2008, might lead to the reactivation of JC virus causing destruction of the brain’s white matter and a development of PML. Vedolizumab is believed to specifically inhibit the gut-tropic α4β7 heterodimer, not the α4 subunit, and therefore may avoid the risk of PML, but these trials are too short and too small to provide solid risk estimates.
Reporting of adverse events did differ in the two trials. In the UC trial, no important differences were reported among the study groups. However in the Crohn’s trial, vedolizumab was associated with higher rates of serious adverse events and infections.
Given the better clinical response and fewer adverse events observed in the trial of ulcerative colitis than in the trial of Crohn’s disease, scientists must still untangle the potentially differential effects of vedolizumab in the two types of inflammatory bowel disease. UC is often considered to be a more localized disease by its limitation to superficial mucosal layers of the bowel; Crohn’s can hit any portion of the GI tract and complicates the situation with transmural inflammation, fistulas, and multi-organ involvement.
Patients with IBD who have failed available therapies and the physicians who treat them are eager for new treatment options and will be interested in the results of these two clinical trials. NEJM Deputy Editor Dr. Mary Beth Hamel said, “The two trials might be steps toward improved treatment for patients with IBD.”