CHICAGO – A first-in-class oral drug targeting diarrhea-predominant irritable bowel syndrome achieved its primary and secondary endpoints in a pair of large phase III trials presented at the annual Digestive Disease Week.
Eluxadoline is a locally active mixed mu-opioid receptor agonist and delta-opioid receptor antagonist. It was compared with placebo at doses of 75 mg and 100 mg b.i.d. in the two double-blind phase III trials, which totaled 2,427 patients with diarrhea-predominant irritable bowel syndrome (IBS-D) by Rome III criteria. The trials featured identical outcome measures; however, one study entailed 12 weeks of double-blind therapy in accord with a Food and Drug Administration request, while the other involved 26 weeks as stipulated by the European Medicines Agency, explained Dr. Anthony Lembo, director of the GI motility center at Beth Israel Deaconess Medical Center, Boston.
Bruce Jancin/Frontline Medical News
Dr. Anthony Lembo
The primary endpoint was a composite requiring at least 30% improvement in daily abdominal pain, compared with baseline, and improved stool consistency as reflected in a Bristol Stool Score of less than 5. In the 12-week trial, this was achieved by 27% of patients on eluxadoline at 100 mg b.i.d. and by 26.2% on 75 mg b.i.d., both significantly better rates than the 16.7% in placebo-treated controls. In the 26-week study, the rates were 31%, 26.7%, and 19.5%, respectively. Improvement in the eluxadoline group was seen within the first several days of treatment.
The drug was equally effective in men and women.
Turning to secondary endpoints, Dr. Lembo highlighted the finding that 42% of the eluxadoline 100 mg b.i.d. group reported more than 50% of their days during weeks 1-12 as being urgency free, compared with 21% of controls. Twenty-nine percent of those on the higher dose reported more than 75% of days were urgency free, compared with 12% on placebo.
Bowel movement frequency improved from a baseline average of 4.9 per day to 2.9 per day at week 26 in the group on eluxadoline 100 mg b.i.d., significantly better than the 3.3 movements per day in controls. A 40% or greater improvement in abdominal pain score was reported at week 12 by 43.2% of patients on eluxadoline 100 mg b.i.d. compared with 35.8% of controls.
Safety concerns arose. Eight confirmed cases of hepatobiliary sphincter of Oddi spasm occurred, all in patients on eluxadoline, and all in patients with prior cholecystectomy. Seven of the eight patients were in the high-dose therapy arm. Six cases occurred during the first week of therapy. All eight cases were rapidly reversed upon prompt drug discontinuation; seven were managed on an outpatient basis.
In addition, there were five confirmed cases of pancreatitis, again all in the eluxadoline group. All five cases were mild, and all occurred in patients with pancreatitis risk factors: Three were chronic heavy alcohol abusers, one had biliary sludge, and one had a history of cholecystectomy with sphincter of Oddi spasm. These five patients had brief hospitalizations with no sequelae.
Several audience members greeted this news as a potential roadblock in the drug’s development. Dr. Lembo took a different view.
"These risks can be mitigated through appropriate patient selection and education," the gastroenterologist said. "There does seem to be a group of patients that seem to be particularly at risk: those with prior cholecystectomy or chronic alcohol use. If that’s true and the drug is relatively safe in the remainder of the population, then I think the risk/benefit ratio would be acceptable, especially since there are relatively few other treatment options for these patients."
Other audience members were critical of eluxadoline’s efficacy. "You have a drug that has at best extremely modest effects, with about a 10% absolute overall improvement over placebo, which is statistically significant primarily because you had so many patients in the studies," one gastroenterologist asserted.
Dr. Lembo replied that this magnitude of benefit is similar to what’s seen with drugs now approved for the common and vexing problem of IBS-D.
The phase III trials were sponsored by Furiex Pharmaceuticals. Dr. Lembo reported serving as an adviser or consultant to five pharmaceutical companies, not including Furiex.