The new drug eluxadoline improved symptoms of irritable bowel syndrome (IBS) with diarrhea in two manufacturer-sponsored phase III clinical trials involving 2,427 patients, according to a report published online January 21 in the New England Journal of Medicine.
At present, treatment options for IBS with diarrhea are limited and are frequently ineffective. Eluxadoline is a peripherally acting agonist of three different opioid receptors which, in the enteric circuitry of the GI tract, act in regulating GI motility, secretion, and visceral sensation. The agent is thought to decrease visceral hypersensitivity without disrupting intestinal motility completely, said Dr. Anthony J. Lembo of Harvard University and Beth Israel Deaconess Medical Center, Boston, and his associates.
Dr. Anthony J. Lembo
They assessed patient response to the drug in two randomized, double-blind, placebo-controlled trials conducted at hundreds of medical centers in the U.S., Canada, and the United Kingdom. Study participants received oral tablets of 75-mg eluxadoline, 100-mg eluxadoline, or matching placebos for 26 weeks, followed by either an additional 26 weeks of treatment solely for safety assessment in one study or an additional 4-week period of placebo withdrawal in the other.
The primary efficacy endpoint was the proportion of patients who reported a reduction of at least 30% in baseline scores for worst abdominal pain together with improvement on stool-consistency scores, on at least half the days of follow-up. This endpoint was reached in a significantly greater proportion of patients taking 75-mg eluxadoline (23.4%) or 100-mg eluxadoline (29.3%) than placebo (19.0%) in the first trial. Treatment responses were similar in the second trial (30.4% and 32.7% vs 20.2%, respectively).
Both doses of eluxadoline also improved secondary endpoints of stool consistency, frequency, and urgency, but did not reduce episodes of incontinence. Both doses also were superior to placebo in providing “adequate” relief of IBS symptoms, improving global symptom scores, and improving disease-related quality of life. Treatment responses were first observed within 1 week of initiating therapy and persisted throughout the 26-week assessment period, and the magnitude of benefit was comparable to that reported for alosetron and rifaximin, the investigators said (N Engl J Med. 2016 Jan 21. doi: 10.1056/NEJMoa1505180).
Regarding safety, no treatment-related trends were noted in serum chemical values or hematologic values over time. Isolated renal and metabolic events occurred, but “there was no pattern across study groups.” Serious adverse events occurred in more patients taking 75-mg (4.2%) or 100-mg (4.8%) eluxadoline, compared with those taking placebo (3.0%). Five patients taking the active drug developed pancreatitis (0.3%) and 8 (0.5%) developed acute abdominal pain in conjunction with abrupt increases in liver enzymes, which was deemed to stem from spasm of the sphincter of Oddi. Most of these events developed within 2 weeks of initiating treatment. No patients in the placebo groups developed these problems.
In addition, two patients taking the active drug reported feeling euphoria and two reported feeling drunk, while none of the patients in the placebo group reported such adverse events. The most common adverse events during the study were nausea, constipation, and abdominal pain. Rates of treatment discontinuation were higher among patients taking both doses of active drug than among those taking placebo.
IBS symptoms did not worsen appreciably during the withdrawal period or for 2 weeks of follow-up after treatment ended.