Eluxadoline (Viberzi, Allergan), a new oral agent with mixed opioid effects, has met fairly stringent criteria for treatment response in men and women with irritable bowel syndrome (IBS) with predominant diarrhea, according to two phase 3 clinical trials published in the January 21 issue of the New England Journal of Medicine.
"Our primary outcome measure required simultaneous improvement in the daily scores for the worst abdominal pain and stool consistency on the same day for at least 50% of the days assessed; this end point is currently one of those recommended by the regulatory agencies in the United States and Europe to show treatment effect in trials involving patients with IBS and diarrhea," Anthony Lembo, MD, from Harvard Medical School, Boston, Massachusetts, and colleagues write.
"Patients who received eluxadoline reported a decrease in stool frequency and in urgency, which are two of the most bothersome symptoms of IBS with diarrhea."
The investigators randomly assigned 2427 adults with IBS and diarrhea to eluxadoline at a dose of 75 or 100 mg or placebo, twice a day, for 26 weeks (the IBS-3002 trial), or to the same three treatment groups for 52 weeks (IBS-3001 trial). Safety data were collected for 26 weeks in the IBS-3002 trial and for 52 weeks in the IBS-3001 trial. Loperamide was allowed as needed during the double-blind study interval, but patients were told they could take no more than four doses over the course of 24 hours.
From weeks 1 through 12, the proportion of patients receiving either dose of eluxadoline in the IBS-3001 trial who achieved a US Food and Drug Administration (FDA) end-point response was significantly greater, at 23.9% among those receiving the 75-mg dose and 25.1% for those receiving the 100-mg dose, compared with 17.1% of placebo controls (P = .01 and P = .004, respectively).
From weeks 1 through 26, the proportion of patients in the IBS-3001 trial receiving active treatment who reached the European Medicines Agency end-point response was higher in both dosing groups, at 23.4% in the 75-mg group and 29.3% for the 100-mg group compared with 19.0% for control patients receiving placebo (P = .11 and P < .0001, respectively).
In the IBS-3002 trial, 30.4% of those in the 75-mg group and 32.7% in the 100-mg group similarly reached a European Medicines Agency end-point response compared with 20.2% of placebo controls (P = .001 and P < .001, respectively).
"In addition, both doses of eluxadoline were significantly superior to placebo with respect to stool consistency, frequency, and urgency, although no significant reduction in episodes of incontinence was noted," the investigators observe.
The superior response to eluxadoline over placebo was seen within the first week of treatment, they add.
"This is a very provocative study looking at multicenter parallel studies in very large numbers of patients and with a really impressive study design which used [FDA] targets of a composite endpoint," David Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, who was not involved in the study, told Medscape Medicine News.
"So it looks like eluxadoline leads to significant improvements in [IBS with predominant diarrhea], and it has minimal side effects, with seemingly very efficacious results."
Abdominal Pain Scores
There was no real improvement in mean scores for the worst abdominal pain or in the percentage of patients who reported a 30% or more improvement in the score for worst abdominal pain in either study.
However, when the researchers used either a 40% or 50% or greater reduction in abdominal pain scores, improvement in abdominal pain was significant for patients receiving the 100-mg dose of the study drug, both as assessed at week 1 through 12 and at week 1 through 26. The same significant improvement in abdominal pain was also seen in patients receiving eluxadoline at a dose of 75 mg, twice daily, from weeks 1 through 12.
"At week 12, the symptoms of abdominal bloating were significantly less severe among patients who received the 100-mg dose of eluxadoline than among those who received placebo," the researchers add.
"[And b]oth doses of eluxadoline were significantly superior to placebo with respect to the end points of adequate relief of IBS symptoms, scores for global symptoms, and scores on the [Irritable Bowel Syndrome Quality of Life] questionnaire."
Data regarding the safety of active treatment were analyzed from all patients up to 26 weeks in the IBS-3002 trial and through 52 weeks in the IBS-3001 study.
The most common adverse events in the 100-mg, twice-daily dosing group were nausea (7.5%) and constipation (8.6%), but discontinuation of active treatment or placebo because of adverse events was infrequent in both studies.
Serious adverse events occurred in 4.2% of individuals who received the lower dose of eluxadoline, 4.8% of those who received the higher dose of the drug, and 3.0% of patients who received placebo.
However, five patients developed pancreatitis while receiving active therapy, whereas eight patients had acute abdominal pain associated with abrupt increases in liver enzymes.
Most cases were associated with the absence of a gallbladder, and the majority occurred within a few weeks after treatment initiation.
"Identifying patients with IBS with diarrhea who are at risk for acute pancreatitis because of the absence of a gallbladder or excessive alcohol consumption is important before initiating therapy with eluxadoline," Dr Lembo and colleagues caution.
Limited Treatment Options
Commenting further on the study, Dr Johnson told Medscape Medical News that up until about 6 months ago, treatments for IBS with diarrhea had been very limited.
"We had one drug, alosetron (Lotronex [Prometheus Laboratories Inc]), that was introduced about 15 years ago, and then it was rapidly withdrawn in the year 2000 because of its ischemic colitis risk, which was real, although it was not that disproportionate from the background risk in this population," Dr Johnson explained.
Alosetron was subsequently reinstated, but the FDA only recently withdrew cumbersome reporting requirements, making the drug easier to prescribe.
Rifaximin (Xifaxan, Salix Pharmaceuticals) was also recently approved for IBS with diarrhea, and an interesting medical food, a slow-release peppermint oil formulation (IBgard, IM HealthScience), appears to significantly reduce severe abdominal symptoms of IBS with diarrhea as well as abdominal pain, according to news reports from Digestive Disease Week in 2015.
In addition, reports of a serum-derived bovine immunoglobulin (EnteraGam, Entera Health, Inc, among others) have also been given a "fair amount of traction" as a possible alternative treatment for IBS with diarrhea, Dr Johnson noted.
"Suddenly we have all these potential alternatives for [IBS with predominant diarrhea], plus the reporting requirements for alosetron have now been relaxed, so we have more opportunities for the treatment of our patients," he said.
"What the FDA will now do is look at what the best dose of eluxadoline might be, and we'll see if the pancreatitis issues that came up in these new studies raise a red flag because even though we are talking about very small numbers of patients, pancreatitis is a clinically significant event, and it could be that other drugs at least at this point in time have better safety profile," Dr Johnson concluded.
The study was supported by Furiex Pharmaceuticals, an affiliate of Allergan. Dr Lembo reports receiving fees for serving on advisory boards from Allergan, Furiex Pharmaceuticals, Prometheus Laboratories, Salix Pharmaceuticals, Valeant Pharmaceuticals, Forest Laboratories, Alkermes, AstraZeneca, and Ironwood Pharmaceuticals. One coauthor reports receiving fees for serving on advisory boards from Ironwood Pharmaceuticals, Forest Laboratories, Prometheus Laboratories, and Salix Pharmaceuticals. Seven coauthors report being employees of Activis (formerly Furiex Pharmaceuticals), and six coauthors hold stock in Furiex Pharmaceuticals. The other authors have disclosed no relevant financial relationships. Dr Johnson reports that he has serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for WebMD, AbbVie, Centoco, CRH Medical, Pfizer, Medico Experience, Medigus, and the American College of Gastroenterology. Dr Johnson reports that he has serve(d) as a speaker or member of a speakers bureau for Takeda, has received a research grant from Exact Sciences and Epigenomics, and has received income in an amount equal to or greater than $250 from AbbVie, Centocor/Janssen, CRH Medical, Pfizer, ACG, Takeda, Medigus, and Epigenomics.
N Engl J Med. 2016;374:242-253. Abstract
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Cite this: Mixed Opioid Agent Adds to Growing List of Therapies for IBS-D - Medscape - Jan 27, 2016.