SAN ANTONIO – Darren M. Brenner, MD, reported at the annual meeting of the American College of Gastroenterology.
“From the totality of the clinical trials data we have now, we believe that eluxadoline can be effective both in patients who are naive to other treatments and in patients who have failed loperamide therapy,” concluded Dr. Brenner, a gastroenterologist at Northwestern University, Chicago.
Eluxadoline (Viberzi) is a novel mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist approved by the Food and Drug Administration for treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. In contrast, loperamide, a mu-opioid receptor agonist, is not approved for that indication. Yet loperamide is widely prescribed for this purpose, despite the fact that both the Canadian Association of Gastroenterology and the ACG now recommend against this practice.
“There is a lack of conclusive evidence to support the use of loperamide for the relief of global IBS-D symptoms. It works on the stool symptoms – stool frequency and texture – but has never been shown to be beneficial for the abdominal pain symptoms or discomfort or bloating. That being said, as practitioners we continue to see loperamide used as a first-line agent,” Dr. Brenner noted.
RELIEF was a multicenter, prospective, double-blind study which randomized 346 patients with moderate to severe IBS-D to eluxadoline at 100 mg twice daily or placebo for 12 weeks. All participants were required to have an intact gallbladder as per the drug’s labeling guidance, and all had a self-reported recent inadequate response to loperamide.
The primary composite endpoint in the RELIEF trial was a 40% or greater improvement from baseline in the 11-point Daily Worst Abdominal Pain score plus a Bristol Stool Form score below 5 on the same day for at least 50% of study days. At baseline, participants had an average Worst Abdominal Pain score of 6.2 on the 0-10 scale and a Bristol score of 6.2. The primary endpoint was achieved at week 12 in 23% of the eluxadoline group, significantly better than the 10% rate in controls. The eluxadoline group also showed significantly greater improvement on the many secondary endpoints having to do with urgency-free days, stool consistency, bowel movement frequency, abdominal discomfort, bloating, and the experience of adequate relief of symptoms.
The safety profile of eluxadoline mirrored that of placebo, with no serious adverse events recorded in either study arm and a 2.9% study discontinuation rate because of treatment-emergent adverse events in the eluxadoline group. Asked why he thinks eluxadoline was effective in improving the full range of IBS-D symptoms when loperamide wasn’t, even though both drugs are mu-opioid receptor agonists, Dr. Brenner replied, “The problem is mu receptors line the entire GI tract, so you can actually push somebody from diarrhea to opioid-induced constipation – and that’s not the goal. What delta does is alleviate some of the adverse events by binding to the receptor, which results in increased transit time, reduced secretion, and increased absorption. Delta brings things back towards the center. We also believe antagonism of delta potentiates analgesic effects at the mu receptor, improves the pain component, gut symptoms, and stool symptoms.”
Dr. Brenner reported serving as a consultant to and member of a speaker’s bureau for Allergan, which markets eluxadoline and sponsored the RELIEF trial.