MuDelta (Mu Opioid Receptor Agonist and Delta Opioid Receptor Antagonist)

Diarrheal predominant irritable bowel syndrome affects about 12 million Americans. The condition involves abdominal pain, bloating and discomfort, and altered bowel habits with overt inflammatory abnormalities. This is an underserved market with limited treatment options for patients.

MuDelta is a Phase III-ready drug candidate that is a “first-in-class” locally active mu opioid receptor agonist and delta opioid receptor antagonist that is being developed for treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). In January 2011, MuDelta was granted a “fast track” development status by the U.S. Food and Drug Administration (FDA).

In vivo studies indicate that the activity of Mu Delta at the two different opioid receptors controls gastrointestinal (GI) function while decreasing the pain and discomfort that can come from over modulating GI function. The activity of MuDelta also suggests it will not have some of the side effect risks of marketed products. For example, Mu Delta is locally active in the gut and very little gets into the systemic circulation, thus potentially decreasing the central nervous system and other systemic side effects associated with other IBS therapies.

Furiex has successfully completed a Phase II proof-of-concept (POC) study on an oral formulation of MuDelta, the primary objective of which was to establish safety and efficacy in a 12-week randomized, double-blind placebo-controlled trial. The study achieved statistically and clinically significant results for its primary endpoint as well as a number of secondary endpoints. MuDelta demonstrated durable efficacy in improving IBS diarrhea and pain symptoms over the 12-week treatment period.

A total of 807 patients with IBS-D (based on the Rome III diagnostic criteria) with baseline weekly average stool consistency scores of at least 5.5 (on a one to seven Bristol Stool Scale, or BSS, with seven representing the worst diarrheal symptoms) and baseline weekly average worst abdominal pain of at least three (on a zero to 10 scale, with 10 representing the worst abdominal pain) were enrolled in the trial and randomized to receive twice daily (BID) treatment with either placebo or MuDelta at doses of 5 mg, 25 mg, 100 mg or 200 mg. The 5 mg dose group was dropped after a planned interim analysis, due to limited efficacy, while the other three doses were continued.

The primary endpoint was a composite analysis of stool consistency and abdominal pain at week four compared with baseline symptoms.

• For the primary endpoint, a significantly higher rate of treatment response was seen among patients treated with MuDelta at 25 mg BID (12.0 percent; P=0.041) and 200 mg BID (13.8 percent; P=0.015) compared to placebo (5.7 percent). A trend toward a higher rate of treatment response was also seen among patients treated with MuDelta at 100 mg BID (11.0 percent; P=0.090) compared to placebo (5.7 percent).

Following discussions with the FDA, additional analyses were performed on the overall study response based on patients meeting pre-specified improvement in symptoms for at least 50 percent of the time on study. Study response was defined by meeting the composite daily responder definition of at least a 30 percent reduction in worst abdominal pain from baseline and a daily BSS score of less than five on the same day for at least 50 percent of the days on study. MuDelta was statistically superior to placebo for this study responder endpoint, which we believe will be suitable for pivotal Phase III trials. As shown in the figure below, a significantly greater percentage of patients met the study responder definition among patients treated with MuDelta at 100 mg BID (28.0 percent; P=0.002) and 200 mg BID (28.7 percent; P=0.002) compared to placebo (13.9 percent).

Statistically significant treatment effects were also seen in pre-specified secondary analyses of patient reported outcomes, namely adequate relief of IBS symptoms and two different measures assessing quality of life. These endpoints assess patients' overall symptom relief and health outcomes:

• A significantly greater percentage of patients reported adequate relief of their IBS-D symptoms at week 12 following treatment with MuDelta at 100 mg BID (72.4 percent; P<0.001) and 200 mg BID (64.0 percent; P=0.031) compared to placebo (51.4 percent). This is the endpoint that has previously been accepted by the FDA for evaluation of IBS therapies.
• A statistically significant increase in improvement on the IBS quality of life questionnaire at week 12 was seen for patients treated with MuDelta at 100 mg BID compared to placebo (P=0.029).
• A statistically significant increase in improvement on the EuroQoL-5 dimension health questionnaire at week 12 was seen for patients treated with MuDelta at 100 mg BID compared to placebo-treated patients (P=0.012).

MuDelta was well-tolerated and had a favorable safety profile. The most commonly reported adverse events included nausea (7.2 percent vs. 4.4 percent placebo), vomiting (4.4 percent vs. 0.6 percent placebo) and abdominal pain (4.2 percent vs.1.9 percent placebo) (average rates across treatment arms). During the study, three patients who received MuDelta experienced pancreatitis (0.4 percent); these events occurred very early in the course of treatment and resolved rapidly. The study investigators assessed these events as unrelated to treatment, and two of the three patients had underlying medical conditions that predispose to pancreatitis. One additional patient reported pancreatitis more than two weeks after discontinuing MuDelta for unrelated reasons. Based on an assessment during the interim analysis, the study protocol was modified to exclude patients who are predisposed to pancreatitis, after implementation of which, 210 additional patients were enrolled with no further events.