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Phase II Results Support MuDelta for Diarrhea-Predominant IBS
by Ted Bosworth
www.gastroendonews.com/ViewArticle.aspx?...&i_id=831&a_id=20623
A novel medication for the treatment of irritable bowel syndrome (IBS) has demonstrated sufficient efficacy and safety in multicenter Phase II studies and is now being sent into the registration trials needed for regulatory approval.
The new agent, currently dubbed MuDelta, combines a μ-opioid receptor agonist with a δ-opioid receptor antagonist, which together are designed to slow motility while offering concomitant analgesia. One of the most attractive features of this paired receptor molecule is that it acts locally on the gut and thus avoids the systemic side effects that have plagued previous IBS treatments. Furiex Pharmaceuticals is developing the drug, which has been granted a fast-track development status by the FDA.
The Phase II results, presented at the 2011 American College of Gastroenterology meeting, support this strategy, according to Charles Randall, MD, medical director of clinical research, Gastroenterology Clinic of San Antonio and a faculty member of the University of Texas Health Science Center, San Antonio.
In the study, the most effective doses of the new agent were consistently more effective than placebo. The intent-to-treat, double-blind, dose-ranging Phase II study initially included five arms, including four MuDelta dosage groups (ranging from 5 to 200 mg) and a placebo group. After a four-week interim analysis, the 5-mg dose was discontinued due to lack of activity, leaving doses of 25, 100 and 200 mg in the efficacy and safety analysis that was conducted at 12 weeks. Although all of the patients initially had diarrhea-predominant IBS, as defined by the Rome criteria, patients also had to demonstrate an ability to complete a symptom diary over one week before they entered a two-week screening.
In an effort to control for the notorious placebo effect associated with trials of IBS treatments, the investigators did not average the rates of symptom relief on patients’ diary cards. Instead, patients needed to achieve a sustained reduction in pain as well as an average Bristol Stool Score (BSS) of 4 or less on two-thirds of the study days. The rationale for this type of evaluation was to reduce the impact of fluctuations in disease activity unrelated to treatment.
“Many studies have averaged scores so that a patient with bad symptoms on days 1 through 4 but few symptoms on days 5 through 7 would demonstrate moderate disease activity even though symptoms often were significant,” Dr. Randall explained.
He also noted that durability of effect is important to patients. For this reason, the FDA is increasingly looking for evidence of sustained relief in considering efficacy of new drugs.
The first analysis at four weeks showed that all doses of MuDelta were superior to placebo. Overall—whether measured using pain relief, diarrhea or both—the proportion of responders was about twofold higher in the MuDelta groups compared with placebo. After 12 weeks of therapy, the 100- and 200-mg doses remained significantly more effective than placebo.
On quality-of-life measures, both the 100- and 200-mg doses were significantly better than placebo overall and in several specific domains, including mood and IBS-related disability.
At four weeks, about 50% of placebo patients reported adequate pain relief, but the proportion of those with adequate pain relief fell in all groups over time except in the 100-mg dose group, which continued to demonstrate relief throughout the study.
About 50% of patients reported adverse events (AEs). Although the rate and type of serious AEs were comparable on active therapy and placebo, there was a higher rate of discontinuation because of AEs among patients on the 200-mg dose. AEs that appeared to be related to therapy included abdominal pain, nausea and vomiting, dizziness and headache. Constipation was more common in patients on the 100-mg dose than in those on other doses of active therapy, but this was reported in only 6% of patients.
Based on the results of this study, there are plans to pursue Phase III studies with the 100-mg dose. According to Dr. Randall, the results support the strategy of a biphasic or paired receptor molecule that relieves diarrhea and IBS-related pain with a relatively low risk for constipation. The exact role that the μ-opioid receptor agonism and δ-opioid receptor antagonism, which are both associated with some degree of analgesia, play in producing the effects observed in this trial are unknown, but Dr. Randall characterized the agent as “promising.”
According to Michael Camilleri, MD, professor of medicine at Mayo Clinic, Rochester, Minn., and a widely recognized expert on IBS, this dual receptor activity “is of potential interest.” He noted that the ability of the μ-opioid agonist in this compound to retard gastrointestinal transit and reduce pain “is consistent with the effects of other μ-agonists.” The key advance would be if this compound does, in fact, avoid central side effects like drowsiness or the potential for addiction. However, he indicated that the clinical advances of an effect on a δ-receptor are less well established, suggesting that “further studies appear to be required to characterize the ability of the combination of pharmacologic actions on both sensation and motility.”
Still, Dr. Camilleri characterized the clinical trial as “quite impressive, despite the apparently small number of responders based on the FDA-recommended end points.” He questioned the lack of a clear dose–response curve, but he did indicate that overall response is similar to those reported for linaclotide, another IBS drug in development, at the 2011 Digestive Disease Week meeting (Rao et al). While calling MuDelta promising, Dr. Camilleri cautioned that the optimal methods for testing new IBS agents are not yet defined.
“The composite end points appear to belittle the potential benefit of these medications,” he said. “Further studies of the pharmacodynamics and central side effects, as well as the clinical efficacy on secondary end points like abdominal pain, bloating, stool consistency and number of bowel movements per week will help clinicians understand the role of such an agent in the management of IBS nonconstipated patients.”
