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Cholecystokinin A Receptor Antagonists

Overview

Cholecystokinin (CCK), a neurohormonal peptide found in both the central and enteric nervous systems, is involved in the regulation of gastrointestinal motility and secretion. Development activity with regard to antagonists at CCK receptors is limited. The only compound in the later stages of development is RottaPharm’ s dexloxiglumide, which recently encountered problems with respect to efficacy in clinical trials.

Cholecystokinin A Receptor AntagonistsMechanism Of Action

Although its physiological role is not well defined, CCK is believed to act on neuronal and smooth-muscle receptors. CCK is often found in conjunction with — and appears to act much like — substance P, which stimulates gastrointestinal smooth-muscle contraction. The peptide is also thought to act as a neurotransmitter of pain signals through actions on NK receptors. Researchers have noted elevated plasma levels of CCK in patients with chronic pancreatitis and abdominal pain; these effects are believed to be mediated predominantly through CCK1 receptors. Agents antagonizing the actions of CCK at CCK1 receptors in the gut potentially reduce abdominal pain symptoms in irritable bowel syndrome patients.

Dexloxiglumide

In August 2000, Forest Laboratories entered into an agreement with the Italian company RottaPharm (specifically, Rotta Research Lab, a branch of RottaPharm) to develop and market the CCK1 receptor antagonist dexloxiglumide for the treatment of motility abnormalities and pain in patients with C-irritable bowel syndrome in the United States. Forest conducted two Phase III trials involving more than 1,400 irritable bowel syndrome female patients in the United States. These trials were completed in mid 2003, and a U.S. launch was expected for 2004. However, in October 2003, Forest discontinued development of dexloxiglumide in the United States for C-irritable bowel syndrome because the trial failed to show significant efficacy over placebo. Despite this setback, RottaPharm is continuing Phase III trials for C-irritable bowel syndrome, pancreatitis, and gastrointestinal motility disease in Italy.

In a Phase I, Italy, placebo-controlled, double-blind study in Europe involving 469 irritable bowel syndrome patients, C-irritable bowel syndrome and D-irritable bowel syndrome subjects were randomized to receive either dexloxiglumide (200 mg three times daily) or placebo for 12 weeks. Dexloxiglumide was more effective than placebo in relieving irritable bowel syndrome symptoms, and both treatments were well tolerated.

The proportion of responders was higher with dexloxiglumide than with placebo, reaching statistical significance in all patients regardless of their irritable bowel syndrome subgroup (59% versus 45% for placebo) and in C-irritable bowel syndrome patients specifically (60% versus 43% for placebo). In the C-irritable bowel syndrome subjects, dexloxiglumide was also significantly more effective than placebo in terms of the number of pain- and bloating-free days, reductions in straining and incomplete evacuation, and improved global well-being.

The primary end point in both Phase III studies conducted in the United States was the Subject’s Global Assessment of Relief (SGA), which measures abdominal discomfort, pain, and altered bowel habits as perceived by the patient. Preliminary results reported by Forest suggest that development was discontinued because of dexloxiglumide’s lack of significant efficacy over placebo; however, a trend toward efficacy was observed in both trials. Importantly, dexloxiglumide was well tolerated and was not associated with an increased incidence of gallstones, a hypothesized side effect of CCK antagonists.

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