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Last updated on October 7, 2021

Renzapride is a 5-HT receptor modulator in development by Alizyme in Europe and the United States. The agent was initially being developed by SmithKline Beecham, but Alizyme gained full ownership of the compound following SmithKline Beecham’s merger with Glaxo Wellcome. Patient recruitment for Phase III trials began in late 2005.

RenzaprideRenzapride differs from currently marketed 5-HT receptor modulators because it has a distinctive pharmacology. The compound displays both 5-HT3 receptor antagonist and 5-HT4 receptor agonist effects; normally, these two actions oppose each other. Inhibition of 5-HT3 receptors slows gastric motility and reduces transmission of afferent signals between the gut and the brain; stimulation of 5-HT4 receptors triggers peristalsis in the gut. This multireceptor action potentially normalizes motility in irritable bowel syndrome patients.

Studies suggest that, overall, renzapride may be a more potent 5-HT4 receptor agonist than 5-HT3 receptor antagonist; its net effect is to accelerate motility. However, in a Japanese study comparing renzapride with a more selective 5-HT4 receptor agonist in early clinical development (YM-53389), renzapride was less effective in facilitating lower gastrointestinal propulsion. The authors suggest this relative weakness stems from renzapride’s conflicting 5-HT3 receptor antagonism. Because it acts at both receptor subtypes, renzapride has the potential to treat more than one subtype of irritable bowel syndrome; studies are being carried out in patients with both constipation predominant irritable bowel syndrome (C-irritable bowel syndrome) and mixed-symptom irritable bowel syndrome (M-irritable bowel syndrome).

In October 2000, Alizyme announced preliminary results of a Phase Ha trial. The single-blind, placebo-controlled trial involved 20 patients (12 female, 8 male) with C-irritable bowel syndrome. Statistical data from the trial have not been released, but the company claims that renzapride improved colonic motility and gastrointestinal transit time better than placebo. Animal models have shown that renzapride is also a potent stimulator of gastric emptying, but it is unknown if this action directly affects whole-gut transit time in irritable bowel syndrome patients.

In April 2003, Alizyme announced the preliminary results of a Phase lib clinical study. The randomized, double-blind, placebo-controlled, parallel-group,dose-ranging study involved 510C-irritable bowel syndrome patients recruited from general practices in the United Kingdom. The researchers compared the efficacy and safety of three once-daily doses of renzapride (1, 2, and 4mg/day) and placebo over a 12-week period, following a two-week run-in period. The primary end point was the patients’ weekly assessment of abdominal pain and discomfort during weeks 5-12 of the treatment protocol. Patients were classified as responders if they recorded adequate relief in 75% of the weeks of treatment.

Treatment with renzapride increased the responder rate for adequate relief of abdominal pain and discomfort by 9% over treatment with placebo, and it increased bowel movements (statistically significant at 2 and 4 mg/day) and improved stool consistency (statistically significant at 4 mg/day). The study demonstrated that renzapride was well tolerated and had no clinically relevant side effects. The most common adverse events were diarrhea (25.2%) and headache (17.8%), compared with 9.6% and 13.6%, respectively, in the placebo arm.

In September 2003, Alizyme announced preliminary data from a Phase II trial involving 168 M-irritable bowel syndrome patients. This randomized, double-blind, placebo-controlled, dose-ranging study — the first of its kind in an M-irritable bowel syndrome population — was carried out in hospitals in the United Kingdom. As with the C-irritable bowel syndrome study, the investigators compared the efficacy and safety of three doses of renzapride (1, 2, and 4 mg/day) with placebo. The study lasted eight weeks and had a two-week run-in period.

The primary end point was satisfactory relief of irritable bowel syndrome on more than 50% of days during treatment. At the optimum dose (2 mg/day), up to 14% more patients receiving renzapride, at any one time (average 6% more over the treatment period), were classified as responders compared with those receiving placebo. The proportion of responders increased to 18% (average 8% more over the treatment period) when data from female patients alone were analyzed. The daily responder rate in the two-week run-up period was approximately 30% for all groups. It increased to 57% in the 2 mg/day renzapride group compared with 43% in the placebo group.

Renzapride will launch into a highly competitive marketplace for 5-HT receptor modulators. The agent will be in direct competition with the selective 5-HT4 receptor agonist tegaserod for the treatment of C-irritable bowel syndrome patients, but it may hold some advantage over tegaserod in that its 5-HT3 receptor antagonist action could help mediate visceral pain. Selective 5-HT4 receptor agonists like tegaserod are not as effective against the pain symptoms of irritable bowel syndrome.

Renzapride’s efficacy in the M-irritable bowel syndrome population could be the key to its success; if the agent gains approval for both C-irritable bowel syndrome and M-irritable bowel syndrome, it will have a larger target population than either of the currently marketed 5-HT modulators (tegaserod and alosetron). Further large-scale trials are needed to assess the agent’s efficacy in this population, and long-term-use investigations are needed to evaluate the compound’s safety, an important issue for agents in this drug class in view of previous regulatory issues.

Alizyme recently filed a new patent application as a result of developments in various features of the commercial manufacturing process for renzapride. If the company is granted the patent, renzapride’s patent life could be extended to 2023. A patent extension would be extremely useful in this case because of

Alizyme’s need to find a licensing partner, a task that may delay the compound’s entry to the marketplace.

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