Cilansetron is a 5-HT receptor modulator being developed by Solvay in the United States and Europe for the treatment of diarrhea-predominant irritable bowel syndrome (D-irritable bowel syndrome) in both men and women. Like the currently marketed alosetron, the agent antagonizes 5-HT3 receptors, thereby slowing gastric motility and providing relief for patients with D-irritable bowel syndrome. The agent also reduces the transmission of afferent signals from the gut to the brain. Cilansetron is preregistered in Europe, where in June 2005, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom (the reference member state under the European Union [EU] mutual recognition procedure) requested data from further clinical trials of the drug in irritable bowel syndrome. In the United States, clinical data supporting a new drug application (NDA) for cilansetron were based on efficacy and safety studies in approximately 4,000 D-irritable bowel syndrome patients, and Solvay reports that its NDA submission included an appropriate-use program — not unlike that of alosetron in the United States — that is based on collaboration with physicians, pharmacists, patients, and risk-minimization experts. However, the FDA issued a non-approvable letter for cilansetron in April 2005, requesting, as did European regulators, that further clinical trials be conducted as a prerequisite to irritable bowel syndrome approval. Solvay reported in November 2005 that it was discontinuing registration activity for cilansetron in the United States rather than undergo additional trials of the drug.
In May 2002, at the Digestive Disease Week meeting in San Francisco, the results of two clinical studies evaluating the efficacy of cilansetron were reported. The two 12-week, double-blind, placebo-controlled studies were conducted in the United States (n = 471; doses: 1, 2, 8, 16 mg three times daily [t.i.d.]) and in Canada and Europe (n = 435; doses: 1, 2, 4, 16 mg t.i.d.) with male and female patients. D-irritable bowel syndrome patients were selected according to the Rome I criteria, and efficacy was measured via response to a weekly questionnaire addressing the adequate relief of irritable bowel syndrome symptoms (abdominal pain/discomfort, abnormal bowel habits). At the start of the trial, subjects were categorized by the severity of their irritable bowel syndrome symptoms: approximately 76% of responders had active irritable bowel syndrome symptoms during the two weeks prior to the start of the study, 13% of patients experienced some symptoms, and approximately 8% experienced no symptoms. Among the patients who had active symptoms, the efficacy benefit (measured as adequate global symptom relief) of cilansetron was significantly greater (25-41%) than that with placebo. Among the patients who experienced some symptoms, cilansetron (2mg) demonstrated a 29% efficacy benefit compared with placebo. Cilansetron’s efficacy in the patients who experienced no symptoms prior to the study was more difficult to discern. The active symptom group, at the start of the study, may represent a more severely ill population that responds well to cilansetron treatment. This study demonstrates that cilansetron is efficacious in relieving symptoms associated with D-irritable bowel syndrome. Furthermore, it is effective in both male and female patients, a factor that will position cilansetron as a significant competitor to alosetron, which is not approved for use in the male population.
Solvay’s Phase III clinical trials program in collaboration with Quintiles has recruited more than 4,000 D-irritable bowel syndrome patients from more than 700 study centers around the world. In October 2003, the company announced that “headline” results from the first two efficacy studies in this program show convincing evidence that patients benefit from treatment with cilansetron. The medical community eagerly awaits publication of further data.
Any 5-HT3 receptor antagonist must demonstrate significant benefits over alosetron with respect to efficacy and safety to make an impact on the irritable bowel syndrome market. The key issue for cilansetron will be its adverse-events profile. With the exception of constipation, no significant adverse events such as ischemic colitis (associated with alosetron use) were reported in the studies presented at the 2002 Digestive Disease Week meeting. Data from long-term studies are needed to assess whether cilansetron is safer than alosetron; without this evidence, the agent may experience difficulties during the approval process in the United States and Europe. In particular, cilansetron’s ability to differentiate itself from other agents in this class has raised questions, given that all 5-HT3 receptor antagonists are pharmacologically similar.