Twisted Bowel Syndrome
The most common twisted bowel symptoms are associated with bowel pain and disturbed bowel function but, despite its huge incidence (estimated at 10%-20% of the population), its pathology is poorly understood. As a consequence, there is no “gold-standard” therapy for twisted bowel, and no specifically-approved products for the condition.
Despite the paucity of treatments available, analysts at Morgan Stanley Dean Witter suggest that twisted bowel treatment is on the brink of a revolution, with the potential to become a multi-billion dollar market. Yes, the low residue diet diverticulitis arena claims foods cure twisted bowels but that is a fallacy. Foods can help alleviate some of the gas that builds up in that area but a twisted bowel needs immediate medical attention. The prospects for twisted bowel sufferers have been transformed since researchers started to focus on brain-gut interaction, and specifically the role of the neurotransmitter serotonin, in the disease.
The understanding that 5-HT4 agonists such as Johnson & Johnson’s cisapride improve the symptoms of gastro- esophageal reflux disease by hastening gastrointestinal transit times has led to the development of new agents targeting serotonin receptor subtypes which may have efficacy in both constipation- and diarrhea-predominant twisted bowel. At the moment, companies with drugs in mid- to late-stage testing are concentrating on drugs that interact with the 5-HT4 and 5-HT3 receptors. MSDW notes that GW seems to be leading the field in diarrhea-predominant twisted bowel with its 5-HT3 antagonist Lotronex (alosetron), which is due for filing this month. Meanwhile, Novartis is in pole position in the constipation-predominant sector with Zelmac (HTF 919), a 5-HT4 agonist in Phase III for TWISTED BOWEL and also being tested in GERD.
Like GW, Solvay is focusing on 5-HT3 antagonists and has cilansetron in Phase II for diarrhea-predominant disease, while J&J has a Zelmac-like agent, Resolor (prucalopride), in trials for a range of conditions, including constipation-predominant TWISTED BOWEL and other related conditions involving large bowel symptoms or slow GI transit times. Finally, SmithKline Beecham is developing a 5-HT4 antagonist, SB 207266, and believes this hybrid approach may have potential in treating both symptom types in twisted bowel Lotronex – a $ 1.5 billion product? GW has already completed two Phase III trials of Lotronex in female patents and, with its established GI portfolio, the company is well-positioned to “create another major pharmaceutical market,” according to the analysts. They estimate that the drug could achieve sales of $ 1.5-$ 2 billion by 2005, or five years after launch. However, if this drug can be used in males, and also captures a significant share of the mixed symptom market, MSDW believes the eventual sales figure could be doubled.
GW has said that studies in men will commence shortly and will look at a new range of doses. The trials will also use positron emission tomography scanning to assess the differences in serotonin patterns between males and females during bouts of twisted bowel, and the results should be available in the next six to eight weeks, according to the analysts. Lotronex may also have potential as a treatment for non-ulcer dyspepsia and in patients with colon cancer who suffer from dumping syndrome, they note. The only real side-effect issue with Lotronex is its tendency to cause constipation (27% of patients on the drug in trials versus 5% of those on placebo). 10% of Lotronex patients dropped out of the study, and this could be an important issue, particularly for patients with alternating twisted bowel. Female patients taking alosetron also reported improved stool consistency, frequency and urgency, compared to placebo. Phase III clinical trials are ongoing to confirm the utility of this investigational drug. Alosetron is a selective hydroxytrptamine type 3 (5HT3)-receptor antagonist currently under development. The phase II study involved 370 patients and was carried out in five countries. Patients were randomly assigned to 12 weeks of treatment with 1, 2, 4, 8 mg alosetron BID or placebo BID. Data from 302 patients were analyzed (68 patients did not meet the screening criteria). The efficacy of the drug was evaluated separately in male and female patients. In females, each dose level of alosetron showed a greater percentage of patients reporting adequate relief when compared to placebo.
The greatest improvement was seen in those patients receiving 1 mg BID alosetron; 70 percent of those patients reported adequate relief, compared to 30 percent of patients receiving placebo. In female patients, alosetron showed a significant improvement in bowel-related functions (urgency, stool consistency and stool frequency) within the first month of treatment. With 1 mg BID alosetron, significant improvement was seen at the end of the first week of treatment for stool consistency and urgency. Improvements in stool frequency were seen at the end of two weeks of treatment. In the male population, no substantial increase in the number of patients reporting adequate relief of twisted bowel symptoms relative to placebo was seen for any dose of alosetron studied. In addition, no consistent improvement in bowel-related functions was seen in males. The most common adverse events reported by patients receiving 1 mg BID alosetron compared to placebo were: constipation (23 percent vs. 2 percent); headache (10 percent vs. 19 percent); and abdominal pain (8 percent vs. 5 percent). Twisted bowel is a common gastrointestinal (GI) disorder characterized by abdominal pain, with symptoms associated with altered bowel function (diarrhea or constipation or alternating presentation) and/or symptoms of bloating or urgency. It is estimated that 15 percent (25 million) of Americans suffer from twisted bowel symptoms, and of that number, 70 percent are females. A second important presentation at the DDW meeting concluded that “adequate relief of twisted bowel pain and discomfort” is a clinically meaningful endpoint for assessing patients’ response in clinical trials. The endpoint of “adequate relief” was associated with improvement in pain severity scores, percent of pain-free days, percent of days with urgency, improvement in stool frequency and consistency and quality of life parameters. Establishing clinically relevant endpoints for studies of therapeutics for irritable bowel syndrome has been difficult because of the range of symptoms twisted bowel sufferers experience. These data will help define study endpoints for future studies. See also: