IBS drug pipeline offers some promise.

MILWAUKEE -- There are a number of drugs in the developmental pipeline that likely will offer benefits to different categories of patients with irritable bowel syndrome, Dr. William D. Chey reported at an international symposium sponsored by the International Foundation for Functional Gastrointestinal Disorders.

New drugs would be welcome, given the scarcity of approved agents for irritable bowel syndrome (IBS), particularly since tegaserod maleate (Zelnorm) was withdrawn from the market on March 30 because of a possible increased risk of serious cardiovascular adverse events. But Dr. Chey cautioned that these new drugs won't be a panacea.

"The one thing that's fair to say is that until we get some biomarkers that stratify patients on the basis of pathophysiology, it's unlikely that you're going to see anything better than what I've shown you repeatedly ... and that is these statistically significant benefits that are not overwhelmingly impressive," he said.

Drugs for Constipation-Predominant IBS

Renzapride, a mixed 5-hydroxy-tryptamine (HT) type 4 receptor agonist and 5-HT type 3 receptor antagonist, is currently in phase III clinical trials in the United States for patients with constipation-predominant IBS. In a small phase II trial, renzapride was shown to improve stool consistency and ease of stool passage (Clin. Gastroenterol. Hepatol. 2004;2:895-904). But the study was underpowered and did not reach a secondary outcome of satisfactory relief, said Dr. Chey, associate professor of medicine and director of the GI Physiology Laboratory, division of gastroenterology University of Michigan Medical Center, Ann Arbor.

Lubiprostone, a chloride channel activator, has just recently been assessed in two phase III trials. Preliminary data suggest that 8 mcg of lubiprostone b.i.d. provided a greater overall response among patients with IBS with constipation than did placebo (17.9% responders vs. 10.1%), Dr. Chey said.

MD-1100 or linaclotide, a potent guanylate cyclase-C agonist that acts luminally to increase the production of cyclic guanosine monophosphate in human colon cells, is heading into phase II trials for both IBS with constipation and chronic constipation. A recent 7-day, multidose phase I study in 48 healthy volunteers reported significant changes in stool consistency, ease of stool passage, stool frequency, and stool weight with MD-1100 (Gastroenterology 2006;130[suppl. 2]:A26).

Asimadoline, a kappa-opioid agonist, was originally developed to treat peripheral pain such as arthritis, and is now in clinical development for the treatment of IBS and postoperative ileus. Early results show decreased sensitivity to balloon distention in a barostat study.

Drugs for Diarrhea-Predominant IBS

Phase II trials were recently completed in the United States for crofelemer, a derivative obtained from the sap of the South American Croton lechleri tree. Data from a 12-week dose-ranging study in 246 patients with diarrhea-predominant IBS show significant improvement in pain and a trend toward improvement in stool frequency, said Dr. Chey at the meeting, cosponsored by the University of Wisconsin.

R-verapamil, a calcium channel antagonist, is expected to go into phase II clinical study in the United States sometime in 2007. In one small unpublished eastern European study, R-verapamil was shown to be of benefit for patients with IBS and diarrhea, Dr. Chey said.

There is also very elegant and interesting basic science work and supportive preliminary clinical data suggesting that corticotropin-releasing factor antagonists might offer benefits to patients with IBS and diarrhea. Also being studied are [alpha]-agonists, including the compound AGN 203818, in later-stage development, and clonidine as well as the benzodiazepine derivatives, tofisopam and dextofisopam, Dr. Chey said.

BY PATRICE WENDLING

Chicago Bureau