As much as 20% of the population suffers from irritable bowel syndrome but treating the underlying condition is difficult
IBS may affect up to 20% of the population, of whom about a third experience constipation and abdominal pains. Linaclotide from US biotech Ironwood Pharmaceuticals is an oral peptide designed to treat constipation-predominant IBS that has a local effect in the gut. It is minimally absorbed and binds to the intestinal mucous membranes, where it agonises the guanylate cyclase-C receptors, stimulating intestinal fluid secretion and transit.1
A double blind, placebo-controlled, parallel group study was carried out in 310 patients with chronic constipation.2 Subjects were given 75, 150, 300 or 600µg of the drug or placebo once a day for four weeks. All dose levels improved the weekly rate of spontaneous bowel movements compared with placebo, ranging from an increase of 2.6 from baseline for the lowest dose to 4.3 for the highest, compared with 1.5 for the placebo group. The drug also significantly improved stool consistency, straining, abdominal discomfort, bloating and quality of life. The only dose-related adverse event was diarrhoea, with six patients discontinuing as a result.
In a similar trial in 420 patients over 12 weeks, bowel habits again improved significantly, along with a reduction in abdominal pain.3 Linaclotide also improved other abdominal symptoms, including discomfort and bloating. Again, diarrhoea was the only dose-dependent side-effect, and this was largely mild or moderate.
Phase III trials have also taken place. A total of 804 patients were given placebo or 290µg of oral linaclotide once a day for 26 weeks; 34% met the FDA’s required endpoint for overall response, compared with 14% of the placebo group.4 Pain responder criteria were met by almost half the treatment group, compared with a third of the non-treatment group. All other criteria were also significantly improved for the linaclotide group.
In a second Phase III trial, over 12 weeks with a four-week randomised withdrawal period, another 800 subjects were given 290µg or placebo.5 A third of the treatment group met the FDA endpoint, compared with 21% of those given placebo. More of the treated group reported a reduction in abdominal pain, and those re-randomised to placebo in the withdrawal period experienced a return of symptoms, while those remaining on linaclotide showed a sustained response. Again, diarrhoea was the most significant side-effect, with 5.7% of the linaclotide group discontinuing as a result, compared with just 0.3% of the placebo group. EMA and FDA have recommended the drug’s approval to treat IBS symptoms.
1. A.P. Bryant et al. Life Sci. 2010, 86, 760
2. A.J. Lembo et al. Gastroenterol. 2010, 138, 886
3. J.M. Johnston et al. Gastroenterol, 2010, 139, 1877
4. W.D. Chey et al. Am. J. Gastroenterol. 2012, September, epub ahead of print, doi 10.1038/ajg.2012.254
5. S. Rao et al. Am. J. Gastroenterol. 2012, September, epub ahead of print, doi 10.1038/ajg.2012.255