Irritable bowel syndrome (IBS) is a condition that affects millions of patients in Western Countries, including up to 55 million Americans, mostly women. IBS is characterized by a number of gastrointestinal signs and symptoms, including diarrhea or constipation, as well as bloating, pain, gas, and the potential for related conditions such as fibromyalgia. IBS is often confused with ulcerative colitis, or just colitis, as IBS can have many things in common with IBD, including diarrhea and abdominal pain. IBS, however, is not an inflammatory condition like IBD, and does not cause bleeding in the intestine or symptoms such as fever and weight loss.
A recent community-based survey found a prevalence of IBS in the US of approximately 14.1% (Hungin A P, Chang L, Locke G R, Dennis E H, Barghout V. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment Pharmacol Ther. 2005;21:1365-1375). More than 80% of the surveyed patients were 18-54 years of age, and 64% were women.
IBS diagnoses are now often classified according to three symptom patterns: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and an alternating pattern of these two (IBS-A). The true prevalence of each IBS subtype is not established, but IBS-A and IBS-D are thought to be more common. The negative impact of IBS symptoms on daily functioning and quality of life can be substantial (Olden K. Targeted therapies for diarrhea-predominant irritable bowel syndrome. Clinical and Experimental Gastroenterology 2012:5 69-100). Nearly 90% of patients with IBS-D report experiencing abdominal pain, gas, and sudden urgency and, as symptom severity increases, in the same way increases the level of impairment in daily functioning and quality of life. Patients with severe IBS symptoms may experience quality of life impairments that are comparable with, or even greater than, those associated with diabetes or depression.
The American College of Gastroenterology Updated in 2009 the Recommendations for Irritable Bowel Syndrome (American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 (1): S1-S35.), including dietary recommendations and the use of the following three classes of drugs: tricyclic antidepressants (TCAs), antibiotics (ie, rifaximin), and the 5-HT3 antagonist alosetron. More recently, the FDA approved for the treatment of IBS symptoms the new agent linaclotide, a guanylate cyclase-C (GC-C) agonist. The effect of GC-C is to stimulate secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit. Linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. Other products used in Europe and other countries are dietary fibers and/or probiotics.
Whichever the treatment, the effect is only on clinical symptoms and does not last very long. Moreover, long lasting treatments are limited by the strong toxicity. Thus, there is still an unsatisfied medical need in terms of efficacy and prevention of relapses.
Pidotimod, whose chemical name is (4R)-3-(5-oxo-L-prolyl)-1,3-thiazolidine-4-carboxylic acid, was disclosed for the first time in IT1231723. It is a synthetic dipeptide with immunological modulatory activity on both the adaptive and innate immune responses. This compound has been shown to induce dendritic cell maturation and up-regulate the expression of HLA-DR and co-stimulatory molecules CD83 and CD86, which are integral to communication with adaptive immunity cells. Pidotimod has also been shown to stimulate dendritic cells to release pro-inflammatory molecules such as MCP-1 and TNF-α cytokines, and to inhibit thymocyte apoptosis caused by a variety of apoptosis inducing molecules.
It has now been surprisingly found that pidotimod, besides being active on illnesses characterized by immune defects, may be of benefit in patients with irritable bowel syndrome, by attenuating the symptoms including diarrhea, intestinal pain and flatulence.
USPTO Backgrounds
USPTO Backgrounds