ATI-7505 is an oral prokinetic drug that has successfully completed Phase 2 clinical trials for the treatment of multiple gastrointestinal disorders including gastroesophageal reflux disease, or GERD, and functional dyspepsia. ATI-7505 was designed to have the same therapeutic benefits as cisapride, a drug marketed by Johnson & Johnson as Propulsid in the United States. Launched in 1993, cisapride reached sales of over $1.0 billion before it was withdrawn from the market in 2000 due to serious cardiovascular side effects. These side effects occurred as blood levels of the drug rose significantly when CYP450 clearance was blocked because of the presence of other drugs cleared by the same metabolic pathway. ATI-7505 is designed to be metabolized through the esterase pathway, eliminating metabolism through CYP450 as well as off-target cardiovascular effects. While some patients may suffer from more than one gastrointestinal disorder, it is estimated that there are more than 100 million cases of gastrointestinal disorders in the United States.
ATI-7505 is an orally bioavailable, small organic molecule that is structurally similar to cisapride. Like cisapride, ATI-7505 is a potent 5-HT4 receptor agonist that has prokinetic effects. However, ATI-7505 is more selective than cisapride, with minimal activity on the hERG channel as well as minimal to no activity at the 5-HT3 or other serotonergic receptors. This selectivity minimizes the potential for off-target pharmacological effects. The results of preclinical animal and clinical human testing to date suggest that ATI-7505 has similar pharmacologic activity to that described in the literature for cisapride but has a substantially different metabolic and cardiac safety profile.
Gastrointestinal Disorders
ATI-7505 has the potential for use in various gastrointestinal disorders for which increased motility would be beneficial. ATI-7505 may help patients in a variety of indications including:
Chronic Constipation results from a lack of an adequate number of bowel movements over an extended period of time (usually defined as greater than six months). When suffering from chronic constipation, patients often try laxatives and fiber supplements prior to physician prescribed therapy. Due to limitations in existing treatments, a significant need exists for a safe chronic constipation therapy. It is estimated that between 36 and 57 million people in the U.S. have chronic constipation and that approximately 33% of them see a physician for this condition.
Functional Dyspepsia is characterized by a number of symptoms associated with upper intestinal discomfort. In 2006, a specialist panel of clinicians issued a report entitled Rome III recommending that certain of these symptoms, including mid-to-upper abdominal discomfort characterized by postprandial fullness, early satiety or upper abdominal bloating, be classified as postprandial distress syndrome, or PDS. These symptoms are believed to be associated with deficiencies in motility of the upper gastrointestinal tract. ATI-7505 is being developed for the treatment of PDS. No currently marketed therapy is considered to be an optimal treatment for this condition. It is estimated that between 35 and 44 million people suffer from functional dyspepsia in the United States.
GERD is a digestive system disorder characterized by the frequent unwanted passage of stomach contents into the esophagus that result in such symptoms as heartburn and, in some cases, damage to the lining of the esophagus. Approximately $17.0 billion is spent worldwide each year on GERD and heartburn medications. Approximately 10 percent of the population experiences GERD symptoms daily. While most patients are treated with drugs that reduce the acid contents of the stomach, approximately 20 to 25 percent of patients (or 6.0 to 7.5 million people in the United States) do not obtain adequate relief from this type of treatment. This is the population that is targeted with ATI-7505.
Gastroparesis is a disorder of the stomach in which contents from the stomach do not move efficiently into the small intestine. The digestive system, including the stomach, uses muscular contractions to move its contents along the gastrointestinal tract. Gastroparesis results when there is some damage or malfunction to this process in the stomach, resulting in symptoms such as nausea and vomiting, severe abdominal pain, bacterial infections and weight loss. Diabetics are particularly susceptible to this condition. It is estimated that approximately five million patients suffer from gastroparesis in the United States. No existing therapies adequately meet this patient need.
IBS is a set of chronic symptoms associated with the lower gastrointestinal tract, particularly the colon, and is usually experienced as abdominal pain, bloating and discomfort. This can include constipation with difficult or painful bowel movements or diarrhea due to excess fluid in the colon. While the causes of IBS are still in question, lack of colonic motility is thought to be a primary cause. As with chronic constipation, patients need an effective motility agent when other remedies, such as change in diet, reduction of stress or consumption of laxatives or fibers, do not relieve the IBS symptoms. ATI-7505 is targeted for use in the segment of IBS patients who also suffer from chronic constipation. An estimated 5.5 million adults in the United States suffer from IBS with constipation while an estimated 28 million adults suffer from IBS with intermittent constipation.
ATI-7505 Development Status
More than 500 patients have been treated with ATI-7505 in clinical trials, including three Phase 2 trials. In these trials, dosing with ATI-7505 showed a reduction in acid reflux, and in some measurements of nighttime heartburn, nighttime acid regurgitation, and multiple functional dyspepsia symptoms, as well as a dose-related increase in GERD erosion healing rates in patients with less severe erosions. In addition, we have shown statistically significant improvement in some measures of both upper and lower gastrointestinal motility in healthy volunteers. Based upon the data generated in these clinical trials, we entered into a collaboration agreement with Procter & Gamble Pharmaceuticals under which they will develop and commercialize ATI-7505. P&G has initiated a Phase 2 clinical trial with ATI-7505 in chronic constipation and plans to initiate an additional Phase 2 clinical trial in functional dyspepsia.
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