GASTROINTESTINAL FUNCTIONAL DISORDERS

The health of the GI system has a major effect on an individual’s daily activities and quality of life. A retrospective review published by the National Institute of Diabetes and Digestive and Kidney Diseases estimated that in 2004 there were more than 97 million ambulatory care visits by patients with a diagnosis of a GI disorder in the United States alone. The annual cost of these GI disorders in 2004, not including digestive cancers and viral diseases, was estimated to be greater than $114.0 billion in direct and indirect expenditures, including hospital, physician, and nursing services as well as over-the-counter and prescription drugs. In 2008, Research and Markets in Business Insights estimated worldwide sales of GI drugs to be worth $49.9 billion, with approximately 38% of this market represented by sales in the United States totaling $18.8 billion. Four major GI market segments can be distinguished:
  • upper GI functional disorders resulting from impaired motility, including diabetic and idiopathic gastroparesis; gastroesophageal reflux disease, or GERD; and functional dyspepsia;
  • lower GI functional disorders resulting from impaired motility affecting the small and large intestines, such as constipation and irritable bowel syndrome, or IBS;
  • inflammatory GI disorders such as Crohn’s disease and ulcerative colitis; and
  • disorders of organs involved in the digestive process, such as the gallbladder, liver and pancreas.
Historically, GI product development efforts have focused on indications with the largest patient populations, such as GERD, constipation, peptic ulcers and IBS. As a result, limited innovation has occurred in other segments of the GI market, in particular upper GI functional disorders, even though these disorders affect several million patients worldwide. Consequently, due to the limited safe and effective treatments available for upper GI functional disorders resulting from impaired motility, we believe there is a substantial market opportunity for us to address these significant unmet medical needs. Therefore, we are focused on the subset of GI disorders associated with underlying defects in GI motility that affect both the upper, and the lower GI tract.

Diabetic Gastroparesis. Our initial focus is on diabetic gastroparesis because there is a substantial unmet medical need, prevalence is high, and there are few available therapeutic options. The only approved drug for gastroparesis has significant limitations and was approved more than 30 years ago. In addition, we believe that successful clinical trials in diabetic gastroparesis will be the foundation for expansion into other upper GI functional indications resulting from impaired GI motility. Diabetic gastroparesis is a debilitating GI disorder in which there is substantial delay in stomach emptying along with associated symptoms of vomiting, nausea, abdominal pain, early satiety, and bloating. Patients often limit their food and liquid intake, leading to poor nutrition and dehydration which can ultimately require hospitalization. If untreated, diabetic gastroparesis causes significant acute and chronic medical problems, including additional diabetic complications resulting from poor glucose control. Diabetes is the most commonly identified cause of gastroparesis. The underlying mechanism of diabetic gastroparesis is unknown, although it is thought to be related in part to neuropathic changes in the major nerves that supply the GI tract. These nerves control the movement of food through the digestive tract and, when damaged, forward movement of food through the GI tract is delayed and/or vomiting may occur. The prevalence of diabetes in the United States is rapidly rising, with the Centers for Disease Control estimating that one in 10 adults currently suffer from the disease. Sedentary lifestyles, poor dietary habits, and a consequent rising prevalence of obesity are expected to cause this number to grow substantially. At present, an estimated 2.3 million type 1 and type 2 diabetic patients in the United States have moderate or severe gastroparesis symptoms and are seeking treatment for these symptoms.

Idiopathic Gastroparesis. Idiopathic gastroparesis afflicts a comparable number of non-diabetics who have the same symptoms of vomiting, nausea, abdominal pain, early satiety, and bloating, along with delayed stomach emptying. Idiopathic gastroparesis, or gastroparesis without a specific cause such as diabetes, can be a manifestation of many systemic illnesses, neuromuscular dysfunction, a complication of select surgical procedures, or due to unknown causes. In a 1998 study, 29% of gastroparesis cases were associated with diabetes, 13% developed as a complication of surgery, and 36% were due to unknown causes. According to the American Motility Society Task Force on Gastroparesis, 4% of the United States population experiences symptomatic manifestations of gastroparesis.

Both diabetic and idiopathic gastroparesis have a significant impact on patients’ lives, as well as significant economic impact. The number of gastroparesis-related hospitalizations has been increasing in the United States, suggesting an increasing prevalence of gastroparesis. Based on the most recent available data, which is from 2004, the economic impact of gastroparesis-related hospitalizations is significant and increasing. Vomiting is the symptom requiring the most medical intervention and is the leading cause of both emergency room visits and hospitalization for gastroparesis patients, followed by abdominal pain. While there is a high prevalence of gastroparesis, there is a lack of safe and effective therapies approved for the treatment of this disorder.

Refractory Functional Dyspepsia and Refractory GERD. Functional dyspepsia is characterized by symptoms that are similar to gastroparesis, such as stomach pain or discomfort, early satiety, bloating, fullness, nausea, and vomiting. Functional dyspepsia occurs in approximately 10% of the general population, and approximately 25%-35% of patients with functional dyspepsia have impaired stomach emptying. Up to one-third of adult patients with GERD also have delayed stomach emptying and are refractory to drugs that treat acid reflux. Relamorelin is a potential therapy for both functional dyspepsia and refractory GERD, since these patients also suffer from impaired GI motility. However, we have not yet initiated clinical trials of relamorelin in patients with functional dyspepsia and refractory GERD. There are currently no safe and effective GI motility, or prokinetic, drugs approved in the United States that address impaired motility in GI functional disorders. The need is particularly acute in refractory functional dyspepsia and refractory GERD, where few treatment options exist for chronic therapy.

Lower GI Functional Disorders. Twelve to 19% of the U.S. population seeks medical care annually for chronic constipation and IBS, and approximately 38% of this group is dissatisfied with traditional treatment options due to lack of efficacy. These conditions are two of the most common GI functional disorders, with significant health consequences and symptoms including constipation, abdominal pain, nausea, bloating, and decreased appetite. Our initial relamorelin lower GI clinical trials focus on refractory constipation, including refractory constipation in patients with Parkinson’s disease. Approximately one million people in the United States are living with Parkinson’s disease. Constipation is common among patients with Parkinson’s disease, with studies reporting that more than 50% of patients suffer from moderate to severe constipation, many of whom are refractory to existing therapies. In addition, GI functional disorders in Parkinson’s disease patients can affect the upper GI tract, resulting in gastroparesis symptoms. GI functional disorders in Parkinson’s disease patients also may undermine the GI absorption of L-DOPA, interfering with this drug’s efficacy in managing the symptoms of Parkinson’s disease.