Disease area: Functional and Motility Disorders

Functional and motility gastrointestinal (GI) disorders are disorders of GI function, affecting gut contractions, sensation and the brain-gut axis. It is estimated that 25 million Americans have functional GI disorders. Common examples of such disorders are irritable bowel syndrome (or IBS - altered bowel consistency combined with abdominal pain that is usually relieved with a bowel movement) and functional dyspepsia (ulcer-like symptoms - upper abdominal pain, feeling of indigestion).

Less common but perhaps even more distressing examples are conditions such as gastroparesis (“lazy” stomach, causing nausea and vomiting) and achalasia (a disorder of the lower esophageal sphincter that causes severe difficulty in swallowing). Similarly, most patients with severe constipation usually have a functional basis to this problem. Other conditions that have a prominent functional component include common diseases such as gastro-esophageal reflux (GERD).

Functional bowel disorders present a major health problem in the United States. Upper gastrointestinal dysmotility, irritable bowel syndrome, and constipation each represent multi-billion dollar markets: 2 percent of Americans (>5 million) report having irritable bowel syndrome; constipation affects another 3 percent of the general population; 14 percent of the US population reports reflux symptoms on a weekly basis; and 20 percent of diabetic patients have Gastroparesis. Gastroparesis is also prominent in other patient populations such as Parkinson’s disease where it affects the pharmacokinetics as well as the overall bioavailability of therapies for the treatment of motor symptoms (levodopa).

Additionally, an unknown number of infants and children have functional bowel disorder and an undetermined number of women are affected with pelvic floor dysfunction.

A large unmet need

Despite their widespread prevalence, there are only a few approved prescription drugs available for this group of disorders. Apart from proton pump inhibitors (PPIs), these include metoclopramide, which is the only approved prokinetic for upper GI disorders but has a black box warning because of the risk of neurological side effects. Two peripherally acting opioid receptor antagonists are approved for treatment of opioid-induced constipation and post-operative ileus but both of these have serious constraints; alvimopan’s (Entereg®) cardiovascular risks limits availability to hospitalized patients meeting special needs and methylnaltrexone (Relistor) requires subcutaneous injections. Additionally, lubiprostone (Amitiza) is a secretory agent approved for constipation but is only marginally effective. In addition, there is lack of “on mechanism” treatments for upper and lower dysmotility disorders in Parkinson’s disease.

Focus on the Enteric Nervous System

Motility and functional disorders arise from disorders of the enteric nervous system and its associated elements. The enteric nervous system (ENS), often referred to as the “second brain”, is a neuronal network present in the wall of our bowels and shares many molecular and morphological components with the central (CNS) and peripheral (PNS) nervous systems with which it is intimately connected. Major neurotransmitters, receptors and transporters present in the CNS and the PNS are also present in the ENS. Although linked to the nervous system, it can and does operate independently of the brain and the spinal cord. Current treatments for this group of disorders are either not target-based (e.g. Amitiza which simply attempts to cause a diarrhea-like process) or comes at the cost of serious side-effects (e.g. metoclopramide). We can take advantage of the unique functionality of the ENS to provide innovative and safe treatment of symptoms present in a large variety of gastrointestinal diseases. Adequate treatment of many of these gastrointestinal diseases presents a large unmet medical need to date. Neurotransmitters such as dopamine and serotonin play a key role in gastrointestinal function and serotonergic and/or dopaminergic neurotransmission is found to be abnormal in several gastric and/or intestinal disorders. Similarities between the ENS and the CNS have the potential to make many drug discovery and development efforts originally focused on the CNS adaptable and relevant for specifically targeting the ENS.