Gastroenterology involves the diagnosis and treatment of disorders of the digestive system. These disorders may affect the esophagus, stomach, small intestine, large intestine (colon), rectum, liver, gallbladder or pancreas. A study at the University of North Carolina at Chapel Hill School of Medicine reported that the most prevalent digestive diseases were non-food-borne gastroenteritis with 135 million cases a year, food-borne illnesses with 76 million cases, gastroesophageal reflux disease with 19 million cases and irritable bowel syndrome with 15 million cases. The study was published in the May 2002 issue of Gastroenterology.

New experimental medications in the gastroenterology field are indicated for constipation, acid reflux, irritable bowel syndrome (IBS), ulcerative colitis, gastroesophageal reflux disease (GERD) and Crohn's disease. Researchers at the Center for Gastrointestinal Biology and Disease estimated the direct costs of all gastrointestinal and liver diseases in 1998 to be roughly $36 billion. In 2002, GERD alone cost Americans more than $9.3 billion in doctor visits and medical treatments.

Conditions	Prevalence (U.S.)
Constipation	4.5 million
Acid reflux	60 million
Gastroesophageal reflux disease	19 million
Irritable bowel syndrome	15 million
Ulcerative colitis	< 1 million
Crohn's disease	< 1 million

Constipation occurs when an excessive amount of water is extracted from the colon causing the stool to become hard and difficult to expel. It can be caused by a lazy colon that does not contract properly or a physical obstruction such as a tumor or diverticulosis, a pouch or a pocket-like opening in the bowel wall. Other factors that can produce a poorly contracting bowel include pregnancy, anal fissures and hemorrhoids, certain drugs, thyroid hormone deficiency, diet and stress. While most patients will treat themselves without seeking direct medical help, about 4.5 million Americans report that they are chronically constipated a vast majority of the time, according to the National Health Interview Survey conducted in 1991. Casual treatment costs Americans $725 million each year, mostly spent on over-the-counter laxatives.

Current treatments for constipation range from diet modifications, such as eating additional fiber or fruits, to more aggressive remedies such as drugs or surgery (colectomy). Approved drugs prescribed for constipation have historically been classified as laxatives, of which there is a variety on the market. Saline (or osmotic) laxatives attract water into the lumen of the intestines and expand the bowel. These products, such as Epsom salt, attempt to aid peristaltic movement. Stimulant laxatives, such as X-lax, Dulcolax and castor oil, increase the motor activity of the bowels by working directly on the intestines and colon. Other gentler varieties include lubricants, stool softeners, lactulose and electrolyte solutions.

Molecular research into more effective treatments for constipation has yielded a much more innovative suite of prospects. Neurotrophin-3 (NT-3), a naturally occurring human protein in injectable formulation is tested for severe constipation and various constipating conditions caused by spinal cord injuries, narcotic analgesics and Parkinson’s disease. NT-3, by Amgen and Regeneron Pharmaceuticals, is currently in phase II development for treatment of constipation. Another drug under development is Methylnaltrexone (MNTX) by Progenics Pharmaceuticals. MNTX is designed to block opioid medication from activating the peripheral receptors that cause such side effects as constipation and urinary retention. MNTX has shown positive results in recent phase II studies.

Another approach is to investigate additional secondary therapeutic effects with previously approved drugs, relying on their proven safety record; Zelnorm (tegaserod maleate), an approved medication from Novartis, targets 5HT4 receptors present throughout the gastrointestinal tract. 5HT4 receptors help control intrinsic sensory reflexes within the gut and could result in a decrease in intestinal tract transit times. The drug is presently indicated for women with irritable bowel syndrome but is currently in phase III clinical trials for the treatment of chronic constipation. Although many millions of Americans suffer from occasional or chronic constipation, CenterWatch has identified fewer than 10 drugs in clinical development for the indication.

Heart Burn, Acid reflux and Gastroesophageal reflux disease (or GERD) are related conditions caused by stomach acid splashing up into the esophagus. Constant exposure to stomach acid can irritate the lining of the esophagus causing serious heartburn or GERD. It has been estimated that more than 50 million Americans use medications to treat heartburn everyday; with approximately 6 million of them suffering from GERD. At $9.3 billion per year, it has the highest annual direct costs in the U.S. of any other gastrointestinal condition. A combination of factors and conditions, such as transient lower esophageal sphincter (LES) relaxation, decreased LES resting tone, impaired esophageal clearance, delayed gastric emptying, decreased salivation, and impaired tissue resistance are believe to cause GERD-like symptoms.

Current treatments rely heavily on diet changes, antacids and a few commonly prescribed medications. Older drugs, such as atropine, do reduce the rate of transient relaxation and the number of reflux episodes; however, proton pump inhibitors (PPIs) are generally considered the drugs of choice for subjects with serious acid-related disorders. Small pumps located on parietal cells actively secrete acid into the stomach cavity; proton-pump inhibitors shut down these acid-transporting pumps. The drug Nexium (esomeprazole) from AstraZeneca, approved in February of 2001, is thought to have more rapid and profound inhibition of acid secretion than do older agents. Surgical procedures such as fundoplication, a treatment where the fundus (upper part of the stomach) is wrapped around the lower esophagus, and endoscopic anti-reflux procedures may be a last resort for patients with very advanced cases. H2 blockers, such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac), help stop acid production. They are available in prescription and over-the-counter strengths.

Recently development of novel medications has focused on the targeting of mechanisms that create an overproduction of gastric acid in the gut. A novel immunological approach is to stimulate the immune system to produce antibodies against gastrin. G17DT is an anti-gastrin immunogen in development in phase II clinical trials by Aphton. It induces antibodies that bind to both gastrin 17 and gly-gastrin, and it removes them from circulation before they can promote gastric acid. Another promising candidate is TAK-370, being developed by Takeda Chemical Industries in phase II clinical trials. TAK-370 enhances gastrointestinal motility by acting on the serotonin 5-HT receptor selectively. The drug is already marketed by Dainippon in Japan for gastrointestinal symptoms. CenterWatch has identified at least five drugs currently in clinical development for these disorders.

Irritable bowel syndrome (IBS), also called spastic colon, is a disorder of the large intestine that is characterized by exaggerated contractions within the lower gut. These abnormal contractions can cause changes in bowel patterns that can result in constipation, diarrhea and pain. Prolonged contractions could lead to diverticulosis. The exact cause of IBS is thought to be a physiological one, stemming from malfunctioning impulses relayed to and from the brain. Many factors could contribute to the problem such as diet, illness or stress and the disorder seems to run in families. Emotional and psychiatric factors, such as anxiety and depression, are present in 40% to 60% of IBS patients. This condition affects between 10% to 20% of the U.S. population, and the sufferers are predominately women. Americans spend more than 8 billion dollars per year for drugs and hospitalizations related to IBS. Patients seek out physicians up to 3.5 million times a year for IBS, resulting in over 2 million prescriptions written annually.

Current treatment options for IBS emphasize constructing custom drug-diet regimes. Anti-cholinergic drugs like Bentyl and Levsin act by decreasing the abnormal sensitivity of choninergic (muscarinic M2) receptors in gut smooth muscle. Two well-known approved medications are Zelnorm (tegaserod) and Lotronex (alosetron hydrochloride). Zelnorm (tegaserod), approved in July 2002, is a serotonin-4 receptor agonist (5HT4 agonist) for women with symptoms of abdominal pain or discomfort, and constipation associated with IBS. Zelnorm stimulates the peristaltic reflex and normalizes impaired motility in the intestines. Lotronex (alosetron hydrochloride), approved in June 2002, is a potent and selective antagonist of the serotonin 5-HT3 receptor type for the treatment of women with severe diarrhea-predominant IBS. Lotronex inhibits the activation of non-selective cation channels, which results in the modulation of the enteric nervous system. Tricyclic antidepressants and serotonin reuptake inhibitors also seem to have a therapeutic effect on some gastrointestinal symptoms and are commonly used to treat IBS.

New drug development approaches for IBS have continued with the recent focus on targeting gastro-neuro receptors in the digestive tract. Dexloxiglumide is a selective cholecystokinin type A (CCKA) receptor antagonist in phase III being developed by Forest Laboratories. CCKA antagonists target receptors in the gastrointestinal system to increase gastric emptying and intestinal motility, as well as modulate intestinal sensitivity to distension. TAK-637 is a neurokinin-1 (NK1) receptor antagonist in phase II for IBS being developed by Takeda Chemical Industries. NK1 receptor expression has been reported from many elements of the central and peripheral nervous systems. Talnetant (SB 223412) is a tachykinin (NK3) receptor antagonist in phase II for IBS being developed by GlaxoSmithKline. NK3 antagonists have been investigated in the treatment of CNS disorders, pain, airway disease, urinary incontinence and intestinal dysfunction. CenterWatch has identified fewer than 10 drugs in clinical development for IBS.

Ulcerative colitis, also called colitis or inflammatory bowel disease (IBD), is a condition that causes inflammation and sores (ulcers) in the rectum and colon. These ulcers are a result of cell death in the lining of the colon caused by inflammation. The tissue damage and swelling causes the colon to empty frequently, resulting in severe diarrhea, fatigue and bleeding. The annual incidence of ulcerative colitis in the U.S. is roughly 10-12 cases per 100,000 people. The disorder starts more frequently between ages 15 to 30 and less frequently between ages 50 to 70. The exact cause of ulcerative colitis is not fully understood. A popular view is that the immune system reacts to a virus or a bacterium by causing ongoing inflammation in the intestinal walls.

Current therapy includes such medications as anti-inflammatories, immunosuppresents and antimicrobials. Sulfasalazine (Azulfidine) acts locally in the colon to decrease the inflammatory response and systemically inhibits prostaglandin synthesis. Anti-diarrhea medications, such as Imodium and Lomotil are used for temporary relief, but only delay symptoms. Antibiotics such as ciprofloxacin and metronidazole are sometimes administered in patients with severe ulcerative colitis in addition to steroids. Colazal (balsalazide disodium), approved in July 2000, is a molecule that produces mesalamine (5-aminosalicyclic acid), thus producing an anti-inflammatory response. For extremely serious cases, surgery can be performed at the site of the inflammation. About 25% to 40% of patients must have their colons removed because of massive bleeding, severe illness, rupture of the colon, or risk of cancer.

Drug development for ulcerative colitis mirrors that of other gastrenterological disorders in its various approaches. One promising new drug is a mucopolysaccharide called heparin. Heparin has anticoagulant properties and has been tested in many areas such as cardiovascular disease, cancer and digestive conditions. OP2000 is an ultra-low molecular weight heparin being tested in phase II/III by Incara Pharmaceuticals and Elan. MLN-02 (formerly known as LDP-02) is an investigational humanized monoclonal antibody in phase II being developed by Millennium Pharmaceuticals. MLN-02 targets a protein called alpha-4-beta-7, an integrin on inflammatory cells that causes these cells to adhere to the gastrointestinal tract. In pre-clinical models, MLN-02 eliminated or reduced diarrhea, chronic inflammation and tissue damage associated with these conditions. RDP58 is an anti-inflammatory peptide by SangStat being tested to treat inflammatory bowel diseases.. It inhibits tumor necrosis factor (TNF) synthesis, gamma interferon synthesis, and IL-12 synthesis, and it up-regulates heme oxygenase-1 (HO-1). CenterWatch has identified more than 10 drugs in clinical development for the treatment of ulcerative colitis.

Crohn's disease is a chronic condition of the intestinal tract, consisting of tiny pockets of swelling that eventually become damaged. The bowel wall eventually becomes thickened and may become narrowed or obstructed requiring surgery. Common symptoms include cramping, abdominal pain, diarrhea, fever, weight loss and bloating. Nearly one million people in the U.S. suffer from Crohn’s disease and the estimated cost for treatment is close to $1.5 billion dollars. The exact cause is not known; however, current theories center on immunologic or bacterial beginnings. Studies have shown that 20%-30% of subjects with Crohn's disease have a family history of inflammatory bowel disease. Recent research indicates that at least some cases of Crohn's disease are caused by Mycobacterium paratuberculosis infection, an obligate pathogen that lives in the gastrointestinal tract.

Current treatments for Crohn’s disease fall into a few categories, which include aminosalicylates, corticosteroids, immunomodulators and antibiotics. Aminosalicylates such as sulfasalazine (Azulfidine) were the first widely used medications to treat inflammatory bowl disorders. Newer, more tolerable varieties of aminosalicylates, such as olsalazine (Dipentum), mesalamine (Asacol, Pentasa), and balsalazide (Colazal,) have since been approved. Corticosteroids such as prednisone, Medrol and methylprednisolone can also help to control inflammation from Crohn’s disease. Remicade (infliximab), a monoclonal antibody approved in 1998, is indicated for patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. It is also indicated for reducing the number of entero-cutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn's disease. Ciprofloxacin (Cipro) is an antibiotic that improves anal symptoms and heals fistulas caused by the disorder.

Treatments now in clinical development include a variety of new molecular strategies. Since Crohn’s disease is primarily an inflammatory disorder, one tactic is to target the mechanisms that cause this swelling in the gut. Alicaforsen (ISIS-2302) is an antisense inhibitor of intracellular adhesion molecule-1 (ICAM-1), a chemical that plays a central role in inflammation. Alicaforsen is being developed by ISIS Pharmaceutical and is currently in phase III trials. Another drug, which targets inflammation, is P54, which is in phase II development by Phytopharm. P54 inhibits the induction of the enzyme NFkB, thereby inhibiting downstream inflammatory genes such as COX II and iNOS.

The connection of Crohn’s disease with a misdirected immune response has been well documented. In January 2003, Elan and Biogen reported positive results from a phase II trial investigating Antegren (natalizumab) for the treatment of Crohn's disease. Antegren is a humanized monoclonal antibody that belongs to a new class of potential therapeutics known as alpha-4 integrin inhibitors. It is designed to block immune cell adhesion to blood vessel walls and subsequent migration of lymphocytes into tissue. Schering- Plough’s Leukine, a yeast-derived granulocyte macrophage colony stimulating factor in phase II trials, is believed to stimulate specific immune system cells in the gastrointestinal tract that might be impaired in patients with Crohn's disease. The drug is currently approved for indications related to bone marrow transplant and acute myelogenous leukemia. CenterWatch has identified more than 20 drugs that are currently in clinical trials for the treatment of Crohn’s disease.

With its relationship to diet, exercise, stress and age, disorders of the gastrointestinal track are on the rise in the United States. As the mechanisms of inflammation and intestinal function become better understood, novel and more effective medications will evolve. Acid reflux and constipation remain some of the widest spread and recurring chronic complaints among American patients. Although these indications are often treated with over-the-counter products, there is a strong need for better treatment options. Irritable bowel syndrome, although not a life-threatening illness, can cause life long pain and discomfort to countless sufferers. The latest research into the neurologic pathways of gut-brain communication system has let to some promising drug targets. Ulcerative colitis and Crohn’s disease, both characterized by serious inflammation of the lower GI tract, are perhaps the most serious of the gastrological disorders. Since other therapeutic areas such as rheumatology and cardiology deal with inflammation as a major disease mechanism, novel inflammatory bowel disorder treatments are sometimes inadvertently discovered. This process may hold true for such options as Cox II inhibitors and ICAM-1s.

In total, CenterWatch has investigated more than 50 drugs in various stages of clinical development for gastrenterological disorders. With the current annual spending for these conditions hovering around $36 billion, it is quickly becoming one of the top disease areas in the clinical trials industry. Recent advancements into functional genomics, immunological vaccines and neurological pathways have paved the way for a robust future in drug development. In May 2003, CenterWatch logged more than 30,000 page views from patients seeking information on the more than 900 gastroentrological clinical trials posted on our site. Gastroenterology remains one of the most promising therapeutic areas in future drug development among all the chronic, non-lethal disease categories.