Laurie Barclay, M.D., April 2005

Gastroesophageal reflux disease (GERD) refers to heartburn and sometimes other symptoms associated with backflow of gastric acid from the stomach into the esophagus. Approximately 5% to 7% of the total population experiences heartburn, or burning beneath the breastbone, at least once daily, and nearly 20% have this symptom at least weekly. Other symptoms may include acid regurgitation, belching, chronic sore throat or throat irritation, laryngitis, gum inflammation, erosion of tooth enamel, bad breath, and hoarseness in the morning.

The mechanism underlying GERD is inappropriate relaxation of the lower esophageal sphincter (LES), a band of muscles at the junction of the stomach and esophagus. Normally the LES and diaphragm prevent reflux of stomach contents into the esophagus. In addition to causing heartburn and other symptoms, acid reflux may damage the esophageal lining, causing esophagitis or erosive GERD.

Chronic erosive GERD may result in stricture (narrowing) of the esophagus or a potentially pre-cancerous condition known as Barrett's esophagus, in which specialized intestinal metaplasia replaces the normal esophageal lining. About 10% of individuals with GERD develop Barrett's esophagus, and approximately 1% of those develop esophageal cancer. Risk factors for Barrett's esophagus include severity and frequency of GERD symptoms, presence of heartburn or reflux for more than five to 10 years, age over 50 years, and being a white male. Endoscopic screening every two or three years is recommended for patients with Barrett's esophagus.

Diagnosis is usually based on relief of symptoms after a two-week trial of a proton pump inhibitor (PPI) that inhibits gastric acid secretion, because confirmatory pH monitoring in the esophagus is perceived by many as overly invasive.

Treatment goals are symptom relief and maintenance of remission, esophageal healing, and prevention or management of Barrett's esophagus or stricture. Although there is no cure for chronic reflux and it does not resolve spontaneously, long-term pharmacological therapy with promotility agents, H2 blockers, or PPIs is usually effective. Lifestyle modifications may be somewhat helpful, and surgery is seldom required. Endoscopic procedures are also available but are less well studied than surgery and pharmacotherapy.

Promotility drugs can help relieve symptoms of non-erosive GERD. However, adverse effects and drug interactions associated with cisapride (Propulsid) led Janssen Pharmaceutica to stop marketing Propulsid in the U.S. as of July 14, 2000.

Currently available H2 blockers, which lower gastric acid secretion, relieve symptoms and permit esophageal healing in approximately half of patients, but lead to sustained remission in only about one-quarter of patients.

Available PPIs reduce gastric acid secretion through their effect on H+, K+-ATPase, and they may be helpful in managing stricture. Compared with H2 blockers, they are more effective, allowing rapid symptom resolution and esophageal healing in 80% to 90% of patients.

Because GERD is a chronic condition often requiring long- term or even lifelong therapy, safety and tolerability of pharmacotherapy are important considerations. Potential areas of improvement in pharmacotherapy include faster onset of complete acid inhibition and improved duration of efficacy.

CenterWatch has identified a pipeline of 12 drugs in various phases of development for GERD, including drugs that limit transient LES relaxation, serotonergic agents acting as prokinetics, potassium-competitive acid blockers, mucosal protectants, histamine H3 agonists and anti-gastrin agents.

Santarus is in Phase III development of the PPI Zegerid (SAN-15, Rapinex), a formulation of omeprazole as 20 mg chewable tablets and oral capsules. In 2004, Santarus received Food and Drug Administration (FDA) approval of Zegerid powder for oral suspension, an immediate-release formulation allowing rapid absorption into the bloodstream and sustained acid control.

Omeprazole is a potent inhibitor of gastric acid secretion, with a good safety profile and the convenience of once-a-day dosing. In powder form, Zegerid reaches peak plasma levels in approximately 30 minutes, maintaining a median 24-hour stomach pH of greater than 4 for 18.6 hours. Zegerid is effective for heartburn and other GERD symptoms, and for short-term treatment (four to eight weeks) of erosive esophagitis diagnosed on endoscopy. It appears to maintain healing of erosive esophagitis, but follow-up in controlled studies is limited to 12 months.

Adverse events of Zegerid may include headache, diarrhea, and abdominal pain. In patients receiving long-term omeprazole treatment, stomach biopsies have occasionally revealed atrophic gastritis. Because Zegerid contains 460mg sodium per dose as sodium bicarbonate, caution is warranted in patients on a sodium-restricted diet, and it is contraindicated in patients with metabolic alkalosis and hypocalcemia.

Prevacid (Takepron, lansoprazole, AG 1749) is another PPI, in Phase III development by TAP Pharmaceuticals in Japan for a new indication. Prevacid is indicated for the short- term treatment of heartburn and other GERD symptoms. In erosive esophagitis, it is indicated for short-term (up to eight weeks) healing, symptom relief and maintenance. Controlled studies for maintenance have been limited to 12 months; those for healing to eight weeks; and those for risk reduction of recurrence to twelve weeks.

As with omeprazole and other PPIs, symptom relief with Prevacid does not preclude the presence of serious stomach problems. Adverse events include diarrhea in 3.8%, abdominal pain in 2.1%, and nausea in 1.3%.

ARYx Therapeutics is in Phase I development of ATI-7505, an analog of cisapride (Propulsid) acting as an acetylcholine release stimulator. This drug is being tested in diabetic gastroparesis as well as GERD. Unlike the originally marketed version of cisapride, this product is said to have prokinetic activity with no metabolic or cardiac liabilities.

Sankyo/Novartis is in Phase II testing of S-526 (R-105266, AKU-517), an orally administered, reversible acid-pump antagonist (APA). In comparison with existing antacid therapies, potential advantages of this drug may include more rapid acid reduction and longer duration of action, allowing faster symptom relief and ulcer healing. Soraprazan (B9106-086, BYK-359) is another APA, in Phase II development by Altana AG. The first two phase IIa trials offered evidence supporting proof of concept and tolerability.

By selectively targeting the serotonin 5-HT receptor, mosapride citrate (TAK-370), in Phase II development by Takeda Chemical Industries, enhances gastrointestinal motility. Mosapride is said to be the world's first selective serotonin 5-HT4 receptor agonist to stimulate gastrointestinal propulsion. In October 1998, Dainippon first launched this drug in Japan to reduce heartburn, nausea, vomiting and other symptoms associated with chronic gastritis. It was then licensed out to Daewoong Pharmaceutical Co., Ltd. of South Korea in April 1999, and was subsequently developed by Takeda.

A different approach to reducing acid secretion is a vaccine directed at the growth hormone gastrin, such as Insegia (G17DT, Gastrimmune), in Phase II development by Aphton. Gastrin is a key hormone in the embryological development of the gastrointestinal system. Although most gastrin receptors and gastrin itself are inactive in the mature gastrointestinal system, the hormone and its receptors remain active in the stomach. Insegia is an immunogen that enlists the immune system to generate high levels of antibodies to gastrin and the gastrin receptor. Because some cancers also express gastrin receptors, this drug is also being tested in pancreatic cancer and in combination with chemotherapy in gastric cancer.

Other hormonal receptors of potential utility as targets for GERD treatment are cholecystokinin (CCK) receptors. Rottapharm is in Phase I testing of itriglumide (CR 2945), a CCK-B (CCK2) antagonist that reduces stomach secretions and is therefore being developed in gastric ulcer disease as well as GERD. Rottapharm has not yet submitted an IND application for dexloxiglumide (CR 2017), a CCK-A (CCK-1) antagonist acting as a prokinetic and digestive antispasmodic of potential value in GERD, irritable bowel syndrome, and chronic constipation.

Thanks to several different pathways regulating LES control and acid secretion, drugs targeting GERD can have several different mechanisms of action. Given the need for chronic and even long-term treatment, prolonged follow-up for safety and tolerability are just as important as demonstrated efficacy in reducing acid reflux and its complications. Other key considerations are rapidity of onset and the ability to maintain remission of symptoms and of esophageal healing for long periods.