In 1935, Asher Winkelstein first described gastroesophageal reflux disease in its present guise. His paper in the Journal of the American Medical Association reviewed five cases that he described as “peptic esophagitis” with damage to the esophageal mucosa attributed to the reflux of corrosive acidic digestive juices. The existence of this condition was not widely accepted for many years.
Along with many physicians, otherwise sagacious pharmaceutical executives introducing anti-secretory drugs argued that their “market” was for treatment of “ulcers.” Gastroesophageal reflux disease (GERD) was thought to be a relatively trivial problem, and there was remarkably little effort to initiate early trials of antisecretory agents for this entity. When the Barbican meeting in London launched ranitidine (Zantac) almost 20 years ago, the session on GERD accounted for only 15 minutes of an extensive three-day scientific program.
Earlier in the history of the histamine-2 receptor antagonists (H2RAs), a distinguished group of esophagologists including Sidney Cohen and Donald Castell pursued the potential use of cimetidine (Tagamet) for gastroesophageal reflux disease. Despite some evidence for symptomatic relief of heartburn, this large U.S. multicenter trial of cimetidine for GERD failed to document healing of erosive esophagitis. Ranitidine trials involving GERD patients were almost an afterthought in a development program heavily weighted toward the treatment of duodenal and gastric ulcers.
Despite patient selection that enrolled relatively few erosive esophagitis cases, almost precluding demonstration of esophagitis healing, slightly more of the erosive cases healed with ranitidine than with placebo. Based on this tenuous finding, Glaxo developed an eventual near marketing stranglehold for ranitidine in this highly productive arena of product sales. Many billions of dollars have been garnered in the GERD market. Glaxo was most successful among purveyors of histamine-2 receptor antagonists, followed at lesser sales levels by Eli Lilly (Axid), Merck (Pepcid) and Smith-Kline-Beecham (Tagamet).
It seems clear that unparalleled successes in sales of anti-secretory and prokinetic drugs for gastroesophageal reflux disease have led to large numbers of clinical investigations and massive relevant literature. Esophageal pH profiling has included studies with each of the drugs marketed for GERD, and such studies have clearly demonstrated the correlation of clinical efficacy with 24-hr esophageal mucosal exposure to pH < 4.0.
Not surprisingly, the major clinical trial thrust of Merck (later Astra Merck) for the first proton pump inhibitor (PPI), omeprazole (Losec renamed Prilosec) involved gastroesophageal reflux disease. As time has passed, each new proton pump inhibitor (lansoprazole, pantoprazole and rabeprazole) has focused major clinical trials on GERD with relatively modest efforts directed toward the treatment of duodenal and gastric ulcers and other indications. Careful studies of each new PPI have addressed both gastric and esophageal pH effects as part of the dose selection process. The overall GERD market in the Western world remains vast, seemingly continuing to grow endlessly.
It is now widely recognized that the pathophysiology of GERD involves deranged esophageal motility with increased transient lower esophageal relaxations and/or deficient basal lower esophageal sphincter tone, impaired esophageal acid clearance, and occasionally impaired gastric emptying. Although prokinetic therapy can be helpful in mild gastroesophageal reflux disease, more advanced esophageal mucosal damage can only be managed with acid suppression. Richard Hunt and his colleagues at McMaster University have demonstrated a very high correlation between degree of acid inhibition and healing of erosive damage to the esophageal mucosa as well as control of reflux-related symptoms. Therefore, although H2RAs and prokinetic medications can be extremely satisfactory for control of heartburn, proton pump inhibitors (PPIs) uniformly surpass even ultra-high doses of H2RAs or the combination of H2RA’s with prokinetic medications for treating the more severe endoscopic grades of erosive esophagitis.
Antacids, considered archaic by many physicians, are actually surprisingly effective at promptly elevating esophageal pH and continuing to neutralize acid at the esophageal mucosal level for up to 90 min after dosing, There is currently great interest in the development of suitable H2RA-antacid combinations to allow both the prompt treatment of heartburn as well as the prevention of subsequent heartburn episodes for many hours. No such combination product currently exists, but the growing over-the-counter market for low-dose or even prescription-level H2R’s will stimulate further ambitious development of effective and reliable chewable formulations of antacids and histamine-2 receptor antagonists.
Helicobacter pylori has been a major scientific focus in gastroenterology for the last several years, and it is clear that most “peptic” ulcers can be attributed to gastric mucosa infected with H. pylori. However, at least at the present time, there appears to be no causal relationship between H. pylori and gastroesophageal reflux disease. Indeed, there is some evidence that the effective eradication of H. pylori, a known inhibitor of gastric acid secretion, may worsen the symptoms of gastroesophageal reflux following gastric or duodenal ulcer healing and bacterial eradication. A fascinating controversy arose over the past two years in relation to the development of chronic atrophic gastritis following long-term PPI therapy of GERD.
Ernst Kuipers’ important 1996 article in the New England Journal of Medicine suggested that Dutch GERD patients infected with H. pylori receiving omeprazole maintenance treatment developed accelerated atrophic gastritis versus a group of Swedish patients who had been managed surgically. Subsequently, it has become clear that the control group may not have been perfectly matched to the medically treated patients; and an FDA-sponsored consensus conference has disputed the relationship between PPI therapy and development of chronic atrophic gastritis. Indeed, careful review of omeprazole and lansoprazole maintenance therapy data by both current PPI sponsors thus far has failed to substantiate any linkage between PPI treatment and any chronic gastric atrophy. Nevertheless, since H. pylori itself can lead to chronic atrophic gastritis, discussions of therapeutic options continue.
It seems clear that there will now be “PPI Wars” similar to the strong conflicts between the various histamine-2 receptor antagonists that occurred in the past. Omeprazole is now known to be potentially variable in its metabolism, and many patients fail to decrease pathological esophageal acid exposure with usual doses of omeprazole. Indeed, recent data confirm that three-fourths of all patients will have significant periods of nocturnal acid exposure despite omeprazole 20 mg twice a day. Somewhat surprising is the finding that this nocturnal acid “breakthrough” responds better to a bedtime dose of an H2RA vs. an additional 20 mg of omeprazole. Both pantoprazole and rabeprazole seem to produce more rapid onset and more complete gastric acid inhibition than omeprazole, and this differentiation seems sure to impact future marketing. The precise levels of dosing required for the newer proton pump inhibitors have yet to be determined, particularly as applicable to refractory GERD patients.
Control of esophageal pH may require multiple doses of all available PPIs, particularly in more difficult cases of gastroesophageal reflux disease. However, the PPI that can be most cost effective will undoubtedly prosper in the increasingly price-sensitive pharmaceutical market. In general, this will entail once daily dosing for the majority of patients. The PPI that can demonstrate such cost effectiveness should garner a substantial marketing advantage.
In summary, it is clear that pH profiling of antisecretory drugs in terms of their effects on gastric and esophageal acidity will continue to be critical to their positioning in the competitive marketplace, and investigators working in this arena should have much additional work ahead. For gastroesophageal reflux disease, the reduction of esophageal acid exposure certainly can be considered as a surrogate measure for clinical efficacy.
Originally posted 2010-04-20 08:10:19. Republished by Blog Post Promoter