The GERD market Ted T. Ashburn Meera S. Gupta info:doi/10.1038/nrd2011 2006-04-00T00:00:00Z 2006-04-00T00:00:00Z (c) 2006 Nature Publishing Group Nature Reviews Drug Discovery 5 4 277 278 1474-1776 (?-mix:\s+\W+|\W+\s+|\s+|\/) GERD PPIs patients 2 effective H RAs symptoms therapies 1 agents associated market or available dysfunctions esophagus Fig gastric mechanisms one stomach billion common development drug drugs durable improving mechanical medical more need not now receptor safe treat US 10 3 5-HT 80 aggressive agonist basis bile branded contents continue damage defence defensive effects emptying episodes esophageal esophagogastric factors GI GlaxoSmithKline healing heartburn imbalance improve incidence Johnson junction lead mature mechanism new nocturnal Novartis particular pathophysiology per pH pockets primarily prn rate reducing reflux salts sphincter still success sufferers Table taking targeting tract unmet 16 1993 20 2000 2003 30 30-day 3–6 4 44 5-hydroxytryptamine-4 50 7 Abbott ABT-229 account ache achieved acid acid-catalysed Acid-reducing acid-suppressing acidity addition address adenocarcinoma adequate administration adults after against agent agonists aimed airways alemcinal alone antacids antagonists antibiotic approved approximately area ARYx aspirated Assuming asthmatic AstraZeneca ATI-7505 attacks attractive augment baclofen Barretts behind biggest-selling block built burning cancer cardiac cause caustic characteristic choice cholesterol-lowering Chronic chronically Chugai Cisapride class classes clear commonly complain complex compounds concern Conclusions condition conditions coupled Current daytime DDP733 decrease derivatives Despite developing different direct disease distal disturbances domperidone dose dull Dynogen dysrhythmias Emerging endoscopic enormous environments enzymes epigastric episode erosive erythromycin esophagitis esophagogastric-junction example exceed experience explored fact facts famotidine fastest final Finally find flow form forms Four Gastroesophageal gastrointestinal GM-611 growing healthy help high higher histamine hyperactive identified improves inappropriate increase indications individuals ineffective inhibitors instance involves involving Janssen-Cilag keeps key Laboratories least less life-threatening lifestyle limited Lioresal lower making many Market markets means meant Merck metoclopramide migrate mild mitemcinal modifications month motilin Motilium neutralization next-generation nine non-erosive number occur occurs off-label omeprazole only opportunities Options otherwise par part past pathway penetration Pepcid Pharma pharmacologically pharynx population possibility PPI precancerous prescriptions present pressure pricing Prilosec procedures production Propulsid protect proton-pump provide pumosetrag range ranitidine rates rearrangement Ref referred refluxate Reglan related relaxations relief repeatedly reported reputation response results sales Schwarz second secretion severe sheer side significant sleep sleepiness sometimes spent standard States sternum subtypes suffering supraesophageal surgical susceptibility symptom tachyphalaxis tegaserod terms Thanks today Todays todays tone treatment treatments TUMS type undergoes United untreated up US$13.5 utility virtually well-tolerated withdrawn year years Zantac (?-mix:\.\s+(?=[A-Z])) Although heartburn is the most common characteristic, GERD can also present as supraesophageal symptoms ( Fig. 1 ), sleep disturbances and daytime sleepiness Assuming that 20% of GERD patients taking PPIs do not find adequate relief, nine (30-day) prescriptions per year, pricing on par with todays branded PPIs and a 50% penetration rate, the market for a safe, effective, durable and well-tolerated agent targeting the unmet medical need in the GERD market could exceed $1 billion in the US alone But the complex pathophysiology of GERD, and the fact that branded PPIs are effective in only ∼80% of patients (and ineffective on a prn basis), means that there are still opportunities for new therapies Chronic, untreated GERD can damage the esophagus and lead to Barretts esophagus, a precancerous condition which can lead to esophageal adenocarcinoma — the fastest growing cancer in terms of incidence in the United States Cisapride (Propulsid; Johnson Johnson), a 5-hydroxytryptamine-4 (5-HT 4 ) receptor agonist that improves both esophagogastric-junction pressure and gastric emptying, was approved in 1993 for the treatment of nocturnal GERD Conclusions Acid-reducing agents such as H 2 RAs and PPIs, and several compounds from within these classes, are available now to treat GERD Current treatments Options range from lifestyle modifications and drug therapies to endoscopic and surgical procedures Despite the clear success of these agents, there are still pockets of unmet medical need in the GERD market Emerging therapies The possibility of pharmacologically reducing inappropriate relaxations of the sphincter mechanism at the esophagogastric junction and/or improving its tone to treat GERD has been explored repeatedly during the past 10 years Finally, PPIs are not effective on a prn basis For example, baclofen (Lioresal; Novartis), metoclopramide (Reglan; Schwarz Pharma) and domperidone (Motilium; Janssen-Cilag) are all effective at improving GERD symptoms For instance, the response rate to a standard dose of a PPI for patients with non-erosive GERD is 30% lower than in patients with erosive esophagitis and, overall, approximately 16% of patients continue to have symptoms while taking PPIs Four different subtypes have been identified ( Fig. 2 ), and the incidence of nocturnal GERD symptoms in the overall population has been reported to be as high as 10% Gastroesophageal reflux disease (GERD) occurs when stomach contents flow into the esophagus GERD is one of the most common conditions in the US, with 44% of adults suffering at least one episode per month GERD results from an imbalance between aggressive factors and defensive mechanisms ( Fig. 3 ) GERD sufferers often complain of a burning or dull ache either behind the sternum or in the epigastric area — a symptom referred to commonly as heartburn H 2 RAs such as ranitidine (Zantac; GlaxoSmithKline) and famotidine (Pepcid; Merck) are used primarily for mild GERD However, H 2 RAs are less effective when used chronically because of tachyphalaxis However, several next-generation 5-HT receptor agonists in development might have such effects ( Table 1 ), such as tegaserod (Novartis), DDP733/pumosetrag (Dynogen) and ATI-7505 (ARYx) However, there are no safe, effective and durable therapies available today for improving mechanical dysfunctions associated with GERD, although many are in development However, these agents are associated with significant side effects In 2003, US$13.5 billion was spent on PPIs in the US, making them the second biggest-selling drug class after cholesterol-lowering agents In addition, asthmatic attacks in patients with hyperactive airways can occur if stomach contents migrate into the pharynx and are then aspirated In particular, the sphincter mechanism at the esophagogastric junction is one of the key defence mechanisms against GERD, and dysfunctions involving this part of the GI tract account for virtually all reflux episodes in healthy individuals and up to 80% of episodes in patients with GERD It achieved sales of more than $1 billion before it was withdrawn in 2000 because it was associated with life-threatening cardiac dysrhythmias Market indications Thanks to the success of H 2 RAs and PPIs, GERD has built a reputation for being one of the more mature markets Of particular concern for these patients is their susceptibility to esophageal damage, because PPIs increase refluxate pH, and bile salts are more caustic in environments in which the pH is between 3–6 (Ref. 7 ) PPIs such as omeprazole (Prilosec; AstraZeneca) block the final common pathway of gastric acid production, provide significantly higher healing rates than H 2 RAs and are now the drugs of choice for healing severe forms of GERD Several drugs that could help improve mechanical dysfunctions associated with GERD are now in development ( Table 1 ). Since then, there have been no safe, effective and durable drugs available to address the mechanical dysfunctions associated with GERD The antibiotic erythromycin — which undergoes an acid-catalysed rearrangement in the stomach to form a motilin agonist and is sometimes used off-label to treat GERD — and its derivatives such as alemcinal (ABT-229; Abbott Laboratories) and mitemcinal (GM-611; Chugai) all have limited utility for GERD The pathophysiology of GERD involves an imbalance between aggressive factors related to the stomach and distal gastrointestinal (GI) tract, and defensive mechanisms meant to protect the esophagus ( Fig. 3 ) These facts, coupled with the sheer number of GERD sufferers, keeps the GERD market attractive for developing new therapies targeting the pockets of medical need in this enormous and otherwise mature market These patients often continue to experience symptoms because PPIs do not decrease the secretion of enzymes and bile salts that can also cause GERD symptoms, nor do they augment any GERD defence mechanisms or improve gastric emptying Todays available drug therapies are aimed primarily at reducing gastric acidity, either through direct neutralization by antacids such as TUMS (GlaxoSmithKline) or administration of acid-suppressing agents such as histamine type 2 receptor antagonists (H 2 RAs) and proton-pump inhibitors (PPIs) Supraesophageal symptoms expressed patients reflux. Source: American Gastroenterological Association, Nightime Heartburn Relief Effort. Supraesophageal symptoms expressed patients reflux. Source: American Gastroenterological Association, Nightime Heartburn Relief Effort. Prevalence mucosal injury different patterns reflux. OR, odds ratio; CI, confidence interval. Source Ref. 1 . Prevalence mucosal injury different patterns reflux. OR, odds ratio; CI, confidence interval. Source Ref. 1 . Possible gastroesophageal reflux disease pathophysiologies. Possible gastroesophageal reflux disease pathophysiologies. 7