Market Report Source

Overview

Introduction
Gastroesophageal reflux disease (GERD), functional dyspepsia (FD) and peptic ulcer disease (PUD) represent a group of common gastrointestinal (GI) conditions, which can be referred to collectively as upper GI disorders. Gastric acid suppression remains the cornerstone of therapy in upper GI disorders, with particular focus on reducing symptoms and eradicating H. pylori, if present.

Scope of this report

• Analysis of patient potential, unmet needs and clinical trials in upper GI disorders.
• Overview of drugs in late- and early-stage clinical development; with analysis of key companies involved in the R&D pipeline.
• Detailed profiles of key compounds in development for use in upper GI disorders, with forecasts of drug revenues to 2016.
• Discussion of R&D company strategies used in upper GI disorder market, focusing on AstraZeneca and TAP Pharmaceuticals.

Research and analysis highlights
The upper GI disorder pipeline is small, with only 33 products, and only 3 drugs in Phase III. In a market that is dominated by PPIs, which are becoming increasingly genericized, and with over-the-counter medicines available, pharmaceutical companies appear to be less than willing to enter this competitive market.

A key company R&D strategy is the development of specific enantiomers of PPIs. This extends patent life and can result superiority to the racemate mixture. TAP Pharmaceuticals has for dexlansoprazole, and Sidem Pharma and Steba Laboratories are co-developing S-tenatoprazole for GERD. Both are expected to quickly achieve blockbuster status.

The inclusion of Nexium (esomeprazole) as a comparator in clinical trials is essential to ensure market success for pipeline products. Companies will also benefit by addressing the unmet needs such as drugs for the PPI unresponsive population. This niche patient subgroup is difficult to treat and is currently underserved.

Key reasons to read this report

• Understand unmet needs in the upper GI disorder market based on key opinion leader comment.
• Benchmark key late-stage pipeline products against the current market leader.
• Assess the sales forecasts of key late-stage pipeline drugs and examine their clinical and commercial potential.

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

About the Immune Disorders and Inflammation pharmaceutical analysis team CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the upper GI disorder market Key metrics Datamonitor Pipeline Assessment Summary Upcoming reports CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS Pipeline overview Drugs in the upper GI disorder pipeline fall into a wide variety of classes, but proton pump inhibitors remain the focus of research Key companies involved in the upper GI disorder pipeline AstraZeneca: a dominant force in the GI disorder market, but for how much longer? AstraZeneca developed and marketed Losec/Prilosec (omeprazole), the first proton pump inhibitor available for the treatment of GERD Nexium (esomeprazole) has been a driver of growth for AstraZeneca Nexium is available in both oral and intravenous formulations AstraZeneca will move its focus away from core research areas including gastroenterology possibly driven by frustration at discontinued projects Challenges to the patents covering Nexium AstraZeneca has three products in the pipeline for upper GI disorders TAP Pharmaceuticals: in-licensing the central strategy to success

Prevacid (lansoprazole) is the sole product in TAP Pharmaceuticals’ GI franchise

Prevacid patent expiry in the US will contribute to slowing growth at TAP Pharmaceuticals TAP Pharmaceuticals looking to follow on from Prevacid with dexlansoprazole and ilaprazole Key R&D company strategies Isomers of PPIs Combination therapies Indication expansion

New PPI formulations

CHAPTER 3 UPPER GI DISORDERS DISEASE OVERVIEW AND MARKET POTENTIAL Gastroesophageal Reflux Disorder (GERD) GERD diagnosis Patient segmentation of GERD Non-erosive reflux disease

Erosive reflux disease

Barrett’s esophagus Refractory GERD Nocturnal acid breakthrough Epidemiology of GERD Variability in the definition of GERD makes it difficult to accurately quantify the prevalence of the disease US: has the highest patient population of GERD in the seven major markets Japan: an increase in the prevalence of upper GI disorders EU

France

Germany Italy

Spain

UK Other prevalence studies

Domestic/International Gastroenterology Surveillance Study

Dyspepsia

Functional dyspepsia and Rome III Epigastric Pain Syndrome (EPS) Postprandial Distress Syndrome (PDS) GERD and dyspepsia: overlap of GI symptoms Treatment of dyspepsia Epidemiology of dyspepsia

The overlap of the symptoms of dyspepsia with other GI disorders makes it challenging to determine the prevalence of the disorder

Peptic Ulcer Disease

Helicobacter pylori infection is a cause of peptic ulcer disease Treatment with non-steroidal anti-inflammatory drugs induces peptic ulcer disease Synergy between H. pylori and non-steroidal anti-inflammatory drugs has been suggested Does eradication of H. pylori exacerbate GERD symptoms?

Epidemiology of PUD

The prevalence of PUD has decreased over the last 20 years

The Kalixanda study

Unmet needs in Upper GI Disorders Drugs for patients unresponsive to currently available PPIs Alternative GERD maintenance therapies PPIs that are not dependent on food intake Long duration and fast onset of action Safer non-steroidal anti-inflammatory drugs that do not cause ulcers CHAPTER 4 R&D APPROACH Classification of pipeline products Histamine receptor antagonists Proton pump inhibitors Irreversible proton pump inhibitors

Potassium-competitive acid blockers (P-CABs)

CCK receptor antagonists GABAB agonists Glutamate receptor antagonists 5HT agonists PPI-based triple therapies Other Clinical trial endpoints in upper GI disorders Assessment of acid suppression Endoscopy The Los Angeles Classification Improvement in GERD symptoms as assessed by questionnaires ReQuest ReQuest/LA Classification Eradication of H. pylori CHAPTER 5 ACID SUPPRESSION THERAPIES LATE-STAGE DRUG ANALYSIS AND FORECASTS Overview for acid suppression therapies

Pipeline summary

Comparative forecasts Definition of current comparator therapy Dexlansoprazole Drug overview Clinical trial data Clinical trial 1

Patient potential

Dexlansoprazole will be beneficial in all GERD and PUD patients

TAP Pharmaceuticals will be looking to switch patients from Prevacid (lansoprazole) to dexlansoprazole (TAK-390MR) Marketing factors TAP Pharmaceuticals was working with Flamel Technologies to develop a controlled-release formulation of lansoprazole; however, TAP decided to pursue dexlansoprazole TAP Pharmaceuticals has vast marketing experience in the area of upper GI disorders, which will benefit dexlansoprazole Satisfaction of unmet needs Forecasts to 2016 Datamonitor drug assessment summary

S-tenatoprazole-Na

Drug Overview Clinical trial data Clinical trial 1 Clinical trial 2 Clinical trial 3 Patient potential Small scale clinical data from the Japanese population demonstrate that racemic tenatoprazole is comparable to omeprazole in the cure rate of peptic ulcers Early clinical studies suggest a faster onset of action and longer duration of action for tenatoprazole compared with esomeprazole Marketing factors Sidem Pharma has taken over the development of tenatoprazole from Mitsubishi-Tokyo Pharmaceuticals Tenatoprazole was undergoing Phase II clinical trial, but these have been suspended Sidem Pharma and Steba Laboratories will need to acquire an experienced marketing partner if they are to take on the marketing power of AstraZeneca Satisfaction of unmet needs Forecasts to 2016 Datamonitor drug assessment summary AGI-010 Drug overview Clinical trial data Patient potential AGI Therapeutics will be looking to position AGI-010 as a treatment for nocturnal acid breakthrough in the upper GI market Marketing factors AGI Therapeutics and Axcan Pharma have signed a co-development agreement for AGI-010 Axcan is an international company with a number of products in the GI market including a 3-in-1 therapy for the eradication of H. pylori and treatment of PUD

Satisfaction of unmet needs

Forecasts OX 17 Drug overview Clinical trial data Patient potential

OX 17’s rapid onset of action and long duration of action will make this drug desirable; however, the perception is that co-administration of an H2 blocker with a PPI is not feasible

Marketing factors Orexo’s lack of experience will result in the company seeking a marketing partner for OX 17 Orexo may position OX 17 as an over-the-counter drug in the US and EU Satisfaction of unmet needs Forecasts Ilaprazole Drug overview Clinical trial data Preclinical data Phase II clinical trial Planned US Phase II study and reported Chinese Phase III completion Patient potential Early Phase I studies show that ilaprazole is superior to omeprazole at reducing acid output in patients with GERD Marketing factors Il Yang does not have a strong presence outside of South Korea TAP Pharmaceuticals will be responsible for the worldwide marketing of ilaprazole Satisfaction of unmet needs Forecast Other novel late-stage acid suppression therapies Revanex (revaprazan) Soraprazan Soraprazan progressing slowly through clinical trials and unlikely to reach market before Protonix patent expiry Dexloxiglumide CCK antagonists will not have great potential in GERD because of low efficacy compared to PPIs Z-360 Other acid suppression therapy under investigation for additional upper GI approvals Omeprazon (omeprazole) Famotidine (YM1170) Protonix (pantoprazole) Late-stage development compounds recently suspended or discontinued CS-526 CS-526 was being co-developed by Daiichi Sankyo and Novartis The discontinuation of CS-526 means that Novartis does not have a presence in the upper GI disorder market AZD0865 AZD0865 is a potassium-competitive acid blocker that was being investigated for GERD AZD0865 was terminated in Phase II development because it showed signals of hepatotoxicity and failed to show clinical superiority over esomeprazole CHAPTER 6 PPI-BASED TRIPLE THERAPIES LATE-STAGE DRUG ANALYSIS AND FORECASTS Overview for PPI-based triple therapies Pipeline summary Definition of current comparator therapy Pylera Drug overview Clinical trial data

Clinical Trial 1

Clinical Trial 2 Patient potential Axcan has developed the first 3-in-1 combined tablet for the treatment of H. pylori eradication; however, availability of generics will limit its potential Clinical trial data demonstrate efficacy in patients with clarithromycin- and metronidazole-resistant H. pylori Pylera will have a reduced patient potential as it has not demonstrated improved compliance over comparator drugs Marketing factors

Axcan has previous experience in the GI market which will be advantageous to Pylera

Satisfaction of unmet needs Forecasts to 2016 Datamonitor drug assessment summary CHAPTER 7 INHIBITORS OF TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATION LATE-STAGE DRUG ANALYSIS AND FORECASTS Overview for Inhibitors of Transient Lower Esophageal Sphincter Relaxation Pipeline summary AZD3355 Drug overview Patient potential AstraZeneca will position AZD3355 in patients who have difficult GERD symptoms and who show an incomplete response to PPIs Potential for side effects of GABAB agonists may affect uptake of AZD3355 Marketing factors AstraZeneca will be well placed for the marketing of AZD3355 Satisfaction of unmet needs Forecasts XP19986 Drug overview Clinical trial data Patient potential Patient potential for XP19986 will be similar to other GABAB agonists in development for GERD Marketing factors XenoPort requires a strong marketing partner for XP19986 in the upper GI market if the drug is going to compete with AstraZeneca’s AZD3355 XenoPort’s lead candidate XP13512 is in co-development with GlaxoSmithKline and Astellas XenoPort must continue to demonstrate a lack of central side effects with XP19986 Satisfaction of unmet needs Forecasts ADX-10059 Drug overview Clinical trial data Patient potential

ADX-10059 will have a similar patient potential to GABAB agonists but side effects are a concern

Marketing factors Addex Pharmaceuticals’ main focus is on CNS rather than GI disorders and needs a marketing partner for ADX-10059 Satisfaction of unmet needs Forecasts to 2016 Datamonitor drug assessment summary Other inhibitors of TLESR

Arbaclofen (AGI-006)

CHAPTER 8 GASTROPROKINETIC LATE-STAGE DRUG ANALYSIS Overview for Gastroprokinetic therapies Pipeline summary Comparator therapy ATI-7505 Drug overview Clinical trial data Patient potential ATI-7505 may be useful for GERD patients with nocturnal acid breakthrough and PPI treatment failures

ATI-7505 may be of more benefit in patients with functional GI disorders

Marketing factors Aryx has granted the worldwide development and commercialization rights to ATI-7505 to Procter & Gamble There is a gap in the gastroprokinetics market for next-generation compounds with improved side-effect profiles

Satisfaction of unmet needs

Forecasts Zelnorm (tegaserod maleate)

Drug overview

Clinical trial data GERD Clinical Trial 1 GERD Clinical Trial 2 Dyspepsia Clinical Trial Patient potential Zelnorm was a promising therapy for functional dyspepsia, but the side-effect profile will be a very difficult challenge for developers Novartis would have positioned Zelnorm in patients with an incomplete response to PPIs Marketing factors The risks associated with Zelnorm outweigh the benefit of the drug and Datamonitor believes trials in GERD and FD will be suspended Satisfaction of unmet needs Forecasts Z-338 Drug overview Clinical trial data Patient potential The patient potential for Z-338 will be large Marketing factors Astellas will be a major marketing force for Z-338 Satisfaction of unmet needs Forecasts CHAPTER 9 “OTHER” LATE-STAGE DRUG ANALYSIS Overview for “Other” Pipeline summary Probactrix Drug overview Patient potential BioBalance may position Probactrix in GERD patients who do not respond fully to PPIs Probactrix may also be useful as a treatment for IBS and other GI disorders, therefore, further increasing the patient population Marketing factors BioBalance is a small pharmaceutical company that develops biotherapeutic agents for the treatment of GI disorders

Satisfaction of unmet needs

Forecasts Vecam (VB101) Drug overview Patient potential Vecam (VB101) may be useful in patients with nocturnal acid breakthrough and those refractory to PPI therapy Marketing factors Vecta is looking for a leading pharmaceutical partner for the development of vecam (VB101) The launch of vecam will be later than predicted by Vecta Satisfaction of unmet needs Forecasts CHAPTER 10 INNOVATIVE EARLY-STAGE PROJECTS Key Phase I and preclinical compounds in upper GI disorders The early-stage pipeline contains few drugs and lacks innovation Despite a crowded market and with many new PPIs in late stages of clinical development there are three PPIs in early-stage development Extended-release Aciphex (rabeprazole) AGN 201904 NMI-826 There is a single 5-HT agonist in early-stage development Pumosetrag (MKC-733, DDP-733) BIBLIOGRAPHY Journals Websites Datamonitor reports APPENDIX A Methodology Datamonitor forecast methodology Product forecasts Definition of a standard unit Contributing experts APPENDIX B

About Datamonitor

About Datamonitor Healthcare Datamonitor Healthcare’s therapy area capabilities About the Disease analysis team Disclaimer List of Tables

Table 1: Forecast key pipeline products for upper GI disorders in the seven major markets, 2006-2016 ($, billion)

Table 2: R&D pipeline for upper GI disorders in the seven major markets, 2007

Table 3: AstraZeneca’s discontinued pipeline projects, 2007 Table 4: AstraZeneca’s pipeline drugs for upper GI disorders, 2007 Table 5: Prevacid’s approved indications, 2007 Table 6: TAP Pharmaceuticals’ pipeline drugs for upper GI disorders, 2007 Table 7: Key prevalence studies of GERD across the seven major markets, 1997-2007 Table 8: Summary of prevalence of GERD in the seven major markets, 2007 Table 9: Description of studies that examine the prevalence of dyspepsia

Table 10: Summary of prevalence of dyspepsia in the seven major markets, 2007

Table 11: Summary of prevalence of PUD in the seven major markets, 2007

Figure 12: Unmet needs in upper GI disorder, 2007 Table 12: An overall comparison between irreversible proton pump inhibitors and potassium-competitive acid blockers

Table 13: The Los Angeles Classification of erosive esophagitis

Table 14: Key proton pump inhibitor class drugs in late-stage upper GI disorder R&D pipeline, 2007

Table 15: AstraZeneca’s Nexium (esomeprazole): key facts

Table 16: TAK-390MR study: mean intragastric pH for each dosing regime Table 17: TAK-390MR study: percentage of each time intragastric pH > 4 for each dosing regime Table 18: Acid suppression by different doses of S-tenatoprazole-Na vs. esomeprazole

Table 19: Mean percentage of time spent above pH 3 and pH 4 in specified periods after treatment with tenatoprazole or esomeprazole

Table 20: Percentage of time with gastric pH above 4 after 1 day and 8 days of treatment with omeprazole, famotidine or a combination of both drugs

Table 21: Suspended R&D projects in proton pump inhibitor class, 2004-07

Table 22: Key drugs from the PPI-based triple therapies class in late-stage upper GI disorder R&D pipeline, 2007 Table 23: Key drugs from the inhibitors of transient lower esophageal sphincter class in late-stage upper GI disorder R&D pipeline, 2007 Table 24: Phase II a clinical trial data summary for 250mg ADX-10059 Table 25: Key drugs from the gastroprokinetic class in late-stage upper GI disorder R&D pipeline, 2007 Table 26: Key drugs from “Other” class in late-stage upper GI disorder R&D pipeline, 2007 Table 27: Key early-stage pipeline products in development for upper GI disorders, 2007 Table 28: Datamonitor drug assessment parameters List of Figures

Figure 1: Forecast key pipeline and marketed products for upper GI disorders in the seven major markets, 2006-2016 ($, billion)

Figure 2: Datamonitor drug assessment summary of pipeline drugs in development for upper GI disorders in the seven major markets, 2007 Figure 3: Upper GI disorders pipeline products by phase of development, 2007 Figure 4: Pipeline products for upper GI disorders split by class and by highest phase of development, 2007 Figure 5: Global sales of Nexium (esomeprazole) and Losec/Prilosec (omeprazole), 2000-06 Figure 6: Takeda’s gastrointestinal franchise will be the key resistor to growth to 2011 Figure 7: Extra-esophageal symptoms of GERD Figure 8: The etiology of upper GI disorders Figure 9: Prevalence of GERD across the seven major markets, 2007 Figure 10: Peptic ulcer disease affects the esophagus, stomach and the upper duodenum Figure 11: Synergism of H. pylori and NSAID in the development of peptic ulcers Figure 13: Secreting parietal cell showing targets for pharmacological intervention to reduce acid exposure Figure 14: ReQuest: an example of a question

Figure 15: Comparative sales ($, billions) forecasts for the proton pump inhibitor drugs in the seven major markets, 2007-16

Figure 16: Datamonitor’s forecast of sales for dexlansoprazole (TAK-390MR) in upper GI disorders across the seven major markets, 2007-2016 Figure 17: Datamonitor’s competitive positioning analysis for dexlansoprazole (TAK-390MR) in upper GI disorders, 2007-2016 Figure 18: Proportion of subjects with a pH above 4 for more than 24 hours in the 48 hours of continuous pH recording Figure 19: Datamonitor’s forecast of sales for S-tenatoprazole-Na in upper GI disorders across the seven major markets, 2007-2016 Figure 20: Datamonitor’s competitive positioning analysis for S-tenatoprazole in upper GI disorders, 2007-2016

Figure 21: Helicobacter pylori eradication rates for bismuth-based quadruple therapy, Pylera, and the triple therapy with omeprazole

Figure 22: Eradication rates in patients with clarithromycin- and metronidazole-resistant Helicobacter pylori

Figure 23: Helicobacter pylori eradication rates: overall and by metronidazole resistance

Figure 24: Helicobacter pylori eradication rates by disease type

Figure 25: Datamonitor’s forecast of sales for Pylera in upper GI disorders across the seven major markets, 2007-2016 Figure 26: Datamonitor’s competitive positioning analysis for Pylera in upper GI disorders, 2007-2016 Figure 27: Datamonitor’s forecast of sales for ADX-10059 in upper GI disorders across the seven major markets, 2007-2016 Figure 28: Datamonitor’s competitive positioning analysis for ADX-10059 in upper GI disorders in the seven major markets, 2007-2016 Figure 29: Breakdown of innovative early-stage projects by mechanism of action and by specific phase of development, 2007