Pipeline Insight: Upper GI Disorders - Generics will limit pipeline profit

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