Pipeline Insight: Upper Gi Disorders - Generics Will Limit Pipeline Profit

Published by: Datamonitor

Published: Jul. 11, 2007 - 226 Pages

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

Abstract

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