Pipeline Insight: Alzheimer's Disease - A Busy Future, with Diagnosis, Disease Modification and Prevention Key to Growing Market

SUMMARY

Over the next ten years the Alzheimer's disease market will becomeincreasingly competitive as potentially disease modifying drugs vie forapproval. Companies will need to scrutinize their plans to ensure implementationof appropriate launch strategies, achieving clear positioning anddifferentiation in a changing environment. What is right for launch in 2005 maynot be effective at a later date.

Scope of this report

• Epidemiology of Alzheimer's Disease across the 7 major markets, as well asanalysis of the main unmet needs in the current treatment of the disease
• Overview of drugs in Phase III, II, I and pre-clinical development, plusanalysis of key companies involved in the R&D pipeline: Pfizer, Lilly& Sanofi
• Comprehensive analysis of key late-stage products phenserine, Alzhemed,PBT-1 and Colostrinin, with Datamonitor forecasts of drug revenues to 2014
• Insight into innovative early stage products, including vaccines, as wellas analysis of key research impacts concerning beta-amyloid

Research and analysis highlights

Marketed products only provide temporary partial symptomatic relief: diseasemodification and prevention are major unmet needs. Opinion leaders considerphenserine (Axonyx) and Alzhemed (Neurochem) to have potential for successfuldisease modification which could challenge Aricept's market domination ifsupported by sufficient marketing strength.

Physicians and sections of the pharmaceutical industry are searching foroptions to prevent Alzheimer's disease. The large number of mechanismscontributing to the etiology and progression of the disorder add complications.There is substantial opportunity but the industry will need to carefullyconsider the challenges of a prophylactic market.

An increasing focus on disease prevention and early identification highlightsa need for simple diagnostic tools and biological markers. Identification of 'atrisk' and early clinical groups would aid trial design and assist patientsegmentation and product positioning strategies, key factors as more playersenter the market

Key reasons to read this report

• Enhance your sales forecasting ability and future product positioningthrough identification of market drivers and key competitors
• Optimize your knowledge of company strategies in the AD market
• Identify areas of the market that are not being targeted by competitorsand gain an objective view of potential in-licensing opportunities

TABLE OF CONTENTS

ABOUT DATAMONITOR HEALTHCARE

About the CNS pharmaceutical analysis team

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the analysis

Datamonitor insight into the Alzheimer's disease market

The major unmet need in this market is for disease modification anddisease prevention. Currently marketed products are perceived to onlyprovide partial and temporary relief from Alzheimer's symptoms. In the shortto medium term opinion leaders are looking to Axonyx's phenserine andNeurochem's Alzhemed in anticipation of successful modification of diseaseprogression. This high level of awareness and positivity bodes well for thelaunches of these products, which could challenge the market domination ofPfizer/Eisai's Aricept (donepezil) if supported by sufficient marketingstrength.

Current diagnosis by specialists, albeit of 'probable' Alzheimer's, isrelatively accurate as verified on post mortem analysis. However, anincreasing focus on early identification and prevention, in addition to agrowing aging population being managed by primary care physicians,highlights a need for simpler diagnostic tools and robust biologicalmarkers. Improved identification of both 'at risk' and early clinical groupswould aid trial design and assist patient segmentation and productpositioning strategies, which will become key as more players enter themarket.

Prevention is better than cure. Over the longer term physicians, andsections of the pharmaceutical industry, are searching for options toprevent Alzheimer's disease. The large number of mechanisms hypothesized tocontribute to the etiology and progression of the disorder complicates thisquest. As these hypotheses are refined and scientific rationale isdemonstrated, the substantial opportunity provided by prevention may becomemore attainable, however Industry will need to pay careful consideration tothe challenges of a prophylactic market.

Although neuroprotective and neurotrophic drugs offer significantpotential commercial benefit, they are also associated with problematicdevelopment. Companies with little threshold tolerance for pipeline failuremay look to balance their risk across a number of potential pathways toAlzheimer's treatment. This approach will increase the likelihood ofproviding a marketable product and could provide a veritable suite of drugsfor Alzheimer's management across the patients' range of needs.

Summary

Key metrics

CHAPTER 2 PATIENT POTENTIAL

Definition of Alzheimer's disease

Segmentation of Alzheimer's disease

Mild cognitive impairment (MCI)

Comorbidities

Treatments for comorbidities

Drugs for treating depression

Drugs for treating agitation, aggression and psychotic symptoms

Drugs for treating anxiety

Drugs for treating sleep disturbances

Commercial analysis of AD comorbidities

Epidemiology of Alzheimer's disease

Diagnosis and treatment rates

Future trends

Unmet needs in Alzheimer's disease

Disease modification

Improved efficacy

Fewer side effects

Reducing numbers of treatment unresponsive patients

Patient compliance

CHAPTER 3 R&D APPROACH

Classification of pipeline products

ACh modulators

Neuroprotective and neurotrophic drugs

Beta-amyloid modulators

Beta-secretase (BACE) inhibitors

Protein deposition inhibitors

Other compounds in development

Clinical trial design in Alzheimer's disease

Patient population

Design

Duration

Gold standard

Clinical trial endpoints in Alzheimer's disease

Alzheimer's disease assessment scale

Mini-Mental Status Exam

Clinician's Interview-Based Impression of Change

Severe Impairment Battery

Alzheimer's Disease Cooperative Study: Activities of Daily Living

Clinical Dementia Rating

Cambridge Neuropsychological Test Automated Battery (CANTAB)

Global Deterioration Scale

Functional Assessment Staging

Clinical Global Impression of Change

Clinical Global Impression of Severity

Neuropsychiatry Inventory

Behavioral Rating Scale for Geriatric Patients

Resource Utilization in Dementia

Disability Assessment for Dementia

Progressive Deterioration Scale

Clinical Dementia Rating

Summary

CHAPTER 4 ALZHEIMER'S DISEASE PIPELINE ANALYSIS

Pipeline overview

Phase III overview

Phase II overview

Phase I overview

Preclinical overview

Key companies involved in the Alzheimer's disease pipeline

Eli Lilly

Pfizer

Sanofi-Synthélabo

Companies specializing in Alzheimer's disease

Axonyx

Mindset

Nymox

Prana

Strategies for success

High risk, high profit versus low risk, low return

Diagnosis of Alzheimer's disease

Ethics and trial design

CHAPTER 5 ACETYLCHOLINE MODULATORS - LATE-STAGE DRUG ANALYSIS &FORECASTS

Overview for ACh modulators

Pipeline summary

Definition of current comparator therapy

Phenserine

Profile

Drug overview

Clinical trial data

Phase III

Phase II

Patient profile

Marketing factors

Satisfaction of unmet needs

Efficacy

Disease modification

Safety

Treatment response

Forecasts to 2014

Other ACh modulator drugs

ZT-1 (Huperzine A)

NS-2330

P58

TC-1734

SIB-1553A

ABT-089

Ganstigmine

CI-1017 (PD-151832)

MKC231

Late-stage development compounds recently discontinued

TAK-147 (PIII)

Comparison of key AChE modulator compounds

Disease modification

Better efficacy than marketed drugs

Side-effect profile

Treatment unresponsive patients

Marketing strength

CHAPTER 6 BETA-AMYLOID MODULATORS LATE-STAGE DRUG ANALYSIS AND FORECASTS

Overview for beta-amyloid modulators

Pipeline summary

Definition of current comparator therapy

Alzhemed (NC 531)

Profile

Drug overview

Clinical trial data

Phase I

Phase II

Phase III

Patient potential

Marketing factors

Satisfaction of unmet need

Efficacy

Disease modification

Safety

Treatment response

Forecasts to 2014

PBT-1 (clioquinol)

Profile

Drug overview

Clinical trial data

PHASE II TRIAL

Patient potential

Marketing factors

Satisfaction of unmet need

Efficacy

Disease modification

Safety

Treatment response

Forecasts to 2014

Other drugs

Egb-761 (Tanakan)

Comparison of key compounds in the beta-amyloid modulator class

Disease modification

Better efficacy than marketed drugs

Side-effect profile

Treatment unresponsive patients

Marketing strength

Comparative forecasts

CHAPTER 7 NEUROPROTECTIVE AND NEUROTROPHIC DRUGS-LATE-STAGE DRUG ANALYSISAND FORECASTS

Overview for neuroprotective and neurotrophic drugs

Pipeline summary

Definition of current comparator therapy

Xaliproden

Profile

Drug overview

Clinical trial data

Patient potential

Marketing factors

Satisfaction of unmet need

Efficacy

Disease modification

Safety

Treatment response

Forecasts to 2014

Other drugs

SR-57667

SGS111

KA-672

T-588

Late-stage development compounds recently discontinued

CX516 (AMPAKINE) (PII)

FK960 (PII)

Neotrofin (PII)

CHAPTER 8 OTHER DRUGS - LATE-STAGE DRUG ANALYSIS AND FORECASTS

Overview for other drugs

Pipeline summary

Definition of current comparator therapy

Antioxidants

Colostrinin

Drug profile

Clinical trial data

PHASE II/III

Patient potential

Marketing factors

Satisfaction of unmet needs

EFFICACY

DISEASE MODIFICATION

SAFETY

TREATMENT RESPONSE

Forecasts to 2014

Bacosides

Vitamin E

PREADVISE

Vitamin E and donepezil

Anti-inflammatory drugs

R-Flurbiprofen (MPC7869)

Dapsone

Statins

Lipitor (atorvastatin)

Zocor (simvastatin)

Comment

B vitamins

Hormones

Estrogen

Drug overview

Clinical trial data

PHASE III TRIAL 1: WOMEN'S HEALTH INITIATIVE MEMORY STUDY (WHIMS)(SHUMAKER ET AL., 2003; BARCLAY, 2004; SHUMAKER ET AL., 2004)

PHASE III TRIAL 2: THAL ET AL., 2003

PHASE III TRIAL 3: MULNARD ET AL., 2000

Datamonitor conclusions

Leuprolide

Testosterone

Rasagiline

Avandia (rosiglitazone)

SGS-742

SL-65.0155

S-8510

COGNIShunt

Late-stage development compounds recently discontinued

NSAIDs (Vioxx, Naprelan) (PIII)

Lovastatin (ADX-159) (PII)

Comparison of key compounds in the other drugs class

Disease modification

Better efficacy than marketed drugs

Side-effect profile

Marketing strength

CHAPTER 9 INNOVATIVE EARLY-STAGE PROJECTS

Key Phase I and preclinical compounds in Alzheimer's disease

Chelators

Gene therapy

HCT 1026

Lithium

Ketone bodies

AMPAKINES

CX-717

S-18986

Vaccines

Neurochem

Elan and Wyeth: ACC-001

Mindset: Amyrex

Pharmexa and Lundbeck: PX-106

Cytos and Novartis: AD Immunodrug

Other vaccines

Comments

VACCINES CAN BE PRICED AT A PREMIUM LEVEL

BARRIERS TO THE USE/DEVELOPMENT OF VACCINES IN AD

LONG-TERM SAFETY ISSUE OF VACCINES

Key research impacts on Alzheimer's disease

Amyloid and blood vessels in the brain

APPENDIX A

Contributing experts

Bibliography

General information

Epidemiology

Clinical trial data

Websites

Report methodology

Introduction

Hypothesis formulation

Hypothesis testing

Ongoing information update

Product specific primary research

Data verification and quality control

Quantification of data reliability

Confidence ratings

Date of research completion

Introduction to Datamonitor Healthcare forecasting

Methodology

Market events

Validation

Pipeline-drug forecast methodology

Predicting initial market share

Clinical competitiveness attributes

Order of entry

Pre-launch awareness

Market composition

Marketing plan

Marketing strength

Forecasting future growth

Influencing factors

APPENDIX B

About Datamonitor

About Datamonitor Healthcare

Datamonitor Healthcare's therapy area capabilities

About the CNS analysis team

Key therapy team members

Disclaimer

List of Tables

Table 1: Key parameters of Alzheimer's disease

Table 2: Forecast key pipeline products in Alzheimer's disease, 2004-14

Table 3: AD comorbidity trials of existing drugs

Table 4: Prevalence of Alzheimer's disease across the seven major markets,2003

Table 5: AD prevalence rates by age group

Table 6: Diagnosis rates across the seven major markets, 2004

Table 7: Drug-treated populations across the seven major markets, 2004

Table 8: Measures used for clinical efficacy endpoints in AD

Table 9: Phase III pipeline in AD, 2004

Table 10: Phase II pipeline in AD, 2004

Table 11: Phase I pipeline in AD, 2004

Table 12: Preclinical pipeline in AD, 2004

Table 13: Preclinical pipeline in AD, 2004 [continued]

Table 14: Preclinical pipeline in AD, 2004 [continued]

Table 15: Eli Lilly's AD pipeline, 2004

Table 16: Pfizer's AD pipeline, 2004

Table 17: Sanofi-Synthelabo's AD pipeline, 2004

Table 18: Axonyx's AD pipeline, 2004

Table 19: Mindset's AD pipeline, 2004

Table 20: Nymox's AD pipeline, 2004

Table 21: Prana's AD pipeline, 2004

Table 22: Key products in late-stage R&D pipeline for ACh modulators,2004

Table 23: Clinical trial summary: Phenserine

Table 24: Global sales forecasts for phenserine

Table 25: Impacting factors on the revenues of phenserine, 2004-14

Table 26: Key products in late-stage R&D pipeline for Aβmodulators, 2004

Table 27: Global sales forecasts for Alzhemed

Table 28: Impacting factors on the revenues of Alzhemed, 2004-14

Table 29: Global sales forecasts for PBT-1

Table 30: Impacting factors on the revenues of PBT-1, 2004-2014

Table 31: Global sales forecasts for Aβ modulator drugs,2004-12

Table 32: Key products in late-stage R&D pipeline for neuroprotectiveand neurotrophic drugs, 2004

Table 33: Key products in late-stage R&D pipeline for other drugsgroup, 2004

Table 34: Global sales forecasts for Colostrinin

Table 35: Impacting factors on the revenues of Colostrinin, 2004-14

Table 36: Drugs in Phase I and preclinical development for AD, 2004

Table 37: Confidence ratings for R&D pipeline data

List of Figures

Figure 1: Alzheimer's disease impacts to 2014

Figure 2: Importance of unmet needs

Figure 3: Drug class by development stage.

Figure 4: Phenserine's satisfaction of unmet needs

Figure 5: Comparative strengths of key ACh modulators

Figure 6: Alzhemed's satisfaction of unmet needs

Figure 7: PBT-1's satisfaction of unmet needs

Figure 8: Comparative strengths of key Aβ modulators

Figure 9: Colostrinin's satisfaction of unmet needs

Figure 10: Comparison of key "other" drugs

Figure 11: ACC-001's mechanism of action

Figure 12: Market events affecting baseline product forecasts

Figure 13: Algorithm depicting key consitiuent variables upon which drugrevenues depend

Figure 14: Overview of Datamonitor Healthcare's forecasting approach forpipeline drugs