Alzheimer s Disease Alzheimer s Disease. Markets, Pipeline and Opportunities. April By John Bates Ph.D. 1 Copyright 2009 Biopharm Reports

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1 Alzheimer s Disease Markets, Pipeline and Opportunities April 2009 By John Bates Ph.D 1

2 About the Author John Bates is a consultant and author in the drug markets and R&D fields. After a first degree in biochemistry and chemistry (1978) and a Ph.D in cancer research in 1981, John joined Upjohn Ltd, managing a team of research scientists in the department of biopharmaceutical sciences and drug metabolism. In 1985 he took a similar role with Glaxo Group Research, in the department of Biochemical Pharmacology. In 1989 he co-founded the contract pharmaceutical research company Melbourn Scientific Ltd, establishing the company's technical and commercial activities. In 2000 John joined ANGLE Technology Ltd, providing due diligence on new pharmaceutical technologies, later moving to Acumen Bioscience (drug discovery instrumentation) as Technical Director. John has held board-level advisory roles with a number of drug discovery companies and provided consultancy services to life science investors. Copyright 2009 BioPharm Reports (Technology and Markets Ltd). This report is published by BioPharm Reports (Technology and Markets Ltd). All Rights Reserved. The reproduction or redistribution of this report is prohibited, without the prior permission of BioPharm Reports (Technology and Markets Ltd). The information contained in this report and the opinions, views and conclusions contained herein, are the views of the publisher. While the information contained in this report is believed to be accurate at the time of publication, BioPharm Reports and Technology and Markets Ltd accept no liability for the information contained herein, nor for its completeness in any respect. Technology and Markets Ltd accepts no liability for any decisions or actions which are taken, based on the content, views or conclusions contained in this report. 2

3 Contents 1. Alzheimer s Disease Alzheimer s Disease 1.2 Statistics and Costs 1.3 Histopathology 1.4 Amyloid Beta (Aβ) 1.5 Tau Proteins and Neurofibrillary Tangles 1.6 Cholinergic Hypothesis 1.7 Diagnosis 1.8 Cognitive Tests 1.9 Treatment 2. Alzheimer s Disease Statistics Background 2.2 Dementia - Global Population 2.3 Global Incidence 2.4 Global New Cases 2.5 Global Prevalence 2.6 Estimated Global Prevalence in Developed and Developing Countries 2.8 Global Trends 2.9 Dementia and AD 2.10 John Hopkins University Study 2.11 Disease Costs 3. The Global Drug Market The Global Drug Market 4. Donepezil Hydrochloride (Aricept ) Donepezil hydrochloride (Aricept ) 4.2 Global Sales 4.3 Global Sales - Eisai 4.4 Japan Sales - Eisai 4.5 US Sales - Eisai 4.6 Regional Sales Eisai 4.7 Global Sales - Pfizer 5. Memantine Axura Namenda Ebixa Memantine 6. Rivastigmine Tartrate (Exelon ) Rivastigmine Tartrate 3

4 7. Piracetam Nootropil Piracetam 8. Galantamine (Razadyne ) Galantamine Hydrobromide 9. Global and Regional Sales Overview 10. Other Marketed Therapeutic Agents Background 10.2 Colostrinin 10.3 Cerebrolysin 10.4 Nicergoline 11. Drug Repurposing in Alzheimer s Disease Background 12. Drug Pipeline - Phases I-III Background 12.2 Phase III 12.3 Phase II 12.4 Phase I 13. Discussion Overview 13.2 Markets 13.3 Drug Pipeline 13.4 Conclusions References 105 4

5 Figures Figure 1.1 Diagram indicating the two cleavage positions of APP (by β- and γ-secretases), generating Aβ Figure 2.1 The global population (millions) of individuals 60. Figure 2.2 The global incidence of dementia (Number of Individuals/1000) in Figure 2.3 Global new cases of dementia (Number of Individuals/1000) in Figure 2.4 The global prevalence of dementia in 2001 Figure 2.5 The estimated prevalence of dementia in 2020 Figure 2.6 The estimated prevalence of dementia in 2040 Figure 2.7 The prevalence of dementia in developed and developing countries in 2001 and estimates of prevalence in 2020 and Figure 2.8 Estimate of changes (% change) in the prevalence of dementia between 2001 and Figure 2.9 Estimate of changes (% change) in the prevalence of dementia between 2001 and Figure 3.1. The global sales (US$, millions) of AD drugs from These figures reflect the sales of the five major anti-ad drugs namely donepezil (Aricept, Eisai), memantine (Axura /Namenda /Ebixa,Merz), rivastigmine (Exelon, Novartis), galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales in 2008 of the drugs donepezil and memantine were estimated, based on a 10% increase in their respective 2007 sales figures. Figure 3.2. The annual change (%) in the global sales of anti-alzheimer s disease drugs from These figures reflect the sales of the five major anti-alzheimer s disease drugs namely donepezil (Aricept, Eisai), memantine (Axura /Namenda /Ebixa,Merz), rivastigmine (Exelon, Novartis), galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales in 2008 of the drugs donepezil and memantine were estimated, based on a 10% increase in their global 2007 sales figures. Figure 3.3 The global sales histogram (US$, Millions) for 2008 of the anti- Alzheimer s disease donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales for 5

6 2008 for the drugs donepezil and memantine were estimated, based on a 10% increase in Eisai and Merz global 2007 sales figures. Figure 3.4 The global sales pie chart (US$, Millions) for 2008 of the anti- Alzheimer s disease drugs donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales for 2008 for the drugs donepezil and memantine were estimated, based on a 10% increase in Eisai and Merz global 2007 sales figures. Figure 3.5 The global sales histogram (US$, Millions) for 2007 of the anti- Alzheimer s disease drugs donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Figure 3.6 The global sales pie chart (US$, Millions) for 2007 of the anti- Alzheimer s disease drugs donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Figure 4.1 Global sales (US$, millions) of Aricept (donepezil hydrochloride) by Eisai and Pfizer (under licence to Eisai) from 1999 to Eisai s own sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase of the company s global 2007 Aricept sales figures. Figure 4.2 The annual growth (as % change) in the global sales of Aricept (donepezil hydrochloride) by Eisai and Pfizer (under licence to Eisai) from 1999 to Eisai s own sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase of the company s global 2007 Aricept sales figures. Figure 4.3 Global sales (US$, millions) of Aricept (donepezil hydrochloride) by Eisai from 1999 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in their global 2007 Aricept sales figures. Figure 4.4 The annual change (as % change) in the global sales of Aricept (donepezil hydrochloride) by Eisai from 1999 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in their global 2007 Aricept sales figures. Figure 4.5 Sales (US$, millions) of Aricept (donepezil hydrochloride) in Japan by Eisai from 1999 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase Eisai s/pfizer s global 2007 Aricept sales figures. 6

7 Figure 4.6 The annual change (as % change) in the sales of Aricept (donepezil hydrochloride) in Japan by Eisai from 1999 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase Eisai s/pfizer s global 2007 Aricept sales figures. Figure 4.7 US Sales (US$, millions) of Aricept (donepezil hydrochloride) by Eisai from 1999 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in their 2007 Aricept sales figures. Figure 4.8 The annual change (as % change) in the sales of Aricept (donepezil hydrochloride) in the US by Eisai from 2003 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in their 2007 Aricept sales figures. Figure 4.9 Global and regional sales (US$, millions) of Aricept (donepezil hydrochloride) by Eisai from 2002 to Sales for 2008 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in their 2007 Aricept sales figures. Figure relative direct sales (US$, millions) of Aricept by Eisai in the US, Japan, Europe and Asia (excluding Japan). Figure 4.11 The annual global change in the sales of Aricept (donepezil hydrochloride) by Pfizer from 2003 to Source: Biopharm Reports. Figure 4.12 The annual change (as % change) in the sales of Aricept (donepezil hydrochloride) in the Pfizer from 2004 to Figure 5.1 Global sales (US$, millions) of Axura Namenda Ebixa (memantine) by Merz and licensees from 2003/4 to 2007/8. Sales for 2008/9 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase Merz and its licensees 2007 sales figures. Figure 5.2 The annual change (as % change) in the global sales of Axura Namenda Ebixa (memantine) by Merz and its licensees from 2004/5 to 2008/9. Sales for 2008/9 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in Merz 2007 sales figures. Figure 5.3 Annual US sales (US$, millions) of Axura Namenda Ebixa (memantine) by Merz and licensees from 2003/4 to 2007/8. Sales for 2008/9 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase Merz and its licensees 2007 sales figures. 7

8 Figure 5.4 The annual change (as % change) in the US sales of Axura Namenda Ebixa (memantine) by Merz and its licensees from 2004/5 to 2008/9. Sales for 2008/9 for the drugs were not available at the time of publication of this reports and have been estimated based on a 10% increase in Merz 2007 sales figures. Figure 5.5 Regional sales (US$, millions) of Axura Namenda Ebixa (memantine) by Merz and licensees from 2003/4 to 2006/7. Figure 6.1 Global sales (US$, millions) of Exelon (rivastigmine tartrate) by Novartis from 2000 to Figure 6.2 The annual change in the global sales of Exelon by Novartis from 2001 to Figure 6.3 US sales (US$, millions) of Exelon Novartis from 2001 to (rivastigmine tartrate) by Figure 6.4 The annual change in the US sales of Exelon 2002 to by Novartis from Figure 7.1. The global sales (US$, millions) of Nootropil (piracetam) by UCB from 2000 to 2008 Figure 7.2 The annual change (as % change) in the global sales of Nootropil by BMS from 2001 to Figure 7.3. The sales (US$, millions) of Nootropil (piracetam) by UCB from 2005 to 2008 (Europe and Worldwide) Figure 9.1 US sales of donepezil, memantine, Rivastigmine and galantamine in Figure 9.2 US sales of donepezil, memantine, rivastigmine and galantamine in Figure 9.3 US sales of AD drugs from Sales of Eisai s Aricept in 2008 have been estimated based on a 10% increase on the company s sales figures of Figure 9.4 US sales of AD drugs from , as % Change. Sales of Eisai s Aricept in 2008 have been estimated based on a 10% increase on the company s sales figures of Figure Alzheimer s disease drug candidates in the development pipeline, Phase I - III 8

9 Figure 12.2 Phase III Alzheimer s disease drug categories. SA: Single Agent (a Figure 12.3 Phase III Alzheimer s disease drug categories. SA: Single Agent (a Figure 12.4 Phase II Alzheimer s disease drug categories. SA: Single Agent (a Figure 12.5 Phase II Alzheimer s disease drug categories. SA: Single Agent (a Figure 12.6 Phase I Alzheimer s disease drug categories. SA: Single Agent (a Figure 12.7 Phase I Alzheimer s disease drug categories. SA: Single Agent (a Figure The global sales of AD drugs from These figures reflect the sales of the five major anti-alzheimer s disease drugs namely donepezil (Aricept, Eisai), memantine (Axura /Namenda /Ebixa,Merz), rivastigmine (Exelon, Novartis), galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales in 2008 of the drugs donepezil and memantine were estimated, based on a 10% increase in Eisai s and Merz global 2007 sales figures. 9

10 Figure The annual change in the global sales of anti-alzheimer s disease drugs from These figures reflect the sales of the five major anti-alzheimer s disease drugs namely donepezil (Aricept, Eisai), memantine (Axura /Namenda /Ebixa,Merz), rivastigmine (Exelon, Novartis), galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Sales in 2008 of the drugs donepezil and memantine were estimated, based on a 10% increase in Eisai s and Merz global 2007 sales figures. Figure 13.3 The global sales histogram (US$, Millions) for 2008 of the anti- Alzheimer s disease donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB). Figure Alzheimer s disease drug candidates in the development pipeline, Phase I - 3 Tables Table 3.1 The global sales (US$, millions) of the anti-alzheimer s drugs donepezil (Aricept, Eisai), memantine galantamine (Razadyne, J&J) and piracetam (Nootropil,UCB) and colostrinin (colostrinin, Regen Therapeutics). * Sales for 2008 for the drugs donepezil and memantine were estimated, based on a 10% increase in Eisai and Merz global 2007 sales figures. Table 9.1 Global and regional sales of the AD drugs donepezil, memantine, rivastigmine, Piracetam, galantamine and colostrinin. *= Sales by Eisai **= sales by Pfizer Table 11.1 Number of drug drugs studies relating to potential repurposing and others which may treat some of symptoms of AD Table 11.2a Phase III studies relating to potential repurposing and others linked to the treatment of some of the symptoms of AD Table 12.2 Phase II Alzheimer s disease drug categories. SA: Single Agent (a Table 12.3 Phase I Alzheimer s disease drug categories. SA: Single Agent (a 10

11 Table 13.1 Phase III Alzheimer s disease drug categories. SA: Single Agent (a 11