Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential of prodromal Alzheimer's disease and beyond

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Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential
of prodromal Alzheimer's disease and beyond
Published on April 2009

Report Summary

Introduction

MCI is a borderline condition between normal aging and dementia affecting around 23.4 million subjects across the seven major
markets (US, Japan, France, Germany, Italy, Spain and the UK) in 2007, 37% of whom were suffering from prodromal Alzheimer's
disease. MCI-specific annual sales are expected to increase seven-fold from 2007 to $3.3 billion across the seven major markets by
2018.

Scope

*Definition and prevalence of MCI and its major sub-types.

*Review of the key unmet needs in the treatment of the MCI subtypes as identified by key opinion leaders.

*MCI-specific drug sales value and number of treated patients forecasts to 2018 in the US, Japan, and five major European markets.

*Pipeline analysis with detailed profiles for key late-stage drugs potentially appropriate for MCI patients.

Highlights

Driven by off-label sales of several products currently in development for Alzheimer's disease, MCI-specific annual sales are expected
to increase seven-fold from 2007 to $3.3 billion across the seven major markets by 2018.

Although Datamonitor anticipates growth in the number of treated MCI patients (2.3% in 2007 rising to 4.27% in 2018), the treatment
rate will remain hampered by the slow uptake of relatively expensive diagnostic tools and lack of marketing authorization for drugs
within the forecast period.

In the long-term, Datamonitor believes that MCI will become a viable indication expansion opportunity for companies marketing

Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential of prodromal Alzheimer's disease and beyond Page 1/12


dementia drugs. However, the current marketed drugs for Alzheimer's disease are not appropriate, and new drugs for dementia are
still a few years from the market.

Reasons to Purchase

*Better understand the concept of MCI and its limits in the identification of the syndromes sub-types and the approval of treatments.

*Quantify the MCI-specific market to 2018 in the US, Japan, and five major European markets and identify the drivers and resistors in
this market.

*Understand unmet needs and opportunities in the definition, diagnosis and management of MCI based on key opinion leader
comments.

Table of Content

ABOUT HEALTHCARE 2
About the Central Nervous System pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the mild cognitive impairment market 5
Key metrics 7
Datamonitor Pipeline Assessment Summary 9
Contributing experts 10
Related reports 10
Upcoming reports 10
CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 12
Pipeline overview 14
Lack of pipeline drugs targeting mild cognitive impairment 14
Mild cognitive impairment pipeline dominated by potentially disease-slowing therapies 15
Key companies involved in the mild cognitive impairment pipeline 18
Allon Therapeutics 18
The only company targeting amnestic mild cognitive impairment as a primary indication 18
AL-108 showed mixed Phase II results in amnestic MCI patients 19
The heterogeneity of the amnestic mild cognitive impairment population may induce misleading Phase II results 19
Trials in mild cognitive impairment patients should not be conducted before the development of diagnostic tools specific to each
disease subtype 20
Pfizer/Medivation/Wyeth 20
Presence in the current market with Aricept 20
License agreements and mergers develop potential MCI portfolio 20
Key R&D company strategies 21
Mild cognitive impairment - a future indication expansion opportunity 21
Working on the development of better diagnostic tools 22
Wyeth has already partnered with diagnostic company Adlyfe to develop better tools 22
TauRx Therapeutics is developing its own biomarkers 22
CHAPTER 3 PATIENT POTENTIAL 23
Definition of mild cognitive impairment 24
Mild cognitive impairment - a borderline condition between normal aging and dementia 24



Evolution of mild cognitive impairment definition 24
Mild cognitive impairment diagnostic criteria 24
Clinical segmentation of mild cognitive impairment 26
Working areas and their significance for pharmaceutical companies 27
The broad definition of mild cognitive impairment is problematic for the development and approval of new drugs 27
Mild cognitive impairment - an early status of several dementia 29
Ongoing discussion on the inclusion of mild cognitive impairment in DSM-V 30
Uncertainty for the inclusion of psychiatric and somatic cognitive impairments in mild cognitive impairment 30
Cognitive disorders - mild cognitive impairment and beyond 31
Other definitions of cognitive impairments - both broader and narrower than mild cognitive impairment 31
Cognitive impairments in international diseases classifications 31
Epidemiology of mild cognitive impairment 32
Prevalence of mild cognitive impairment 32
Mild cognitive impairment affects up to 20% of the seven major markets' population aged 65 years and over 32
Mild cognitive impairment prevalence increases with age 35
Prevalence and progression of mild cognitive impairment subtypes 35
Mild cognitive impairment patients are at increased risk for dementia 35
Alzheimer's disease is the most frequent outcome of mild cognitive impairment 36
Link between amnestic mild cognitive impairment and early dementias 36
Imprecise relationship between symptoms and outcomes 37
Relationship between amnestic-mild cognitive impairment and prodromal Alzheimer's 38
Different types of dementia 40
Treatable population 41
Number of treated MCI patients estimated at around 548,300 in 2007 41
Presentation and diagnostic combined rate lower than 10% in MCI 42
Mild cognitive impairment treatable population in 2007 43
Segmentation of the mild cognitive impairment population in 2007 44
Etiology of mild cognitive impairment 46
Etiology of mild cognitive impairment can be linked to underlying neurodegenerative disorder 46
Causes of mild cognitive impairment - Alzheimer's disease etiology 46
Causes of mild cognitive impairment - frontotemporal dementia etiology 48
Diagnosis of mild cognitive impairment 49
Lack of consensus in diagnostic tools 49
Heterogeneity of mild cognitive impairment measures and rating scales 49
Variability on normal reference standards across studies 49
Accurate diagnosis may demand a combination of exams 51
Diagnostic tools 51
Neuroimaging tests - a beneficial tool for mild cognitive impairment future diagnosis 52
Proposed criteria for effective biomarkers in mild cognitive impairment 55
Example of other biomarkers potentially suitable to MCI 56
Urine and serum biomarkers 56
Neurological tests and questionnaires 57
Unmet needs in mild cognitive impairment 61
Unmet need overview 61
Consensus on the definition and categorization of mild cognitive impairment 62
Improving the definition of each subtype of the mild cognitive impairment population in correlation with a specific outcome 62
Development of diagnostic tools 63
Need to develop diagnostic tools able to identify specific subtypes of patients 63
Consensus on diagnosis criteria 64
Specific and sensitive biomarkers could help to diagnose mild cognitive impairment patients likely to progress to Alzheimer's disease



or other dementia 65
Need for more sensitive neurological tests 65
Development of therapeutic solution 66
Delay of progression to dementia with the approval of disease-slowing drugs 66
Approval of effective symptomatic drugs will slightly improve MCI patients' quality of life 67
CHAPTER 4 MARKET OVERVIEW AND POTENTIAL 68
Current market size 70
Market value methodology 70
Mild cognitive impairment-specific sales estimate methodology 70
ATC class choice 70
Medical data for indication-specific sales 71
Age range choice 71
Mild cognitive impairment-specific sales calculations 74
MCI market value estimates 74
MCI-specific market value estimated at $440m in 2007 74
Mild cognitive impairment sales revenue led by anti-Alzheimer's products 75
Disparities in mild cognitive impairment market across regions 76
Forecast methodology 77
Overview of Datamonitor's forecast methodology 77
Evolution in patient numbers over the forecast period 79
Mild cognitive impairment presentation and diagnosis combined rate forecast to increase from around 8% in 2007 to 20.1% in 2018
80
Market forecast overview 83
Total market forecasts 83
MCI-specific sales revenue expected to increase by seven-fold to 2018 84
Key late-stage pipeline drug forecasts 85
CHAPTER 5 R&D APPROACH 88
Classification of pipeline products 89
Lack of pipeline drugs targeting MCI as a primary indication 89
Patient potential 89
Patient potential of pipeline drugs depends on their mechanism of action 89
Symptomatic treatments 90
Symptomatic drugs possess a large patient potential 90
Disease-modifying treatments 91
Disease-slowing treatments will satisfy the most important unmet need of mild cognitive impairment 91
Clinical trial design in mild cognitive impairment 91
CHAPTER 6 POTENTIAL DISEASE SLOWING THERAPIES 92
Overview for potentially disease-slowing therapies 93
Definition of current comparator therapy - Aricept 94
Aricept - a symptomatic drug prescribed off-label for the treatment of mild cognitive impairment 94
Aricept's strengths and weaknesses 95
Historical sales for Aricept and other anti-Alzheimer's diseases drugs in mild cognitive impairment 95
Factors required to compete with Aricept 96
Bapineuzumab 97
Drug overview 97
Forecasts to 2018 97
US - forecast methodology 98
5EU - forecast methodology 99
Japan - forecast methodology 100
Datamonitor drug assessment summary 100



Marketing factors 101
Price of bapineuzumab and influencing factors 101
Competitive environment 102
Bapineuzumab market penetration 103
Potential limited to ApoE4 non-carriers with prodromal Alzheimer's disease' 104
Intravenous administration and MRI monitoring 104
Satisfaction of unmet needs 105
Clinical trial data 105
Positive post-hoc analysis results in ApoE-negative patients with mild-to-moderate Alzheimer's disease patients 105
Phase II clinical trial data 105
Ongoing clinical trials 107
LY450139 - semagacestat 108
Drug overview 108
Price for LY450139 and influencing factors 112
LY450139 market penetration 113
Competitive environment 113
LY450139's potential limited to MCI patients with prodromal Alzheimer's disease symptoms 114
Ongoing and completed clinical trials 114
Phase II results: reduction of beta-amyloid fragment (1-40) concentration in plasma but no change in cognition 116
Gammagard 117
Drug overview 117
Gammagard's large production may represent a challenge 118
Price for Gammagard and influencing factors 121
Gammagard market penetration 121
Gammagard's potential possibly limited to prodromal Alzheimer's disease MCI patients 122
Phase II clinical trial 122
Ongoing Phase III clinical trial 124
Rember 125
Drug overview 125



Price for Rember and influencing factors 128
Rember market penetration 129
Rember potential possibly limited to MCI patients with prodromal Alzheimer's disease symptoms 130
A Phase IIb trial of a tau aggregation inhibitor therapy 130
PBT2 133
Drug overview 133
Historical research program 133
Price for PBT2 and influencing factors 137
PBT2 market penetration 137
PBT2's potential limited to prodromal Alzheimer's disease MCI patients 138
Higher dose of PBT2 proved to be safe and effective in early Alzheimer's disease patients 138
PBT2 - preclinical results 140
AL-108 140
Drug overview 140
AL-108 - potential disease-slowing treatment for cognitive disorders 140
AL-208 - the injectable formulation of NAP 141
Partnership needed for further development in Alzheimer's disease 141
Projects for 2009 142
AL-108 demonstrated mixed results in amnestic MCI patients 142
LY2062430 145
Drug overview 145
Phase II clinical trial 145
PF-04494700 (TTP488) 147
Drug overview 147
Phase IIa clinical results 148
Ongoing clinical trial program 149
Rosiglitazone XR 149
Drug overview 149
Amyloid vaccines 150
ACC-001 151
Drug overview 151
Ongoing clinical trial 151
CAD106 152
Drug overview 152
Clinical trial 152



CHAPTER 7 SYMPTOMATIC TREATMENTS 154
Overview for symptomatic drugs 155
Definition of current comparator therapy - Aricept 156
Dimebon 156
Drug overview 156
A promising therapy co-developed by Medivation and Pfizer 156
Dimebon's mechanism of action 157
Modes of action may be confusing for prescribers 161
Price for Dimebon and influencing factors 161
Dimebon market penetration: potentially beneficial for the entire MCI population 161
Pfizer - a highly valuable partner in Alzheimer's disease and associated markets 162
Impressive Phase II results in patient with mild-to-moderate Alzheimer's disease 164
Ongoing clinical trials 165
Aricept (donepezil) SR 167
Drug overview 167
Price for Aricept (donepezil) SR 170
Aricept SR market penetration expected to decline over the forecast period 171
SB-742457 171
Drug overview 171
Datamonitor comments 172
BIBLIOGRAPHY 173
Journals 173
Websites 181
Annual reports 186
Datamonitor reports 187
APPENDIX 188
Methodology 188
Datamonitor forecast methodology 188
Patent's expiry dates of key branded treatments 188
Current market estimate 189
Treatments for MCI 189
Definition of a standard unit (only use if ForeSight model used to forecast) 189
Epidemiology forecasts 189
Pipeline product forecasts 190



Contributing experts 192
About Datamonitor 193
About Datamonitor Healthcare 193
Datamonitor Healthcare's therapy area capabilities 194
About the Disease analysis team 195
Disclaimer 196
List of Tables
Table 1: Key parameters of mild cognitive impairment (MCI) across the seven major markets, 2007-2017 7
Table 2: Key pipeline product sales in mild cognitive impairment (MCI) across the seven major markets to 2018 8
Table 3: Key potential disease-slowing treatments in development for Alzheimer's disease and potentially appropriate for mild
cognitive impairment, 2009 16
Table 4: Key symptomatic treatments in development for Alzheimer's disease and potentially appropriate for mild cognitive
impairment, 2009 17
Table 5: Number of key late-stage pipeline drugs potentially suitable for mild cognitive impairment per class and phase of
development, 2009 18
Table 6: Allon Therapeutics's drug pipeline, 2009 19
Table 7: Prevalence of mild cognitive impairment (MCI) in the seven major markets, 2007 33
Table 8: Epidemiological studies on mild cognitive impairment, 2001-08 33
Table 9: Description of different types of dementias mild cognitive impairment patients can go on to develop 40
Table 10: Mild cognitive impairment-specific sales value ($) and volume (IMS standard units, SU) and number of patients treated
across the seven major markets, 2007 42
Table 11: Examples of cerebrospinal fluid tracers for beta-amyloid plaques and acetylcholinesterase 56
Table 12: Example of alternative tests to cerebrospinal fluid biomarkers in neurological conditions 57
Figure 9: Unmet needs in mild cognitive impairment (MCI), 2009 62
Table 13: ICD-10 codes excluded from mild cognitive impairment (MCI) sales estimate 71
Table 14: Evolution of MCI patients flow across the seven major markets, 2007-2018 80
Table 15: Sales forecasts for the key late-stage pipeline drugs across the seven major markets ($m), 2011-18 86
Table 16: Key potential disease-slowing treatments in development for Alzheimer's disease and potentially appropriate for mild
cognitive impairment (MCI), 2009 93
Table 17: Pfizer/Eisai's Aricept: key facts, 2009 94
Table 18: Bapineuzumab - forecast methodology in mild cognitive impairment in the US, 2012-18 99
Table 19: Bapineuzumab - forecast methodology in mild cognitive impairment in the 5EU, 2012-18 99
Table 20: Bapineuzumab - forecast assumptions in mild cognitive impairment in Japan, 2013-18 100
Table 21: LY450139 - forecast methodology in mild cognitive impairment in the US, 2013-18 110
Table 22: LY450139 - forecast methodology in mild cognitive impairment in the 5EU, 2013-18 110
Table 23: LY450139 - forecast methodology in mild cognitive impairment in Japan, 2014-18 111
Table 24: Clinical trial summary for LY450139 in Alzheimer's disease, 2009 115
Table 25: Gammagard - forecast methodology in mild cognitive impairment in the US, 2013-18 119
Table 26: Rember - forecast methodology in mild cognitive impairment in the US, 2014-18 126
Table 27: Rember - forecast methodology in mild cognitive impairment in the 5EU, 2014-18 127
Table 28: PBT2 - forecast methodology in mild cognitive impairment in the US, 2014-18 135
Table 29: PBT2 - forecast methodology in mild cognitive impairment in the 5EU, 2014-18 135
Table 30: Clinical trial results for high dose of AL-108 (15mg twice a day) in mild cognitive impairment (MCI) subjects 143
Table 31: Key symptomatic treatments in development for Alzheimer's disease and potentially appropriate for mild cognitive
impairment (MCI), 2009 155
Table 32: Dimebon - forecast methodology in mild cognitive impairment in the US, 2012-18 158
Table 33: Dimebon - forecast methodology in mild cognitive impairment in the 5EU, 2012-18 159
Table 34: Dimebon - forecast methodology in mild cognitive impairment in Japan, 2015-18 160
Table 35: Clinical trial summary for Dimebon in Alzheimer's disease, 2009 166
Table 36: Aricept (donepezil) SR - forecast methodology in mild cognitive impairment in the US, 2011-18 168



Table 37: Aricept (donepezil) SR - forecast methodology in mild cognitive impairment in the 5EU, 2011-18 169
Table 38: Patent's expiry dates of key branded anti-Alzheimer's disease drugs across the US, the 5EU and Japan 188
Table 39: Datamonitor drug assessment parameters 191
List of Figures
Figure 1: Datamonitor's drug assessment summary of key late-stage therapies in development for Alzheimer's disease and potentially
effective in mild cognitive impairment, 2007-2018. 9
Figure 2: Number of symptomatic and potential disease-slowing late-stage pipeline drugs potentially appropriate for mild cognitive
impairment, 2009 15
Figure 3: Diagnosis algorithm and mild cognitive impairment (MCI) segmentation according to clinical characterization of the
symptoms 27
Figure 4: Mild cognitive impairment prevalence by age in Unverzagt et al.'s study, 2001 35
Figure 5: Prevalence of each subtype within the mild cognitive impairment (MCI) population 37
Figure 6: Potential relation between symptom classification and outcomes in mild cognitive impairment patients 38
Figure 7: Prevalent, diagnosed and treated population with mild cognitive impairment aged 65 and over across the seven major
markets, 2007 43
Figure 8: Segmentation of the mild cognitive impairment population and the treatable population across the seven major markets 45
Figure 10: Datamonitor's mild cognitive impairment (MCI) sales methodology, 2009 70
Figure 11: US IMS diagnostic value sales ($m) for ATC classes N6D and N7D limited to non-dementia indications per age group,
2007 72
Figure 12: US IMS diagnostic value sales ($) for ATC classes N6D and N7D limited to non-dementia indications per 1,000 persons,
2007 73
Figure 13: Mild cognitive impairment (MCI)-specific sales value ($m) by class across the seven major markets, 2005-08 75
Figure 14: Mild cognitive impairment (MCI)-specific sales volume (IMS standard units) by class across the seven major markets,
2005-08 76
Figure 15: Mild cognitive impairment (MCI)-specific sales revenue ($m) in the US, 5EU and Japan, 2007 77
Figure 16: Datamonitor's methodology for estimating the treatable MCI population across the seven major markets. 79
Figure 17: Evolution of the mild cognitive impairment presentation and diagnosis combined rate across the seven major markets,
2005-2018 82
Figure 18: Number of mild cognitive impairment (MCI) patients treated by drug type across the seven major markets ($m), 2005-2018
83
Figure 19: Mild cognitive impairment (MCI)-specific sales revenue distribution by drug type across the seven major markets ($m),
2005-2018 84
Figure 20: Sales forecasts for key mild cognitive impairment-specific late-stage pipeline drugs across the major markets, 2010-2018
85
Figure 21: Datamonitor's drug assessment summary of key late-stage therapies in development for Alzheimer's disease and
potentially effective in mild cognitive impairment, 2007-2018 87
Figure 22: Mild cognitive impairment patient potential according to the type of treatment 90
Figure 23: Aricept (donepezil) - strengths and weaknesses, 2009 95
Figure 24: Historical sales for the current anti-Alzheimer's disease products in the mild cognitive impairment market across the seven
major markets, 2005-08 96
Figure 25: Off-label sales forecast for bapineuzumab in mild cognitive impairment (MCI) to 2018 across the seven major markets 98
Figure 26: Datamonitor's competitive positioning analysis of bapineuzumab in mild cognitive impairment across the seven major
markets, 2007-2018 101
Figure 27: Off-label sales forecast for LY450139 in mild cognitive impairment to 2018 across the seven major markets 109
Figure 28: Datamonitor's competitive positioning analysis of LY450139 in mild cognitive impairment (MCI) across the seven major
markets, 2007-2018 112
Figure 29: Off-label sales forecast for Gammagard in mild cognitive impairment (MCI) to 2018 in the US 119
Figure 30: Datamonitor's competitive positioning analysis of Gammagard in mild cognitive impairment (MCI) across the seven major
markets, 2007-2018 120
Figure 31: Off-label sales forecast for Rember in mild cognitive impairment (MCI) to 2018 in the US and 5EU 126



Figure 32: Datamonitor's competitive positioning analysis of Rember in mild cognitive impairment (MCI) across the seven major
markets, 2007-2018 128
Figure 33: Off-label sales forecast for PBT2 in mild cognitive impairment (MCI) to 2018 in the US and 5EU 134
Figure 34: Datamonitor's competitive positioning analysis of PBT2 in mild cognitive impairment (MCI) across the seven major markets,
2007-2018 136
Figure 35: Off-label sales forecast for Dimebon in mild cognitive impairment to across the seven major markets, 2012-2018 158
Figure 36: Datamonitor's competitive positioning analysis of Dimebon in mild cognitive impairment across the seven major markets,
2007-2018 160
Figure 37: Off-label sales forecast for Aricept (donepezil) SR in mild cognitive impairment (MCI) to 2018 in the US and 5EU 168
Figure 38: Datamonitor's competitive positioning analysis of Aricept (donepezil) SR in mild cognitive impairment (MCI) across the
seven major markets, 2007-2018 170
Figure 39: Datamonitor's drug assessment summary of key late-stage therapies in development for Alzheimer's disease and
potentially effective in mild cognitive impairment, 2007-2018 192



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Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential of prodromal Alzheimer's disease and beyond