alzheimer’s disease therapeutics market to 2019 · alzheimer’s disease therapeutics market to...

Alzheimer’s Disease Therapeutics Market to 2019 Early Stage Innovation Points to Disease Modifying Therapies and Market Transformation

GBI Research Report Guidance

© GBI Research. This is a licensed product and is not to be photocopied GBIHC310MR / Published OCT 2013

GBI Research Report Guidance

Chapter two provides an introduction to Alzheimer’s Disease, detailing the etiology, epidemiology, diagnostic techniques, disease staging of the disease and typical prognoses for patients. An analysis of current treatment algorithms and options is also included.

Chapter three profiles the marketed products approved for mild, moderate and severe AD and discusses their efficacy and safety profiles

Chapter four provides detailed analysis of the pipeline for Alzheimer’s Disease by stage of development, molecule type, program type, mechanism of action and molecular target. It also analyses recent clinical trials in this indication by enrollment, duration and failure rate. Finally, promising late-stage pipeline molecules are analyzed and assessed in terms of their potential competitive strength.

Chapter five supplies forecasting data on the epidemiology, pricing and market size for the 2012–2019 period across seven major developed markets (US, Germany, UK, France, Italy, Spain and Japan) with further analysis of key market drivers and barriers.

Chapter six describes the major deals that have taken place in the global AD market in recent years. This coverage analyzes licensing and co-development agreements, segmented by stage of development, year, molecule type, mechanism of action and value. Network graphs for these deals by location of company headquarters are also included.

An appendix is included in chapter seven and provides tables of all pipeline products and the market forecasting data in a tabular format. The references, abbreviations and methodology are also provided.


Executive Summary

Executive Summary

Moderate Innovation in the Early Pipeline

Despite a number of recent high-profile failures, there is still a great deal of interest surrounding Alzheimer’s Disease (AD) as an indication, with XX drugs in the discovery and preclinical stages alone. There is also a certain degree of novelty associated with these drugs, with previously unexamined targets and mechanisms of action strongly affecting the early pipeline. An example of this would be immunomodulatory drugs. An increasing amount of evidence is beginning to emerge implicating inflammation in AD pathology. As a result of this, immunomodulatory drugs have begun to appear with greater frequency in the early to mid-pipeline stages and could well prove to be effective therapies in the future.

However, while there is a certain degree of innovation in the pipeline, a larger proportion of drugs are still targeting the mechanisms of action that have defined the AD pipeline for years. These factors all surround amyloid beta (Aβ) aggregation and clearance, which has proven to be a popular therapeutic target in the past. While there are notable high-profile failures associated with drugs targeting Aβ, the understanding surrounding the target is somewhat uncertain. It is currently known that AβXX is toxic, although the extent and localization toxicity of soluble monomeric and oligomeric isoforms remains a contentious point. A growing body of evidence suggests that Aβ oligomers could potentially be integrally involved in disease initiation for AD. Therefore, while certain forms of Aβ have proven ineffective as targets historically, research into the peptide as a target could still yield an effective therapy.

Additionally, a large number of drugs across the pipeline target neuromodulatory signaling pathways including acetylcholine and glutamate. Drugs targeting acetylcholinesterase and the N-Methyl D-Amino (NMDA) receptor are currently marketed and have been shown to have modest potential for the reduction of cognitive decline in early-stage AD. In spite of their established market presence, the wealth of neuromodulatory targets currently in the pipeline could yield a more effective neuromodulator drug. That said, the scope with which neuromodulators can be disease modifying relies heavily on when they are initiated, as in late stage AD they provide primarily symptomatic relief.

Therefore, in order for the AD therapeutic landscape to improve, a greater understanding of disease pathogenesis as well as a greater breadth of molecular targets must be achieved.

Limited Late-Stage Pipeline

In order for the AD therapeutic landscape to undergo a meaningful change in the forecast period until 2019, a drastic alteration in the drugs that are currently available is required. However, the later stages of the pipeline are somewhat limited, with a reasonable XX molecules in Phase II, but only XX in Phase III. This reflects an endemic problem in AD therapeutics, as the progression rate from Phase II to Phase III and then to filing for marketing approval after Phase III studies is among the lowest across the entire pharmaceutical industry.

The lack of strong potential disease-modifying therapies in the pipeline that could have a substantial impact upon the market is particularly troubling as the overall global prevalence of the disease is forecast to increase. Changes therefore need to be made regarding either drug mechanisms of action or the design of clinical trials themselves. Most trial durations are too short, with the result that the full scope of a drug’s potential in the long term is rarely established in the trial period. Additionally, many trials use symptomatic patients rather than pre-symptomatic patients, meaning that drugs with potential actions in early disease may have been overlooked. Changes are required if the later pipeline stages are to become more promising.

Alzheimer’s Disease Market to Register a Decline

As a result of the limited late-stage pipeline as well as the patent expiration of all currently available treatments, the market for AD is expected to register a moderate decline during the forecast period. Following the patent expiration of memantine in 2015, the market for AD will register a decline of almost $XX billion, falling from a global total of $XX billion to $XX billion in 2017, due to the generic erosion of sales revenue. Additionally, due to the narrow therapeutic window and purported lack of efficacy of currently available drugs, the treatment population of AD is likely to remain proportionally low in spite of an increasing prevalence population. However, following this initial decline, the anticipated approval of the Phase III therapy LMTX is expected to cause the market to increase again to $XX billion by 2019.


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Table of Contents

1 Table of Contents

1 Table of Contents ................................................................................................................................. 5 1.1 List of Tables ............................................................................................................................. 7 1.2 List of Figures............................................................................................................................ 8

2 Introduction......................................................................................................................................... 9 2.1 Symptoms ................................................................................................................................ 9 2.2 Etiology ...................................................................................................................................10 2.3 Pathophysiology ......................................................................................................................11

2.3.1 Amyloidosis......................................................................................................................11 2.3.2 Tau Hyperphosphorylation ...............................................................................................11

2.4 Comorbidities/Complications ...................................................................................................12 2.5 Diagnosis .................................................................................................................................12

2.5.1 Physical Examination........................................................................................................13 2.5.2 Mini Mental State Exam ...................................................................................................13 2.5.3 Alzheimer’s Disease Assessment Scale-cognitive ...............................................................15 2.5.4 Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory .....................16 2.5.5 Other Diagnostic Tests .....................................................................................................16 2.5.6 Blood Tests ......................................................................................................................16 2.5.7 Imaging Tests...................................................................................................................16 2.5.8 Lumbar Puncture..............................................................................................................16 2.5.9 Disease Biomarkers ..........................................................................................................17 2.5.10 Biomarker Market ............................................................................................................18

2.6 Prognosis .................................................................................................................................19 2.7 Treatment Options ..................................................................................................................19

2.7.1 Treatment Algorithm........................................................................................................20 2.7.2 Non-Pharmacological Treatments.....................................................................................20

3 Marketed Products .............................................................................................................................21 3.1 Namenda/Axura/Memary (memantine), Merz Pharma/Lundbeck/Forest Laboratories/Daiichi

Sankyo.....................................................................................................................................21 3.2 Aricept (donepezil), Eisai Inc. ....................................................................................................22 3.3 Exelon (rivastigmine), Novartis AG............................................................................................23 3.4 Razadyne (galantamine), Janssen Pharmaceuticals ...................................................................23 3.5 Cognex (tacrine), Shiniogi Inc. ..................................................................................................24 3.6 Unmet Need ............................................................................................................................25

4 Pipeline for Alzheimer’s Disease Therapeutics .....................................................................................26 4.1 Overall Pipeline........................................................................................................................26 4.2 Mechanisms of Action within the AD Pipeline ...........................................................................28 4.3 Clinical Trials ............................................................................................................................30

4.3.1 Clinical Trial Failure Rate ..................................................................................................30 4.3.2 Clinical Trial Size...............................................................................................................34 4.3.3 Clinical Trial Duration .......................................................................................................36

4.4 Notable Pipeline Drugs .............................................................................................................39 4.4.1 Solanezumab – Eli Lilly and Company ................................................................................39 4.4.2 LMTX (Methylene Blue) – TauRX Therapeutics Ltd. ............................................................40 4.4.3 RG-1540 (gantenerumab) – Roche ....................................................................................40 4.4.4 AD-02 – AFFiRiS AG ..........................................................................................................41 4.4.5 MK-8931 – Merck & Co.....................................................................................................42 4.4.6 CAD-106 – Novartis AG .....................................................................................................42 4.4.7 LuAE58054 – Lundbeck .....................................................................................................43 4.4.8 Crenezumab (RG7412) – Genentech ..................................................................................43

4.5 Conclusion ...............................................................................................................................43


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Table of Contents

5 Market Forecast to 2019 .....................................................................................................................45 5.1 Geographical Markets ..............................................................................................................45

5.1.1 Key Developed Markets ....................................................................................................45 5.1.2 US....................................................................................................................................48 5.1.3 Leading Five EU Countries (EU5) .......................................................................................50 5.1.4 Japan ...............................................................................................................................54

5.2 Drivers and Barriers .................................................................................................................56 5.2.1 Drivers .............................................................................................................................56 5.2.2 Barriers ............................................................................................................................57

6 Deals and Strategic Consolidations ......................................................................................................59 6.1 Key Licensing Deals ..................................................................................................................59

6.1.1 Forest Laboratories Inc. Enters into Agreement with Adamas Pharmaceuticals Inc. ............61 6.1.2 AC Immune SA Enters into an Agreement with Genentech Inc. ...........................................61 6.1.3 Cephalon Inc. Enters into Agreement with Mesoblast Limited ............................................61 6.1.4 Acadia Pharmaceuticals Inc. Enters into Agreement with Biovail Laboratories International

SRL ..................................................................................................................................61 6.1.5 Astellas Pharma Inc. enters into Agreement with CoMentis Inc. .........................................61

6.2 Key Co-development Deals.......................................................................................................62 6.2.1 Evotec AG Enters into Agreement with F. Hoffman-La Roche Ltd. .......................................64 6.2.2 Alectos Therapeutics Inc. Enters into Agreement with Merck & Co. Inc. ..............................64 6.2.3 Targacept Inc. Expands Agreement with AstraZeneca PLC. ................................................64 6.2.4 GlaxoSmithKline Enters into an Agreement with Epix Pharmaceuticals...............................65

7 Appendix ............................................................................................................................................66 7.1 All Pipeline Drugs by Phase - Tables ..........................................................................................66 7.2 Market forecast to 2019 - Tables ..............................................................................................71 7.3 References ..............................................................................................................................73 7.4 Abbreviations ..........................................................................................................................77 7.5 Methodology ...........................................................................................................................79 7.6 Secondary Research .................................................................................................................80 7.7 Therapeutic Landscape ............................................................................................................80 7.8 Contact Us ...............................................................................................................................80 7.9 Disclaimer................................................................................................................................81


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Table of Contents

1.1 List of Tables

Table 1: Alzheimer’s Disease, Global, All Pipeline Products (Discovery) ..................................................66 Table 2: Alzheimer’s Disease, Global, All Pipeline Products (Preclinical) .................................................67 Table 3: Alzheimer’s Disease, Global, All Pipeline Products (Phase I) ......................................................68 Table 4: Alzheimer’s Disease, Global, All Pipeline Products (Phase II) .....................................................69 Table 5: Alzheimer’s Disease, Global, All Pipeline Products (Phase III) ....................................................70 Table 7: Alzheimer’s Disease, Global, Market Forecast, 2012–2019 .......................................................71 Table 8: Alzheimer’s Disease, US, Market Forecast, 2012–2019 .............................................................71 Table 9: Alzheimer’s Disease, UK, Market Forecast, 2012–2019.............................................................71 Table 10: Alzheimer’s Disease, France, Market Forecast, 2012–2019 .......................................................72 Table 11: Alzheimer’s Disease, Germany, Market Forecast, 2012–2019 ...................................................72 Table 12: Alzheimer’s Disease, Italy, Market Forecast, 2012–2019 ..........................................................72 Table 13: Alzheimer’s Disease, Spain, Market Forecast, 2012–2019 .........................................................73 Table 14: Alzheimer’s Disease, Japan, Market Forecast, 2012–2019 ........................................................73


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Table of Contents

1.2 List of Figures

Figure 1: Mini-Mental State Exam ..........................................................................................................14 Figure 2: Alzheimer’s Disease Assessment Scale Cognitive Subscale ........................................................15 Figure 3: Alzheimer’s Disease, Overall Pipeline .......................................................................................27 Figure 4: Alzheimer’s Disease, Mechanisms of Action in the Pipeline, 2006–2013 ...................................30 Figure 5: Alzheimer’s Disease, Failure Rates of Clinical Trials, 2006–2013 ...............................................31 Figure 6: Alzheimer’s Disease, Failure Rates by Mechanism of Action, 2006–2013 ..................................32 Figure 7: Alzheimer’s Disease, Reasons for Clinical Trial Failure, 2006–2013 ...........................................33 Figure 8: Alzheimer’s Disease, Clinical Trial Size by Phase, 2006–2013 ....................................................34 Figure 9: Alzheimer’s Disease, Clinical Trial Size by Molecule Type, 2006–2013 .......................................35 Figure 10: Alzheimer’s Disease, Clinical Trial Duration by Phase, 2006–2013 .............................................36 Figure 11: Alzheimer’s Disease, Clinical Trial Duration by Molecule Type, 2006–2013 ...............................37 Figure 12: Alzheimer’s Disease, Global, 2012–2019 ..................................................................................47 Figure 13: Alzheimer’s Disease, US, 2012–2019........................................................................................49 Figure 14: Alzheimer’s Disease, EU5, Patient Number (‘000) 2012–2019 ...................................................51 Figure 15: Alzheimer’s Disease, EU5, Annual Cost of Treatment ($), 2012–2019 .......................................52 Figure 16: Alzheimer’s Disease, EU5, Market Size ($m), 2012–2019 ..........................................................53 Figure 17: Alzheimer’s Disease, Japan, 2012–2019 ...................................................................................55 Figure 18: Alzheimer’s Disease, Global, Licensing Deals by Region and Year, 2012–2019 ...........................59 Figure 19: Alzheimer’s Disease, Global, Licensing Deals by Phase and Molecule Type, 2012–2019 .............60 Figure 20: Alzheimer’s Disease, Global, Co-development Deals by Region and Year, 2012–2019 ...............62 Figure 21: Alzheimer’s Disease, Global, Co-development Deals by Phase and Molecule Type, 2006–2013 .63


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Introduction

2 Introduction

Alzheimer’s Disease (AD) is the most common form of senile dementia, affecting approximately 36 million people worldwide and accounting for XX—XX% of all cases of dementia (National Alzheimer’s Association, 2012). The disease is characterized by a progressive decline in cognitive function starting with short term memory, progressing to a total loss of cognitive faculties in the end-stage disease.

AD was first described in 1907 by Dr. Alois Alzheimer, a German physician who first noticed the disease’s typical ‘plaque and tangle’ deposition in the brain of a woman he had been treating. In line with the increases in average life expectancy since then, the prevalence of the disease has increased exponentially to the point where it represents a major problem for public health authorities worldwide.

The disease presents itself in two forms, although both forms share the same symptoms. Senile AD occurs in patients over the age of XX and accounts for the majority of cases. Indeed, after the age of XX, the likelihood of developing AD increases from one in 100 to just XX in six in patients over the age of XX.

A less common form of the disease presents itself earlier in life, usually between the ages of 40 and 64. This type is known as Familial-onset Alzheimer’s Disease (FAD) and, although it accounts for a lower number of cases – around XX% – it is no less severe. It is estimated by the World Health Organization (WHO) that, by 2040, due to the increasing life expectancy of humans, there will be over 80 million cases of AD worldwide, equating to one person in every 85 (WHO, 2012).

AD is a progressive and incurable disease, and potential treatments have only emerged in the last 20 years. However, current treatments are lacking in terms of efficacy. Indeed, only four drugs are currently marketed for dementia associated with AD, and all of them are recognized as symptomatic treatments rather than disease-modifying therapy . Since the discovery of what plaques and tangles comprised – amyloid β (Aβ) peptide and hyperphosphorylated tau (p-tau) protein respectively – attempts have been made to develop therapeutics which can limit the rate of synthesis, reduce the toxicity or clear these factors from the brain. However, these attempts have been largely unsuccessful. Therefore, given the enormous (and continually growing) prevalence population, as well as the small host of drugs available as treatments, AD presents a lucrative opportunity for an effective disease-modifying therapy to enter the market.

2.1 Symptoms

AD can be classified as preclinical, mild, moderate or severe, and there is a relatively distinct set of symptoms associated with each classification. Preclinical AD can be largely asymptomatic, and can be indistinguishable from normal symptoms of aging such as memory loss and intermittent confusion. It is only once the disease progresses to early AD that the symptoms become more obvious. Early AD is characterized by, but not limited to:

Memory loss (particularly short term memory loss)

Confusion about the location of familiar places, with disorientation being common

Mood and personality changes

This then progresses to moderate AD, which is characterized by, but not limited to:

Increasing memory loss and confusion

Difficulty recognizing friends and family members

Short attention span

Problems with language and numeracy, including difficulties reading and writing

Loss of impulse control

Disturbed sleep

Repetitive or obsessive behavior

Difficulty in spatial orientation and spatial judgment

[...] only four drugs are currently marketed for dementia associated with AD, and all of them are recognized as symptomatic treatments rather than disease-modifying therapy


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Pipeline for Alzheimer’s Disease Therapeutics

4 Pipeline for Alzheimer’s Disease Therapeutics

4.1 Overall Pipeline

The total number of drugs in the AD pipeline is fairly large at XX, which is unusual considering the high degree of failure in this indication as well as the degree of uncertainty regarding the disease etiology, as illustrated in FFigure 3.A. This is indicative of the potential value attached to AD as an indication. The overall pipeline for AD is still very much dominated by small molecule drugs. With the number of small molecules in the pipeline amounting to XX, equivalent to XX% of the total pipeline, it would appear that there may be reduced scope for biologics to infiltrate the pipeline, as illustrated in FFigure 3.B. However, there is still a considerable number of biologics in the pipeline, with 86 in total, represented across all stages of development, as illustrated in FFigure 3.B. The breakdown of biologics as a class reveals no particular trend in relation to any one type, with proteins/peptides and monoclonal antibodies (mAbs) occupying a roughly equal share with XX and XX molecules respectively, and two of the biologic molecules were of an undisclosed type, as illustrated in Figure 3.D. This does not suggest any particular sign of a major transition in the market however, as the influence of small molecules appears to be overwhelming. The diversity of the different molecule types in the biologic group shows a certain level of innovation, with newer avenues being explored in light of recent failures.

In terms of stage of development, small molecules are dominant across every stage of development, in particular in the preclinical and discovery stages with XX and XX molecules in each respectively, as illustrated in Figure 3.C. Biologics are less well-represented, despite a strong presence in the preclinical Phase, with XX molecules, as illustrated in Figure 3.C. Only around 20% of the total pool of biologics are in Phases II and III, as illustrated in Figure 3.C. However, the relatively high proportion occupying the early stages of development hints at the increased innovation in biologics for AD. Gene/cell therapies are poorly represented in the pipeline overall, with a grand total of XX therapies accounting for only three percent of the entire pipeline in total, as illustrated in Figure 3.B. This could be attributable to the relative novelty of the drug class as well as the difficulty of the manufacture of these therapies.

Across the pipeline as a whole, a number of molecules occupy the early stages of development with the XX, XX and XX drugs in discovery, preclinical and Phase I stages respectively, as illustrated in Figure 3.A. This is not surprising considering the fairly high degree of novel targets, such as neuromodulators and APP metabolism currently in the early pipeline.

This translates favorably to Phase II, where there are currently XX molecules constituting XX% of the total pipeline. In contrast, there are only seven molecules occupying Phase III, which reflects the difficulty of achieving success in Phase II trials, as illustrated in Figure 3.A.

In general, late stage clinical trials have highlighted very few molecules that could potentially supplant current treatments during the forecast period. While there is some promise in Phase III trials, most notably the Phase III product LMTX, the recent high profile failures of drugs such as bapineuzumab and Gammagard have cast doubt upon similar drugs, such as solanezumab. Therefore, while innovation and investment appears to be strong, it is unlikely that treatment algorithms will change substantially during the forecast period.

As far as molecular targets are concerned, the pipeline tends to fit into the established groups of drugs that have been a mainstay of AD therapeutics for years. Most notable is the continued presence of drugs targeting Aβ, which have yielded little in terms of workable products. The pipeline holds some degree of promise as a wealth of new targets in the pipeline that were not especially prominent in the past are coming to prominence, such as tau. This implies that companies are reacting to the continuing failures of drugs with popular targets in favor of novel mechanisms of action, which could yield a greater degree of success.

More diverse targets are also beginning to emerge, based on recently published literature. A notable example of this is the presence of estrogen analogues in the pipeline, based on a study establishing a link between post-menopausal women and increased AD risk, or the signaling cascade linking Aβ to the β-adrenergic receptor (Wharton et al., 2011). Continued research into the causes of AD is likely to reveal novel therapeutic targets, which will then impact upon the pipeline. A recent example of this is the groundbreaking study in which neurodegeneration was halted in mice through interference with the Unfolded Protein Response (UPR). As a result of the inhibition of Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), a key UPR pathway modulator, the proliferation of neurodegeneration no longer occurred in the brains of the mice (Moreno et al., 2013). Although in very early stages, this research could

More diverse targets are beginning to emerge [...]


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Pipeline for Alzheimer’s Disease Therapeutics

provide the basis for future pipeline products with a novel target rather than the commonly targeted Aβ and tau.

However, despite all these factors, the current pipeline for AD as a whole is relatively weak. Even with additional innovation in terms of drug targets, there are still a large proportion of drugs targeting factors such as Aβ, which is involved in AD but whose place in the causal network of events in relation to the disease remains unclear. Although the high-profile failures of Aβ-targeting therapies over the last few years have been disappointing, the evidence from both basic research and clinical studies is insufficient to discredit Aβ as a viable therapeutic target.

The primary challenges for therapeutics targeting Aβ include uncertainty with regards to whether the intracellular or extracellular targeting of either soluble or oligomeric isoforms represents the greatest therapeutic promise. In addition, the timing of therapeutic intervention is a critical issue, particularly for Aβ-targeting products. By the time AD is symptomatic and can be diagnosed, structural and functional changes to active neurons and neuronal degeneration are already well-established. Evidence suggests that different Aβ isoforms exert differentiated toxic effects in different neuronal compartments, with the result that there is a strong scientific and clinical rationale for therapeutic interventions targeting Aβ, but timing is critical. In light of the neurotoxic effects, an earlier intervention at pre-symptomatic disease stages could slow disease progression and provide greater therapeutic benefits than in mild to moderate patient populations. Developmental programs such as Roche’s gantenerumab, which are currently conducting clinical trials within the prodromal patient population in addition to mild to moderate AD, indicate a shift in the R&D environment. However, further progress to extend clinical trials to pre-symptomatic patient groups is currently hindered by a lack of effective biomarkers with the capacity to elucidate Aβ in presymptomatic patients

Additionally, the current efficacy of all AD drugs continues to be impeded by the lack of an effective biomarker for the early presentation of the disease. While mechanisms for the detection of current biomarkers, including Amyvid, are becoming more effective, a novel biomarker for early AD is still not available, in spite of ongoing research. The implications of such a biomarker being discovered could result in earlier treatment initiation and a more favorable prognosis. Considering that the vast majority of drugs only work on mild to moderate AD, this could well stifle progress for a number of years.

Figure 3: Alzheimer’s Disease, Overall Pipeline

Pipeline by Phase (%)

DiscoveryPreclinicalPhase IPhase IIPhase III

n = XX

Pipeline by Molecule Type (%)

Small molecule

Biologics

Gene/cell therapy

B

Discovery Preclinical Phase I Phase II Phase III

Num

ber o

f dru

gs

Pipeline by Molecule Type and Phase

Small molecule Biologic Gene/cell therapy

C Breakdown of Biologics in Alzheimer's Disease Pipeline

Monoclonal antibodyVaccine

Protein/peptide

D

A

Source: GBI Research Proprietary Pipeline Products Database


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Deals and Strategic Consolidations

6.2 Key Co-development Deals

In total, XX co-development deals took place between 2006 and 2013 in the AD market. Of these, the majority took place in North America, while others took place between companies in North America and other continents. The largest share of deals took place between North America and Europe. Of the XX deals that were completed, XX had disclosed values ranging from under $XXm to over $XX billion. There were six deals with disclosed values of more than $XXm. In terms of drug molecule types, XX deals had disclosed molecule types, with XX being small molecules and the remaining deal involving a biologic (polysaccharide). The majority of deals took place in 2006 and 2010, with XX deals and XX deals occurring in each of these years respectively. By phase, there was no concrete majority, with XX to XX deals occurring on average from the preclinical to Phase III stages of development. One deal concerned a marketed product.

Figure 20: Alzheimer’s Disease, Global, Co-development Deals by Region and Year, 2012–2019

Co-development Deals by Value

$10m

$10-50m

$51-100m

$101-200 million>$200 million

A

2006 2007 2008 2009 2010 2011 2012 2013

Agg

rega

te d

eal v

alue

s ($

m)

Tota

l num

ber o

f dea

ls

Co-development Deals by Value and Year

Number of undisclosed deals Number of disclosed dealsTotal disclosed value ($m) Total upfront value ($m)

B

Source: GBI Research Proprietary Database, Deals, Strategic Alliances


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Appendix

7 Appendix

7.1 All Pipeline Drugs by Phase - Tables

Table 1: Alzheimer’s Disease, Global, All Pipeline Products (Discovery)

Product Name Company Stage of development Mechanism of action

Source: GBI Research


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Appendix

Table 2: Alzheimer’s Disease, Global, All Pipeline Products (Preclinical)




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Appendix

Table 3: Alzheimer’s Disease, Global, All Pipeline Products (Phase I)




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Appendix

Table 4: Alzheimer’s Disease, Global, All Pipeline Products (Phase II)




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Appendix

Table 5: Alzheimer’s Disease, Global, All Pipeline Products (Phase III)




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Appendix

7.2 Market forecast to 2019 - Tables

Table 6: Alzheimer’s Disease, Global, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR

Prevalence population (millions)

Treatment population (millions)

Maximum revenue ($bn)

Projected revenue ($bn)

Minimum revenue ($bn)


Table 7: Alzheimer’s Disease, US, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR

Prevalence population (millions)

Treatment population (millions)

Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)

Maximum revenue ($bn)

Projected revenue ($bn)

Minimum revenue ($bn)


Table 8: Alzheimer’s Disease, UK, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR

Prevalence population (thousands)

Treatment population (thousands)

Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)

Maximum revenue ($m)

Projected revenue ($m)

Minimum revenue ($m)



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Appendix

Table 9: Alzheimer’s Disease, France, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR



Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





Table 10: Alzheimer’s Disease, Germany, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR



Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





Table 11: Alzheimer’s Disease, Italy, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR



Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)






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Appendix

Table 12: Alzheimer’s Disease, Spain, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR



Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)





Table 13: Alzheimer’s Disease, Japan, Market Forecast, 2012–2019

Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR



Maximum ACOT ($)

Projected ACOT ($)

Minimum ACOT ($)






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Appendix

7.3 References

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Agid Y, et al., (1998). Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type. Current Therapeutic Research; 59(12): 837–845.

Alzheimer Europe (2012). France national plans for Alzheimer’s and related diseases. Alzheimer Europe. Available from: http://www.alzheimer-europe.org/Policy-in-Practice2/National-Dementia-Plans/France?#fragment-1 [Accessed October 28, 2013].

Blass N, et al., (1976). Dyed but not dead—methylene blue overdose. Anaesthesiology: 45: 458–459.

Bottini G, et al., (2012). GOOD or BAD responder? Behavioural and neuroanatomical markers of clinical response to donepezil in dementia. Behavioural Neurobiology: 25(2): 61–72.

Braak H, et al., (2011). Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. Journal of Neuropathology and Experimental Neurology: 70(11): 960–969.

Burns A, et al., (1999a). The Effects of Donepezil in Alzheimer’s Disease – Results from a Multinational Trial. Dementia and Geriatric Cognitive Disorders; 10: 237–244.

Burns A, et al., (2009). Safety and efficacy of Razadyne (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurology; 8: 39–47.

Castellani R and Perry G (2012). Pathogenesis and Disease Modifying Therapy in AD: The Flat Line of Progress. Archives of Medical Research. 43: 694–698.

Chintamaneni M and Bhasker M (2012). Biomarkers in Alzheimer's Disease: A Review. ISRN Pharmacology; 2012.

Choi S, et al., (2012). Correlation of amyloid PET ligand florbetapir F 18 binding with Aß aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Disease and Associated Disorders; 26(1): 8–16.

Citron M (2010). Alzheimer's Disease Strategies for Disease Modification. Nature Reviews Drug Discovery; 9: 387–398.

Courtney C, et al., (2004). Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000) randomised double-blind trial. Lancet; 363 (9427): 2105–2115.

Cronin-Stubbs D (1997). Weight loss in people with Alzheimer's disease: a prospective population based analysis. British Medical Journal; 314: 178–179.

Dementia Collaborative Research Centers (2013). ADCS-ADL Scale. Available from: http://www.dementia-assessment.com.au/function/ADCS-ADL_Scale.pdf

Duthie A, et al. (2011) Non-psychiatric comorbidity associated with Alzheimer’s disease. QJM; 104: 913–920.

Eckman C, et al., (1997). A New Pathogenic Mutation in the APP Gene (I716V) Increases the Relative Proportion of Aβ42(43). Human Molecular Genetics; 6(12): 2087–2089.

Elan Corporation (2012). Elan Announces Johnson & Johnson Release of Discontinuation of Phase 3 Development of Bapineuzumab Intravenous (IV) In Mild to Moderate Alzheimer’s Disease. Elan Corporation. Available from http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-newsArticle&ID=1722933&highlight=bapineuzumab [Accessed June 2, 2013].

Eli Lilly and Co. (2013). Lilly Announces Detailed Results of the Phase 3 Solanezumab EXPEDITION Studies Following a Presentation of the Independent Analyses by the Alzheimer's Disease Co-operative Study (ADCS). Eli Lilly and Company. Available from http://newsroom.lilly.com/releasedetail.cfm?releaseid=711933 [Accessed June 2, 2013].

Erkinjuntti T, et al., (2002). Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. The Lancet: 359(9314): 1283–1290.


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Appendix

7.4 Abbreviations

5-HT: 5-hydroxytryptamine

5-HT6: 5-hydroxytryptamine receptor subtype 6

α: alpha

β: beta

γ: gamma

δ: delta

µg: microgram

Aβ: amyloid β

AAN: American Academy of Neurology

ACh: acetylcholine

AChE: Acetylcholinesterase

AChEI: Acetylcholinesterase Inhibitor

AChR: Acetylcholine receptor

ACoT: Annual Cost of Treatment

AD: Alzheimer’s Disease

ADAS: Alzheimer’s Disease Assessment Scale

ADAS-cog: Alzheimer’s Disease Assessment Scale-cognitive

ADCS-ADL: Alzheimer’s Disease Co-operative Study –Activities in Daily Living

ADHD: Attention Deficit Hyperactivity Disorder

ADNI: Alzheimer’s Disease Neuroimaging Initiative

ACT–AD: Accelerate Cure and Treatment for Alzheimer’s Disease

AGE: Advanced Glycation End-products

ALT: Alanine aminotransferase

APP: Amyloid Precursor Protein

AST: Aspartame Transaminase

BACE1: β-site APP Cleaving Enzyme 1

BChE: Butyrylcholinesterase

CAGR: Compound Annual Growth Rate

CEEDD: Center of Excellence for External Drug Discovery

CNS: Central Nervous System

CDS: Cognitive Dysfunction in Schizophrenia

CSF: Cerebrospinal Fluid

CT: Computed Tomography

DIAN TU: Dominantly Inherited Alzheimer's Network Trials Unit

FAD: Familial-onset Alzheimer’s Disease

FDC: Fixed-Dose Combination

GPCR: G-Protein Coupled Receptor


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GSK: GlaxoSmithKline

IgC: immunoglobulin G

IL: Interleukin

IVD: In Vitro Diagnostics

LDL: Low-Density Lipoprotein

LP: Lumbar Puncture

LPS: Lipopolysaccharhide

LTP: Long-Term Potentiation

mAbs: monoclonal antibodies

MAP: Microtubule Associated Protein

MMSE: Mini-Mental State Examination

MRI: Magnetic Resonance Imaging

NFT: Neurofibrillary Tangle

NMDA: N-methyl D-amino

p-tau: hyperphosphorylated tau

PERK: Protein kinase RNA-like Endoplasmic Reticulum Kinase

PET: Positron Emission Tomography

PiB: Pittsburgh compound B

PID: Primary Immune Deficiency

PMA: Pre-Market Approval

PPAR: Peroxisome Proliferator Activated Receptor

RAGE: Receptor for Advanced Glycation End-products

Redox: oxidation-reduction

SALA: Selective Amyloid beta 42 Lowering Agent

t-tau: total tau

TGFβ: Transforming Growth Factor β

TNF-α: Tumor Necrosis Factor α

TSH: Thyroid Stimulating Hormone

UPR: Unfolded Protein Response

UTI: Urinary Tract Infection

WHO: World Health Organization

7.5 Methodology

GBI Research’s dedicated research and analysis teams consist of experienced professionals with marketing, market research and consulting backgrounds in the pharmaceutical industry as well as advanced statistical expertise.

GBI Research adheres to the codes of practice of the Market Research Society (www.mrs.org.uk) and the Strategic and Competitive Intelligence Professionals (www.scip.org).

All GBI Research databases are continuously updated and revised.


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7.6 Secondary Research

The research process begins with exhaustive secondary research on internal and external sources being carried out to source qualitative and quantitative information relating to each market.

The secondary research sources that are typically referred to include, but are not limited to:

Company websites, annual reports, financial reports, broker reports, investor presentations and US Securities and Exchanges Commission (SEC) filings

Industry trade journals, scientific journals and other technical literature

Internal and external proprietary databases

Relevant patent and regulatory databases

National government documents, statistical databases and market reports;

Procedure registries

News articles, press releases and web-casts specific to the companies operating in the market

7.7 Therapeutic Landscape

Revenues for each indication are calculated by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of revenues of all seven countries covered in this report.

The annual cost of therapy for each indication is arrived at by considering the cost of the drugs, dosage of the drugs and the duration of the therapy.

The treatment usage pattern which includes quantitative data on the diseased population, diagnosed population and treated population for an indication, is arrived at by referring to various sources as mentioned below.

GBI Research uses the epidemiology-based treatment flow model to forecast market size for therapeutic indications.


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7.9 Disclaimer

All Rights Reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research.

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