The State of Innovation inHighly Prevalent Chronic Diseases

Volume IV:
Alzheimer’s Disease
Therapeutics
by David Thomas, CFA and Chad Wessel
BIO INDUSTRY ANALYSIS

About BIO
BIO is the world’s largest trade association representing biotechnology
companies, academic institutions, state biotechnology centers andrelated organizations across the United States and in more than 30
other nations. BIO members are involved in the research and developmentof innovative healthcare, agricultural, industrial, and environmental
biotechnology products. BIO also produces the BIO International
Convention, the world’s largest gathering of the biotechnology industry,along with industry-leading investor and partnering meetings heldaround the world.

Access BIO Industry Analysis reports here: www.bio.org/iareports

The State of Innovation in Highly Prevalent Chronic Diseases

Volume IV: Alzheimer’s Disease Therapeutics
Introduction
This is the fourth report in a series on the innovation landscape of highly prevalent, chronic diseases. In our previously publishedresearch, emerging company investment for drug development in many of these common diseases was shown to be declining
and low relative to total healthcare costs (Figure 1). This prompted the ongoing investigation to determine if the slowdown isindustry-wide, beyond privately funded companies.1 Thus far, we have identified a broader contraction of R&D in depression,
pain, addiction, type II diabetes, and obesity.2 The persistence of this trend could have implications for the future output ofinnovative medicines in these disease areas. The cause for concern is magnified by the impact these chronic disease areas
have on the overall healthcare system in the US. Thus, it is important that barriers to therapeutic innovation are identified and removed.
This volume takes an in depth look at the state of innovation for therapeutics in Alzheimer’s disease, a devastating highly prevalentchronic disease. Alzheimer’s disease comprises up to 80% of all diagnosed dementia, which affects 5.7 million people in the U.S.
alone and costs the U.S. healthcare system $277 billion annually, with Medicare and Medicaid shouldering $186 billion (67%) of
the total.3 The growing Alzheimer’s disease epidemic is expected to affect more than 13.8 million people in the U.S. by 2050, andcost well over $1 trillion annually.4 Global estimates for dementia by 2050 suggest close to 152 million people with a cost at over
$2 trillion annually. 5
Herein, we analyze disease-modifying drug candidates progressing through the clinical pipeline. The analysis aims to assessthe depth and breadth of innovation to meet the urgent needs of patients suffering from Alzheimer’s disease. Historical clinicalsuccess rates and failed mechanistic strategies are identified, as well as trends in venture financing and investment into newclinical trials.

Key Takeaways for Alzheimer’s Disease•

Marketed drugs: There are currently no FDA approved disease-modifying drugs for Alzheimer’s disease.

•

Venture investment: Venture capital funding of U.S. companies with lead stage programs in Alzheimer’s disease is 16
times below oncology funding ($1.0 billion vs. $16.5 billion over the last decade).

•

R&D success rate: Clinical development success for disease-modifying drug programs for Alzheimer’s has beendifficult in late-stage trials, with no disease-modifying drugs moving beyond Phase III to FDA filing. Since the start of2008, a total of 87 clinical-stage disease-modifying programs have been suspended. Disease-modifying drug
programs moving from Phase I to Phase II have experienced a 47% probability of success (vs. 59% across all disease
areas). Phase II to Phase III success is lower, with only a 36% probability of success (vs. 31% across all disease areas).

•

Clinical trial initiations: Clinical trial starts for disease-modifying Alzheimer’s drugs have ranged from 11-21 trial
starts per year since 2008 with no detectable trend. Phase III trial starts have been the least consistent, ranging
from 0-5 per year.

•

Pipeline: There are 74 clinical-stage programs with disease-modifying potential in Alzheimer’s disease. The drugcandidates in these programs are attempting to stop, prevent, or slow the progression of Alzheimer’s disease using 10
strategies involving 30 distinct molecular targets. Small emerging companies account for 77% of the Alzheimer’s
clinical programs.

		 Thomas, D., Wessel, C. BIO Industry Analysis. Emerging Company Trend Report, (2018) (www.bio.org/iareports)
		 Thomas, D., Wessel, C. BIO Industry Analysis. Highly Prevalent Chronic Disease Series, (2018) (www.bio.org/iareports)
3
		 Alzheimer’s Association. 2018 Alzheimer’s Disease Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures4
		 Alzheimer’s Association. 2018 Alzheimer’s Disease Facts and Figures. (page 23). The cost of caregiver support adds an extra $237 billion in costs.
5
		 Alzheimer’s disease International. World Alzheimer Report 2018. https://www.alz.co.uk/research/world-report (accessed March 2019)
1

2

BIO Industry Analysis | 1

U.S. HEALTHCARE COST VS. U.S. VENTURE CAPITAL FUNDING OF NOVEL R&D FORHIGHLY PREVALENT CHRONIC DISEASES$14
CancerVenture Funding($B, 2008‐2017)

$12
$10
$8
$6
$4
$2
$0

Respiratory$50

Heart Disease
PsychiatricObesity

Diabetes Pain Dementia

Addiction$75 $100 $125 $150 $175 $200 $225 $250 $275 $300
U.S. Healthcare Direct Costs (billions)Figure 1. Healthcare Cost vs. Venture Capital Funding into novel chemical entity development 2008-2018 for Oncology and highly
prevalent chronic diseases. Source for healthcare costs – Dementia: Alzheimer’s Association, 2018. Diabetes: March 2018 ADA
report; Obesity, Heart Disease, Respiratory, Oncology are based on 2013 data cited in Health Affairs, 35, No. 6 (2016); Pain: The
Journal of Pain, 2012; Addiction: NIDA website 2018. Source for venture data: BIO Industry Analysis, Emerging Company Trend
Report, 2008-2017 (accessed in June 2018 at www.bio.org/iareports).

2 | BIO Industry Analysis

Alzheimer’s Disease - Background
Alzheimer’s disease is a complex chronic disease characterized biologically by the accumulation of extracellular protein plaques,
neurofibrillary protein tangles, a loss of functional synaptic connections, and eventually complete loss of neurons. The loss ofneuronal activity often begins in regions of the medial temporal lobe, an area deep inside the brain where long-term memory is
consolidated.6 Clinically, it is a type of dementia characterized by progressive deterioration in cognition and memory, andimpairment in the ability to carry out activities of daily living.7
Most cases of Alzheimer’s are diagnosed later in life (over the age of 65); however, Alzheimer’s can appear as early as 40 yearsof age. Because of this observation, the disease can be referred to as early-onset and late-onset Alzheimer’s. A detailed
categorization of the disease progression includes a pre-symptomatic phase, called “preclinical-stage Alzheimer’s”, a “prodromalstage” characterized by mild cognitive impairment (MCI), followed by mild, moderate, and severe stages of dementia.8
Early-onset Alzheimer’s disease occurs in 5% of patients with many patients having genetic mutations in genes associated withneuronal protein and lipid processing.9 A number of these genes are specifically associated with the trafficking and processingof amyloid protein, a drug target that will be discussed in more detail below.
Scientists have also identified genes involved in late-onset Alzheimer’s disease, a far more common form of the disease throughgenome wide association studies. More than two dozen genes are known to correlate with increased risk of late-onset Alzheimer’s.
A recent study funded by the NIH, and the largest conducted to date, found five new genes, in addition to many previously
identified genes, from a genomic screen of 35,000 individuals with late-onset Alzheimer’s.10 The new genes and the previously
identified genes have functional roles in pathways currently targeted for drug development, such as amyloid and /or tau clearance
described in more detail below.
A well-known gene mutation associated with late-onset Alzheimer’s is the ApoE gene variant, ApoE4. This gene codes forapolipoprotein E, a critical protein for dendritic lipid and protein trafficking required for synaptic plasticity and other changes
involved in long-term memory, neuron growth and maintenance. In the case of ApoE4 gene carriers, lipid and protein trafficking
is impaired and cognitive decline is much more rapid.11 Interestingly, another less common gene mutation, known as ApoE2, isassociated with a lower probability of developing late-onset Alzheimer’s.12 Clues such as this have provided direction for drug
developers seeking to uncover the root cause or key molecular influencers of the disease.

		 Within the temporal lobe is the entorhinal cortex, the hub connecting the neocortex to the hippocampus. Pathological markers of Alzheimer’s disease have beenshown to spreads from the entorhinal neocortical area to the hippocampus, and then to other areas of the brain. Querfurth, H., et al. Mechanism of Disease,
Alzheimer’s Disease. NEJM 362, 4, p.329-344 (2010)7
		 Jalbert, J., et. al. Dementia of the Alzheimer Type. Epidemiologic Reviews, 30 (1) p15–34 (2008)8		 https://www.brightfocus.org/alzheimers/question/what-are-stages-alzheimers-disease9		 Three genes identified with early-onset are APP (Amyloid Precursor Protein, PSEN1 and PSEN2 (genes for enzymes of the gamma secretase complex that cuts APP
to form amyloid). See more at: https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet, and https://www.mayoclinic.org/diseases-conditions/
alzheimers-disease/in-depth/alzheimers/art-20048356
10
		 Kunkle, B., et.al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature
Genetics, 51 p414–430 (2019)11
		 Aisen, P., Cummings, J., et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimer’s Research & Therapy, 9 (60) (2017)12
		 Yu, J., et al. Apolipoprotein E in Alzheimer’s Disease: An Update. Annual Review Neuroscience, 37 p79-100 (2014). Note that the most common ApoE form is ApoE3
and that the other two alleles (ApoE4 and ApoE2) produce apolipoprotein with single amino acid differences in the lipid binding domain.
6

BIO Industry Analysis | 3

Despite the identification of gene mutations associated with Alzheimer’s Disease, many unknowns remain. For example, individuals
without specific gene mutations know to be associated with Alzheimer’s develop the disease. Others progress through life
without clinical dementia yet have the hallmark brain signatures (such as plaques and fibrillary tangles). 13 Furthermore,
epidemiological studies correlate increased risk of developing Alzheimer’s Disease in individuals with diabetes, obesity,
hypertension, and individuals who smoke.14
Recent studies have also shown that lack of sleep may be a potential contributing factor. A January 2019 study detected higher
tau and amyloid β (targets within the clinical pipeline discussed below) in individuals with poor slow wave sleep.15 Last year, an
NIH funded study demonstrated an increase in amyloid levels after losing just a single night of sleep.16 During sleep, the brain
undergoes much of the clearing of unwanted protein debris that builds up during waking hours. In the aging brain, this clearance
system, known as the glymphatic system, slows and sleep disruption has long been correlated with early stages of cognitive decline.17
Furthermore, chronic stress, head injuries, gum disease, patient lifestyles (such as physical activity and diet), and various
environmental exposures (such as metals and infectious agents), may all play a role in the progression of Alzheimer’s disease.
Large population studies, perhaps with the help of real-world data collection technologies, will give us additional clues to unravel
this complex and varied disease.
In this report we review molecular targets that have been validated preclinically and are now in clinical development for Alzheimer’s
disease. Each program is grouped by the overall hypothesis-driven strategy taken to target this deadly disease. Although many
molecular targets discussed below have been found to correlate with disease symptomology, no molecularly targeted diseasemodifying drug has been approved by a regulatory agency. Only four symptom-modifying drug entities have been FDA approved,
as described in the Appendix. These marketed drugs do not block the progression of the disease. This is unfortunate for the
millions of families struggling with this disease but underscores how complex this disease is and how difficult it has been tointervene clinically.

		 Corrada, M., et al. A population-based clinicopathological study in the oldest. Current Alz. Research 9 p709-717 (2012). This study showed 50% of non-dementia
brains autopsied had Alzheimer’s pathology (see Figure 2 in the study).
14
		 Aisen, P., Cummings, J., et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimer’s Research & Therapy, 9 (60) (2017)15
		 Lucey, B., et al. E Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Science Translational Medicine,
11 (474) (2019)16
		 Shokri-Kojori E, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. PNAS 115 (17) p.4483-4488 (2018). Also, see https://www.nih.
gov/news-events/lack-sleep-may-be-linked-risk-factor-alzheimers-disease17
		 Boespflug, E., et al. The Emerging Relationship Between Interstitial Fluid–Cerebrospinal Fluid Exchange, Amyloid-b, and Sleep. Biological Psychiatry, 83
p328–336 (2018)13

4 | BIO Industry Analysis

Clinical Pipeline - Therapeutic Approaches
The total clinical pipeline for Alzheimer’s disease contains 120 drug programs with 74 potentially disease-modifying and theremaining 46 intended to modify cognitive symptoms of the disease. For the purpose of this report, our analysis of the pipeline
will focus only on the 74 disease-modifying clinical programs that are aimed at stopping or reversing the progression of thedisease. A breakdown of symptom-modifying drug programs can be found in Appendix A1, which includes anti-psychotic,
anti-depression, and other mood enhancing or cognition stimulating drugs, that act primarily on neurotransmitter pathways (i.e.
acetylcholine and glutamate).
In Figure 2a, the 74 disease-modifying clinical programs are shown by phase of development. in Figure 2b, they are organizedby mechanism of action. More than 80% of the 74 novel programs are split between Phase I (27) and Phase II (34). Only 13
programs (20%) are in phase III.
CLINICAL-STAGE DRUG PIPELINE OF DISEASE-MODIFYING THERAPETUICS FOR ALZHEIMER’S DISEASE# of Disease‐Modifying Clinical‐
Stage Alzheimer's Programs

34
27

13

Phase I

Phase II

Phase III

Figure 2a. The currently active Alzheimer’s disease clinical pipeline by phase (as of February 28, 2019, n=74), based on Biomedtracker’sclassification methodology by phase of development as well as company website information. Twelve programs listed as “Ex-US” in the
Biomedtracker database are included here by phase based on independent research of company websites. This “Ex-US” listing implies thecompanies have not yet intended to seek FDA approval. No NDA/BLA filings were active for Alzheimer’s Disease as of February 28, 2019.
Only novel approaches with disease modifying potential in Alzheimer’s disease are shown.

# of Disease‐Modifying Clinical‐Stage Alzheimer's Programs

33

Amyloid pathway
Tau pathway

12

Neuro‐regeneration

12
7

Neuroinflammation

3

Epigenetic
Metabolic pathway

2

Glucocorticoid2

Antioxidant

1

Antibacterial

1

Epichaperome1

Figure 2b. The number of programs in each of the 10 target strategies in the Alzheimer’s disease clinical pipeline.

BIO Industry Analysis | 5

Over the last decade, there has been significant progress in advancing our understanding of the biological mechanisms underlying
Alzheimer’s disease. This is exemplified in the range of pipeline strategies, with 10 broad approaches that may potentially haltor reverse the progression of the disease (Figure 2b). Some of these approaches are likely interconnected, with some dependent
on others, or existing in complex feedback loops that could eventually make all of them implicated in the disease. The interplayof different pathways involved in the pathology of Alzheimer’s illustrates the complexity of this disease.
The most pursued approaches target the buildup of nefarious forms of amyloid β or tau protein (n=45, 60% of the pipeline).
These two proteins, and their various forms, are the hallmark signals of the brain’s potential progression toward cognitive decline.
It is possible that the other eight approaches play a role either downstream or upstream of amyloid β and tau accumulation but
have been separately categorized herein due to the wide range of other pathways they are involved in. The other eight approaches(as show in Figure 2a and 2b) are categorized into the following categories: neuro-regeneration (n=12), inflammation pathways(n=7), epigenetic (n=3), metabolic/energy pathways (n=2), glucocorticoids/cortisol (n=2), antioxidant (n=1), antibacterial (n=1),
and the epichaperome (n=1).
Driving these diverse approaches are the small emerging companies, accounting for 77% of all clinical programs. Roughly 40%of these small company programs are partnered .
For the Phase III programs, 10 are amyloid focused and the other three target tau, inflammation, or metabolic pathways. The
only categories that do not currently have a Phase II or Phase III are the antioxidant (n=1), antibacterial (n=1), and the epichaperome
approaches which are all in Phase I testing. However, as will be described below, the antioxidant pathway has seen three failuresin the last decade at more advanced stages. Compared to the other strategies, the antibacterial and epichaperome approaches
are more recent approaches without history of prior clinical program work. As will be discussed later, the remaining eightstrategies have a history of failed programs over the last decade.

6 | BIO Industry Analysis

2019 ALZHEIMER’S DISEASE CLINICAL PIPELINE BY SUB-STRATEGY AND PHASE
Strategy
Amyloid
Pathway

Tau
Pathway

Phase I

Phase II

Phase III

Clinical
Programs

removal/clearance (Mab)

3

2

3

8

Sub-Strategy
removal/clearance (non-Mab)

3

6

2

11

slowing production

1

4

2

7

disaggregation

2

2

3

7

removal/clearance (Mab)

1

4

0

5

removal/clearance (non-Mab)

1

1

0

2

slowing production

1

2

0

3

disaggregation

0

0

1

1

stabilization (microtubules)

1

0

0

1

growth/neurotophic proteins

4

1

0

5

cell therapy

1

3

0

4

sigma receptors

0

1

0

1

plasma fraction

0

1

0

1

unknown

0

1

0

1

signaling (kinases)

1

1

1

3

leukotrienes (CysLTR)

0

1

0

1

macrophages (chlorite/taurine)

1

0

0

1

microglia (TREM2)

1

0

0

1

potassium channels

1

0

0

1

bromodomains

1

0

0

1

histone deacetylase

0

1

0

1

histone demethylase

0

1

0

1

ketogenic (lipids)

0

0

1

1

glycolytic/ketogenic (PPAR)

0

1

0

1

Glucocorticoid

cortisol (11ß-HSD)

1

1

0

2

Antioxidant

reactive oxygen species (mPES-1)

1

0

0

1

Antibacterial

protease

1

0

0

1

Neuro
Regeneration

Neuro
Inflammation

Epigenetic

MetabolicEpichaperomeepichaperome

1

0

0

1

Total

27

34

13

74

Figure 2c. The breadth of target sub-strategies in the current disease-modifying Alzheimer’s clinical pipeline listed by phase ofdevelopment. Data for program phase was obtained was obtained from Biomedracker. Mab, Monoclonal antibody.

BIO Industry Analysis | 7

Strategy #1 – Targeting the Amyloid Pathway
The most heavily researched and drug-targeted pathway relates to amyloid β formation in the brain. In the brains of Alzheimer’s
patients, amyloid extracellular plaques are found in three forms (amorphous, nonfibrillar, and fibrillar). This small amyloid protein
is generated on neuronal membranes when its precursor form is cleaved by protease enzyme complexes. This cleavage cangenerate different length amyloid protein, such as the 1-40 and 1-42 amino acid lengths, as the most prominent forms and canaccumulate extracellularly. However, it is the oligomeric form of amyloid β(1–42) in particular that is correlated with pathophysiologicalevents, such as synaptic dysfunction, Tau hyperphosphorylation (discussed below), mitochondrial dysfunction, and neuronal
stress or death.
In the current pipeline, there are 33 drug programs targeting the amyloid pathway. These can be grouped into three sub-strategies:
1) drugs targeting the removal or clearance of amyloid β from the brain (for example, via antibody), 2) drugs that break up amyloid
aggregated or disrupt its binding to other receptors or cofactors involved in the pathology of Alzheimer’s disease, or 3) drugs
that prevent or slow the production of amyloid β (for example, shifting the processing of amyloid precursor protein, APP).
1. Removal/clearance of amyloid. This has been the area with the highest concentration of R&D within Alzheimer’s drug
development.18 Removal of amyloid β(1–42), and its varied oligomeric and aggregated forms, has been hypothesized todecrease its toxic effects and possibly stop the progression of neuronal damage. This continues to be pursued throughthe use of antibodies (n=8 programs) that directly bind to amyloid, as well as vaccines aimed at training the native
immune system to produce anti-amyloid antibodies (n=6 programs). The natural removal of amyloid is carried out
through a clearance processes known as the glymphatic clearing system and is active at night. This system may not work
sufficiently in the aged brain. It is possible that key proteins, such as purine receptors, ATP-binding cassette transporters,
and even albumin can make this process more efficient. There are five drug programs in the pipeline taking thisapproach. Interestingly, ApoE, a key protein believed to act as a chaperone for amyloid (and other proteins and lipids), is
not a direct target found in the current clinical pipeline.
2. Disaggregate/disrupt amyloid. These drugs prevent amyloid proteins from binding together, blocking aggregation, or
they can act to disrupt unfavorable interaction of amyloid and certain receptors. One example from the pipeline is a small
molecule that blocks the filamin A scaffolding protein and its binding of toxic amyloid species to acetylcholine receptors.
This filamin A blockage reduces the secondary effect of signaling to tau phosphorylation and pro-inflammatory cytokine
release (via toll-like receptor 4).19 There are currently seven molecules in the clinic that act through a disaggregating/disrupting process.
3. Prevent/slow the production of amyloid. As amyloid β is a biproduct of cleaved APP, either slowing or shifting thecleavage of APP to the less toxic amyloid β(1-40) form is a strategy employed by seven drugs. The beta secretase (BACE)
and gamma secretase inhibitors exemplify this strategy. Although there have been numerous failures (discussed below)
three secretase inhibitors remain active in clinical trials. Another four approaches have less direct evidence ofmodulating APP processing, but biochemical evidence suggests they can slow or block APP production itself.20,21 As an
example, the enzyme PKC is involved in physiological processes related to learning and memory, but its activation has
also been shown to slow amyloid as well as tau aggregation (by either shifting secretase toward sAPP or slowing thephosphorylation of tau).22

		 Panza, F., et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nature Reviews Neurology, 15 p73-88 (2019)
		 Wang, H., et al. Reducing amyloid related Alzheimer’s disease pathogenesis by a small molecule targeting filamin A. J. Neurosci. 32, p9773–9784 (2012)20
		 Teich, A., et al. Posiphen Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse. Alzheimer’s &Dementia: Translational Research & Clinical Interventions 4 p37-45 (2018)21
		 Melnyk, P., et al. Chloroquine and Chloroquinoline Derivatives as Models for the Design of Modulators of Amyloid Peptide Precursor Metabolism. CS Chem. Neurosci.
6(4), p559–569 (2015)22
		 Talman, V., et al. Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer’s Disease: Is there a Role for Embryonic Lethal Abnormal Vision-likeProteins? Basic Clinical Pharmacology Toxicology 119(2) p.149-160 (2016) (see Fig. 3)
18

19

8 | BIO Industry Analysis

Strategy #2 – Targeting the Tau Pathway
The second most pursued strategy, and one that has had increasing interest in recent years, in part due to the lack of successwith amyloid targeting drugs, is the targeting of malfunctioning tau protein, either directly or indirectly. As far back as the 1980s
researches have known that tau plays a role in the pathology of the disease.23 The tau protein is an essential stabilizing component
for neuronal microtubules and may serve a role in cell signaling.24 Microtubules are key building blocks in cells, but also facilitatetransport of vesicles containing neurotransmitters. When tau becomes unstable, the microtubules can fall apart, disrupting
neuron function.
Tau protein can be destabilized by phosphorylation, but it is possible that other post-translational modifications (acetylation,
glycosylation, etc.) contribute to its demise.25 Once the state of tau is altered, tau can form fibrils inside the cell and can also be
excreted and passed on to other cells.26
In the pipeline, there are 12 drug programs under the tau targeting approach as shown in Figure 2c. These can be grouped into
three sub-strategies: 1) drugs that target the removal or clearance of tau from the brain (for example, via antibody), 2) drugs thatprevent tau aggregation or disrupt abnormal tau activity, 3) drugs that prevent or slow the production of tau (for example, using
antisense to block translation), or 4) drugs that stabilize microtubules.
1.

Removal/clearance of tau. This is the sub-strategy with the most R&D activity for tau targeting, with seven of the 12
drug programs aimed at the direct removal or clearance of tau. Five of the seven drugs target tau via monoclonal
antibodies, with four of these in Phase II and one in Phase I. These antibodies act extracellularly and are thus designed tointercept the cell-to-cell spread of pathological Tau. They likely differ in epitope binding and in their affinity for
aggregated states of tau.27 Another tau clearing approach is to create a vaccine against the pathological form of the tau
protein. There is one Phase II and one Phase I program underway that aim to stimulate an immune response against tau
and thus prevent the formation of tau oligomers and neurofibrillary tangles. A final drug program aims to use purine
receptor activation to allow for tau mobilization, a potential gateway open during the glymphatic system
mentioned above.

2. Disaggregate/disrupt tau. The drug program furthest along in the pipeline has been in various clinical trials over thelast 10 years and in Phase III trials since 2012 but has seen multiple setbacks with different formulations. This drug works
to prevent the aggregation of tau.28
3. Prevent/slow the production of tau. Two drugs under the tau strategy target the post-translational modifications oftau, such as phosphorylating/dephosphorylating, thought to promote tau instability. There are two of these drugs in theclinic, one is a Phase II program drug that works by inhibiting a kinase and the other a Phase I program testing aphosphatase agonist. A third drug works via anti-sense to down-regulate tau gene expression. Lowering levels of tau byintervening at the translational level has, in mouse studies, been shown to prevent neuronal loss and tauopathy.29
4. Microtubule stabilization. There is one microtubule stabilizing agent, derived from the structure of Taxol, in Phase I.
Taxol is used to prevent otherwise rapidly dividing cancer cells from dividing as it binds microtubules, preventing the
depolymerization needed for cell division. Such chemical stabilization of microtubules could be mimicking the role tau
plays in neuron microtubule stabilization.

		 Manelkow, E., et al. Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration. Cold Spring Harb Perspect Med. 2(7) a006247 (2012)
		 Jadhav, S., et al. A walk through tau therapeutic strategies. Acta Neuropathologica Communications 7(22) (2019)25
		 See a more extensive list on this company poster reference at the 2017 Annual Meeting of The American Neurological Association: http://ir.ionispharma.com/
static-files/4ab8c591-c51b-45e1-8b0d-ef83a46c0853
26
		 Katsinelos, et al. Cell Reports 23, p2039–2055 (2018)27
		 Preclinical studies have shown that tau has different oligomer states before forming fibrils. See Takashima, A. Tauopathies and tau oligomers. J Alzheimer’s Disease37(3) p565-85 (2013)28
		 Schirmer R., et al. “Lest we forget you--methylene blue...”. Neurobiology of Aging 32(12) p2325 (2011)29
		 Devos SL, et al., Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy, Sci Translational Medicine
25(9) 374 (2017)
23

24

BIO Industry Analysis | 9

Strategy #3 – Regeneration of Neurons
Neurotrophic factors, such as nerve growth factor (NGF), have been shown to regenerate and/or restore neuron function. Threeclinical-stage programs are using direct formulations of NGF itself. Another drug candidate activates hepatocyte growth factor(HGF) to stimulate regeneration, while a fifth therapeutic in this sub-group is a truncated version of motoneuronotrophic factor(MNTF), which is believed to work on a broad range of receptors to promote neuronal survival. Four of these five programs arein Phase I, as shown in Figure 2c.
Three additional Phase II drug programs aim to regenerate neurons through different mechanisms. One drug candidate acts onsigma-1 receptors with high affinity, functioning as a neurotrophic and neuroprotectant.30 Another Phase II program in this subgroup is an extract from mastic gum (Pistacia lentiscus) believed to promote neuro regeneration. This is one of the few drugs in
the Alzheimer’s disease pipeline without a specific target. Lastly, a blood plasma fraction from young donors, containing a mixtureof proteins and possibly growth factors known to regenerate neurons, was included in the neuro-regeneration category.
Four cell therapies are also included in this approach as they can supply neurotrophic factors or can be used to replace
dysfunctional neurons. These clinical-stage cell therapies are created from adult human bone marrow mesenchymal stem cells(MSCs, n=2)), placenta-derived stem cells (n=1), and adipose-derived stem cells (n=1).

Strategy #4 – Reversing Neuroinflammation
Over the last decade, significant evidence supports a strong inflammatory contribution to the etiology of Alzheimer’s disease. 31
There are currently seven drug programs directly targeting inflammatory processes. Interestingly, none of the molecular targets
in these programs target the same inflammatory signaling pathways.
Three anti-inflammatory drugs target cytokine signaling, release, or overall dampening of cytokine effects on microglial cells,
mast cells, or macrophages, for example, by targeting signaling kinases in the TNF or other inflammatory pathways. Anotherfour drugs work by inhibiting activation or recruitment of microglia cells or macrophages, resulting in an overall decrease inneuroinflammation.

Strategy #5 – Targeting Epigenetic Modification
Post translation modification of DNA binding proteins may also play a role in the regulation of genes involved in many of thepathways discussed above.32,33 For example, sequencing the brains of Alzheimer’s disease patients has revealed highly acetylated
histones binding to areas of the genome associated with amyloid processing and clearance.34 Once acetylated or methylated,histones in promoter regions may reduce or enhance gene expression. Histone methyltransferase and acetyltransferase (HMTsand HATs) are responsible for adding extra carbons to histones, whereas histone deacetylases and demethylases (HDACs andHDMs) remove them. Thus, all four histone modifying enzymes types could be drug targets within the epigenetic approach.
The current clinical pipeline contains three epigenetic programs. One targets a specific HDM, and simultaneously, monoamineoxidase. In preclinical studies, the drug candidates reduced memory loss and neuroinflammation.35 A second clinical programis a combination drug, containing a pan HDAC inhibitor plus a bile acid that may serve as a mitochondrial membrane protectant.
There is preclinical evidence showing histone deacetylase inhibitors can reverse Alzheimer’s disease in mouse models.36 Lastly,
there is a drug in Phase I targeting bromodomains, regional modules in chromatin-associated proteins and enzymes (such as
HATs) that can bind acylated areas of histones.
		 Yano, T., et.al. Sigma-1 receptor is a molecular target for novel neuroprotectant T-817MA. Alzheimer’s & Dementia, 11(7) p861 (2015)
		 Glass, C., et.al. Mechanisms Underlying Inflammation in Neurodegeneration. Cell 1406, p918-934 (2010) and McCaulley, M., et al. Alzheimer’s Disease: Exploring theRole of Inflammation and Implications for Treatment. Int J Alzheimer’s Disease, ID515248 p.1-10 (2015)32
		 Fischer, A. Targeting histone-modifications in Alzheimer’s disease. What is the evidence that this is a promising therapeutic avenue? Neuropharmacology 80
p95-102 (2014). (There are two main epigenetic regulatory systems that cells use to control gene expression without any change in the genes themselves: histone
modifications described here, and direct DNA medication via methylation. In addition to the histone modifications described above, other modifications exist andcould be the target for future epigenetic drug discovery: ADP-ribosylation, ubiquitination, citrullination, and phosphorylation.)
33
		 Fischer, A., et al. Targeting histone-modifications in Alzheimer’s disease. What is the evidence that this is a promising therapeutic avenue? Neuropharmacology,
80, p95-102 (2014)34
		 Marzi, S. et al. A histone acetylome-wide association study of Alzheimer’s disease: neuropathology associated regulatory variation in the human entorhinal cortex.
Nature Neuroscience, 21(11), p1618-1627 (2018)35
		 Company press release (2018)36
		 Cuadrado-Tejedor, M., et al. A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in
Alzheimer’s Disease Mice. Neuropsychopharmacology, 42(2) p.524-539. (2017)30
31

10 | BIO Industry Analysis

Strategy #6 – Targeting Metabolic Pathways
Glucose and ketones are essential for energy utilization in the brain. Dysfunctional glucose or ketone metabolism has beencorrelated with neurodegeneration and could be a precursor to other pathologies such as inflammation, protein plaque buildup,
and oxidative stress.
Two drugs in Phase II approach the glucose utilization issue in the context of Alzheimer’s disease. One drug does this by selectively
agonizing PPAR delta, a key nuclear receptor that regulates genes involved in glucose energy expenditure and other metabolicallypathways. The other program is a delivery system for insulin that may increase brain exposure to the peptide. A third drug indevelopment using a metabolic strategy for treating Alzheimer’s is a purified fatty acid that can be converted to ketone bodies
and thus used as an alternative energy source for brain cells with defective glucose metabolism.

Strategy #7 – Targeting Glucocorticoids
High levels of glucocorticoids over long periods of time have been linked to cognitive decline.37 Studies have shown a strong
association between plasma cortisol levels and amyloid β levels.38 One strategy employed by drug developers to address thisimbalance has been to block cortisol production in the brain. Two clinical-stage drugs do this through inhibiting a key enzyme
involved in cortisol synthesis, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).39

Strategy #8 – Targeting Oxidative Stress
The human brain consumes a large portion of the total oxygen inhaled, with 98% of it used by the mitochondria for energy
production. However, some of the remaining 2% can lead to reactive oxygen species (ROS) that, if misregulated in the aging
brain, can lead to unstable forms of free radicals. The imbalance of natural antioxidant mechanisms has been shown to play avital role in the pathophysiology of neurodegenerative diseases, as excessive generation of ROS can lead to direct, lipid, protein,
and DNA damage.40
There is currently one drug candidate in Phase I targeting ROS through inhibition of microsomal prostaglandin E2 synthase-1.
Preclinical work with this compound showed a suppression of neuronal loss in mice models of Alzheimer’s disease.41

Strategy #9 – Targeting Infectious Agents
Bacteria and viruses can enter then brain and either inflict direct damage or elicit an immune response that could itself impose
damage to neurons or neighboring cells. There is only one clinical-stage product being tested that targets infectious agents, anantibacterial drug. Preclinical evidence shows a correlation between periodontal (gum) disease caused by certain bacteria and
Alzheimer’s disease.

Strategy #10 – Targeting the Epichaperome
A more recent hypothesis behind the cause of neuron malfunction is the dysregulation of the epichaperome, a protein complex
made of molecular chaperones and other co- factors. There are now more than 300 chaperones and co- factors known toassociate with the epichaperome complex, expanding the target universe for this approach.42 As the chaperome system plays
a role in disaggregating proteins, one of the primary correlating factors found in Alzheimer’s patients, it has been the subject ofdrug research. Currently, there is one epichaperome drug in Phase I. Preclinical studies with the drug demonstrated tau reduction.

		 J. Neuroscience. 26(35) p9047–9056 (2006)
		 Pietrzak, P., et.al. Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study BiologicalPsychiatry: CNNI 2 p45–52 (2017)39
		 Sooy K., et al. Cognitive and Disease-Modifying Effects of 11β-HSD Type 1 Inhibition in Male Tg2576 Mice. Endocrinology, 156(12) p4592-603 (2015)40
		 Hueng, W., et al. Role of oxidative stress in Alzheimer’s disease. Biomed Rep. 4(5) p519–522 (2016)41
		 Baek, I., et al. AAD-2004 Attenuates Progressive Neuronal Loss in the Brain of Tg-betaCTF99/B6 Mouse Model of Alzheimer Disease. Exp Neurobiology
22(1) p31–37 (2013)42
		 Joshi, S. et al. Adapting to stress — Chaperome networks in cancer. Nature Reviews Cancer, 18 p562–575 (2018)
37

38

BIO Industry Analysis | 11

Modalities in the Clinical-Stage Pipeline
Modalities under development for disease-modifying Alzheimer’s programs are weighted toward small molecules, at 53% of
the pipeline, as shown in Figure 3. Although this makes intuitive sense as small drugs can be designed with greater accessibility
to regions of the brain enclosed by the blood brain barrier, it should be noted that more than half of the overall industry pipeline
is comprised of small molecules. Almost a third of the drugs in the Alzheimer’s clinical pipeline are proteins (such as antibodies
or smaller peptides). There are four cell-based therapies and one antisense drug. The eight vaccines in the clinical pipeline are
split between cell-based (n=4) and peptide-based (n=4).
2019 ALZHEIMER’S DISEASE PIPELINE BY MODALITY

Cellular
10%

Vaccine Antisense
1%
5%

Protein
31%

Small
Molecule
53%

Figure 3. Breakdown of modalities in the current disease-modifying Alzheimer’s disease clinical pipeline.

Preclinical Pipeline
To predict what may enter the clinical pipeline soon, we examined novel preclinical disease-modifying Alzheimer’s diseaseprograms in the Biomedtracker databases and recently published literature. We found that 23 of the 102 preclinical programs
listed had unique targets not currently in the clinic, indicating further advances may be on the horizon. The mechanistic strategies
are quite varied within the 23 new targets, including caspases, different growth receptors, inflammation factors, kinases, andmodified blood proteins that may restore or protect neuronal function. Sixteen of the preclinical programs had unknown mechanisms.

12 | BIO Industry Analysis

Clinical Development Success Rates for Novel Alzheimer’s
Disease Drug Programs
The clinical trial success rates for Alzheimer’s disease drug candidates were found to be lower than what is observed acrossall disease areas combined, except for those Alzheimer’s disease therapies that advance to Phase II. Based on data obtained
from the Biomedtracker database and annotating for disease-modifying programs only, 139 advanced or suspended programs
were analyzed over the period January 2008 through January 2019.43 As shown in Figure 4, no disease-modifying Alzheimer’s
drug development program has been successful in Phase III. Drug development programs in Phase I had a 47% chance oftransitioning to Phase II, vs. the industry average of 59%. However, the chance of transitioning to Phase III was higher than theindustry average: 36% chance of transitioning from Phase II to Phase III vs. 31% for all diseases.

Probability of Success

CLINICAL DEVELOPMENT SUCCESS RATES FOR ALZHEIMER’S DISEASE DRUGS 2008-2019
59%

57%
47%

31%

36%

0%
Phase I

Phase IIAll Diseases

Phase III

Alzheimer's Disease

Phase of Program Suspension
Strategy

Phase I

Phase II

Phase III

Total

Amyloid pathway

30

13

9

52

Tau pathway

4

2

0

6

Neuroinflammation

3

2

2

7

Metabolic pathway

2

2

2

6

Neuro-regeneration

0

4

1

5

Antioxidant

1

2

1

4

Glucocorticoid

0

3

1

4

Calcium channels

0

1

1

2

Unknown

1

0

0

1

Total

41

29

17

87

Figure 4. Clinical success rates for all Alzheimer’s disease indications compared to success rates for all other disease areas combined,
January 2008 through February 2019. Data for Alzheimer’s Disease is based on approximately 139 drug program transitions in the
Biomedtracker database. Right: Suspended programs since 2008 are listed by phase and the strategy pursued for the failed drug program.
Under glucocorticoids, although this is primarily cortisol targeting in the current pipeline, we include neurosteroids (such as DHEA
derivatives) in this category.

		 Prior study on success rates, (Thomas, D., et al. BIO, BioMedtracker, Amplion. Clinical Development Success Rates 2006-2015 (2016)) can be accessed at www.bio.
org/iareports), showed success rates from Phase I to approval at 9.6% for all diseases.

43

BIO Industry Analysis | 13

Analyzing clinical programs that were active at any point during January 2008 to February 2019, we found 87 suspended clinicalprograms. Note that this is different from individual clinical trial failures and encompasses complete program shut downs. Thisis significant for Alzheimer’s R&D because individual drugs can fail late-stage dementia and move to mild or moderate, or even
“Preclinical” stage (pre-dementia) clinical trials, adding to the total development cost and time. Indeed, some currently active
programs have failed multiple trials but are not yet suspended. This indicates that the number of trial failures is much higher
than suspensions over the time period examined.
Examples of failed programs within individual strategies are numerous, but many strategies continue to be pursued even after
multiple failed programs. In the case of the amyloid strategy, although 52 suspensions have been recorded since January 2008,
there are currently 33 clinical-stage amyloid targeted programs ongoing (Figure 2a). This illustrates both the conviction behindscientific evidence pointing to the role of amyloid in the disease pathogenesis, but also speaks to the number of ways to target
the amyloid pathway as discussed above. For example, the antibody approach for binding amyloid has multiple epitopes andconformational states that can be targeted, possibly with varying impacts on the disease.44 Within the 52 suspended amyloid
programs, eight have failed in Phase III, suggesting a significant amount of investment dollars consumed by these efforts as
Alzheimer’s trials for Phase III programs tend to be relatively large (compared to cancer Phase III studies for example).
In addition, different modalities, from small molecules to nucleic acid-based drugs and cell therapies, can be tested for a single
target. For example, 14 small molecules targeting beta or gamma secretase are found within the suspended amyloid program
list. Although this certainly does not support the preclinical evidence behind shutting down or altering APP processing, otherroutes of slowing APP may be physiologically more conducive to the final objective of showing clinical benefit, and thus wecannot rule out this strategy.
There is only one suspended strategy in the time period studied that is no longer in clinical development: The Calcium channel
hypothesis. One of these was a repurposed drug program of an approved calcium channel blocker approved for treating
hypertension. Like other repurposed drugs in Alzheimer’s, although showing hints of activity in preclinical models (even antiinflammatory and anti-tau activity) this program did not succeed in late-stage studies. A novel calcium channel blocker also
failed at Phase IIb.
Certain sub-strategies are now no longer pursued after clinical development setbacks. For example, the “metal ion hypothesis”
is no longer in the current clinical pipeline. Metals (iron, copper, manganese, aluminum, and zinc) could serve as beneficial
antioxidants as cofactors in metalloproteins involved in neuronal metabolism. However, they have also been proven in thelaboratory setting to have negative effects such as binding to amyloid directly and facilitating accumulation. In clinical practice,
removing excess metal ions has not shown significant benefit. Regardless, there are still supporters of this hypothesis.45
Other targets that were suspended but not in the current clinical pipeline include RAGE, NFKB, RIPK1, Lp-PLA2, GnRH receptors,
GDNF, casein kinase, glycogen synthase kinase (GSK), HMG CoA reductase, eicosanoids, mTOT, and calpain. Targets withsuspended histories but still under clinical investigation include amyloid and tau pathways, microtubules, sigma receptors, NGF,
11ß-HSD, and PPAR.

		 Panza, F., et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nature Reviews Neurology, 15 p73-88 (2019)
		 Mirza A, et al. Aluminum in brain tissue in familial Alzheimer’s disease. J Trace Elem Med Biol. 40 p30-36 (2017)44
45

14 | BIO Industry Analysis

Trends in Venture Investment and Clinical Trial Initiations in
Alzheimer’s Disease
We calculated venture funding for private companies with lead compounds in Alzheimer’s Disease for each year over the last
decade. A more comprehensive method for assessing investment across the industry, based on quantifying the number ofclinical trials starts, is also presented below.
2008-2017 VENTURE INVESTMENT INTO U.S. COMPANIESWITH LEAD NOVEL DRUG PROGRAMS IN ONCOLOGY VS. ALZHEIMER’S DISEASE$2,000$1,500

2018
2018

2017
2017

2016
2016

2015
2015

2014
2014

2018
2018

2017
2017

2016
2016

2015
2015

2014
2014

2013
2013

2012
2012

2011
2011

2010
2010

$0

2013
2013

$1,000
$500
2011
2011

$1,000$500$3,000$2,5002010
2010$2,000$1,500$4,000$3,500

2009
2009

Total
Total Invested
Invested ($M)($M)

$3,000$2,500

2009
2009

Total
Total Invested
Invested ($M)($M)

$4,000$3,500$0Alzheimer’s$5,000$4,5002012
2012

Oncology$5,000$4,500Figure 5. Left: Venture funding of companies with lead products in oncology, 2009-2018. Right: Venture funding of companies with leadproducts in Alzheimer’s disease, 2009-2018.

As can be seen in Figure 5, venture investment into U.S. companies with lead Alzheimer’s disease programs from 2008 to 2017
totaled $741 million. This is 16 times less than the funding received for novel oncology drugs ($12.2 billion) during the period from2008 to 2017. Nine companies with lead Alzheimer’s disease drugs were financed each year, on average. By comparison, there
were 79 oncology companies financed each year, on average, suggesting that early-stage investors currently prioritize otherdisease areas, such as oncology, over Alzheimer’s disease.
The above methodology, whereby lead asset is used as a proxy for private investment, tends to underestimate venture dollars
ultimately used for Alzheimer’s disease R&D in small companies. Although most capital will tend to be used for the lead asset,
this is not always the case, and precise data on internal R&D spending per project is not available. Thus, some companies withlead drugs in Parkinson’s, ALS, and other related neurologic diseases may in fact have earlier stage programs in Alzheimer’s
disease. Using the broader Neurology disease area excluding pain, we still get $3.4 billion for Neurological diseases versus $12.2
billion for cancer.

BIO Industry Analysis | 15

We also use a method for approximating broader industry R&D investment activity (combining small, midsize, and large publiccompanies and private biopharmaceutical companies) and the annual level of funding for private emerging biotech companies.
This requires the use of the TrialTrove database, which tracks clinical trial start dates by indication. From 862 Alzheimer’s trial
starts, we categorized trials for novel drugs, vs. nonintervention trials, reformulations, combinations of older drugs and otherduplicate trials per phase, identifying 170 novel drug intervention trial starts over the 10-year period.
2008-2017 CLINICAL TRIAL STARTS FORALZHEIMER’S DISEASE DRUG INTERVENTION TRIALS

Alzheimer's Trial Starts for Disease
Modifying Novel Drugs

25
1

20
2
15

2
7

8
1
3

10
5
0

5

1

10

10

8

8

8

6

9

4
5

4

2

12

2
6

3
12

8

8

7

8

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
Phase I

Phase II

Phase III

Figure 6. Clinical trial starts for novel drugs for Alzheimer’s disease, 2008-2017. TrialTrove data accessed October 2018. A total of 862
clinical trial starts were retrieved from TrialTrove. Trials were individually assessed for disease modifying vs. symptom modifying drugs
and trial phase cohorts de-duplicated. A total of 170 novel drug intervention trials were initiated during this time period.

As shown in Figure 6, clinical trial starts involving potential disease modifying Alzheimer’s disease drugs remained in a rangeof 11-21 starts per year, with the average being 17, over the last decade. Two of the highest years of trial initiation were in 2015 and2017, with the two lowest years in 2010 and 2014.
Trials were also grouped by phase in Figure 6. Phase I trial initiations for disease modifying drugs have been constant over thelast decade, but low in volume (ranging from 7-12 per year). Phase II and Phase III trial starts have been less consistent, ranging
from 3-12 and 0-5 per year, with no detectable trend.

16 | BIO Industry Analysis

Discussion
Alzheimer’s disease in elderly populations of both developed and developing nations is growing. Along with the hardship ofcaring for patients, the staggering economic costs that nations will be facing over the next few decades are unprecedented.
Solving for this coming crisis should be front and center of policy initiatives aimed at reducing future economic societal burden.
It is likely that the hope for change comes in the form of therapeutic interventions to stop the progression of this disease, but
this will require a fully functional, seamless ecosystem of regulators, industry, patients and academia.
Unfortunately, to date there has yet to be a disease-modifying pivotal program that has transitioned to NDA/BLA filing. In thecurrent clinical-stage pipeline we found 74 drug programs with disease-modifying potential for Alzheimer’s in Phase I-III. This
compares to a report published by Cummings, J., et al. that found 70 disease-modifying therapies in the January 2018 pipeline. 46
This total number remains below the number of novel clinical programs in a single sub-indication for oncology. For example,
breast cancer has 158 active, novel clinical development programs, lung cancer has 180, and leukemias have 211 – each well
above the total of 74 found in the Alzheimer’s disease clinical pipeline for disease-modifying agents.47
Although there could be more shots on goal, the fact that there are 10 differentiated approaches and more than 30 moleculartargets in the clinic, offers hope. To deliver on these and beat historical odds, creative solutions are required during the development
lifespan. Coordinated dialogue between stakeholders will help optimize development programs that aim to make meaningful
differences in patient’s lives. For example, academic and industry findings have helped inform the recent modernization of the
FDA’s endpoint guidelines in Alzheimer’s trials.48 As our scientific understanding of the disease evolves, so must the way wedevelop drugs. Policies supporting efficient and effective regulatory environments will encourage investments into new treatments.
For example, expanded utilization of biomarkers to stratify patient populations to better predict what treatments work best,
and when and for whom they work best, would serve to incentivize innovation and change the paradigm of how we treat thiswidespread disease.
Meanwhile, more effort upstream is still needed. Continued funding of basic research to advance our understanding of thebiology of Alzheimer’s disease will arm drug developers with new targets and approaches to attack this complex disease.
Although we now have identified multiple players in the etiology of the disease, the exact detailed molecular mechanism behind
Alzheimer’s remains unknown. Many therapies found to be very effective in animal models, and even some with promising Phase
II results, have failed to show significant effects in statistically rigorous trials. To find the right intervention may require morepredictive animal models and more advanced biomarkers. Although a few biomarkers for Alzheimer’s have been established,such as the CSF measurement for amyloid and tau, or via PET scans with tracer agents, more biomarkers for early-stages ofthe disease are needed.49,50
All of this will require more funding. Fortunately, there has been a substantial increase in government funding for Alzheimer’s
research in recent years. The U.S. National Institute of Health has seen a tripling of its budget from Congress over the last three
years for Alzheimer’s and related dementias. Much of this increase, to $1.9 billion in 2018, is for exploratory research grants
funded via the National Institute on Aging (NIA).51 A few venture capital-backed Alzheimer’s focused start-ups have also launchedin the last few years. Although dwarfed by levels seen in oncology (by 16x), the venture funding trend is upward and small emerging
companies now account for 77% of all Alzheimer’s clinical programs. Other sources for basic research funding are also trending
up. For example, The Bill and Melinda Gates Foundation and other family office investors have recently added $30M to the
Alzheimer’s Drug Discovery Foundation, while the American Association of Retired Persons (AARP) has recently added $60
million to the Dementia Discovery Fund.52
The Biotechnology Innovation Organization (BIO) and member companies view innovation as the key to helping patients with
Alzheimer’s disease. Advancements in science, more choices for patients, and a policy environment that stimulates investment
in R&D are necessary to achieve this goal.

		 Cummings, J., et. al. Alzheimer’s disease drug development pipeline: 2018. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 p195-214 (2018)
		 Data for oncology R&D pipeline is taken from the Biomedtracker database, NMEs and novel biologics only, and current as of January 2019. A total count by disease
area can be found in Thomas, D., Wessel, C. BIO Industry Analysis. Emerging Company Trend Report, (2018) (www.bio.org/iareports)48
		 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf
49
		 Aisen, P., Cummings, J., et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimer’s Research & Therapy, 9 (60) (2017).
50
		 https://www.scientificamerican.com/article/better-biomarkers-could-help-us-treat-alzheimers/
51
		 https://www.sciencemag.org/news/2018/08/alzheimer-s-gamble-nih-tries-turn-billions-new-funding-treatment-deadly-brain-disease52
		 https://www.aarp.org/health/dementia/info-2018/aarp-investment-dementia-alzheimers.html and https://www.gatesnotes.com/Health/A-better-way-of-diagnosingAlzheimers (accessed February 2019)46
47

BIO Industry Analysis | 17

Appendix
Marketed Drugs for Alzheimer’s Disease
There are four active compounds on the market that treat symptoms of Alzheimer’s disease, such as mental alertness anddepression. However, as of this writing, there are no disease-modifying therapeutics FDA approved for Alzheimer’s disease.
Three of the four active substances marketed for Alzheimer’s are cholinesterase inhibitors that work primally through stabilizing
the acetylcholine neurotransmitter levels by slowing its breakdown. It has been known for more than 30 years that a breakdownin highly cholinergic neurons is associated with Alzheimer’s. Numerous drugs have been in development targeting choline
acetyltransferase or acetylcholinesterase under this “Cholinergic Hypothesis”, but they have not been as useful in earlier stagesof the disease. The fourth compound marketed (memantine) is an N-methyl-D-aspartate (NMDA) antagonist which acts toblock overactive functioning, or toxicities, related to of the neurotransmitter glutamate.

Clinical-stage drug programs with symptom-modifying potential in Alzheimer’s disease.
SYMPTOM-MODIFYING CLINICAL PIPELINE FOR ALZHEIMER’S
Strategy

Phase I

Phase II

Phase III

Total

Acetylcholine

9

4

1

14

Monoamine

4

4

4

12

Glutamate

3

1

0

4

Synaptic function

3

2

0

5

Cannabinoid receptors

0

2

0

2

GABA

0

1

0

1

Glutamine

1

0

1

2

Circadian

0

2

0

2

Unknown

4

0

0

4

Total:

24

16

6

46

TOTAL ALZHEIMER’S PIPELINE
Category

Phase I

Phase II

Phase III

Total

Symptom Modifying

24

16

6

46

Disease Modifying

27

34

13

74

Total:

51

50

19

120

A1. Clinical-stage drug programs with symptom-modifying potential in Alzheimer’s disease, as well as the total Alzheimer’s pipeline.

18 | BIO Industry Analysis

Authors
David Thomas, CFA
Vice President, Industry Research
Biotechnology Innovation Organization (BIO)
dthomas@bio.org

Chad Wessel
Senior Manager, Industry Research & Policy Analysis
Biotechnology Innovation Organization (BIO)

Acknowledgements
We would like to acknowledge BIO staff (Cartier Esham, Danielle Friend, Sesqui Ramon) for their editorial review of this report.

BIO Industry Analysis | 19

www.bio.org/iareports

20 | BIO Industry Analysis