Investigational drugs in Alzheimer's disease: current progress.

Review

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Southern California on 04/05/14 For personal use only.

Investigational drugs in Alzheimer’s disease: current progress 1.

Introduction

2.

Amyloid-based approaches

3.

Metabolic approaches

4.

Anti-tau approaches

5.

Multitarget approaches

6.

Conclusion

7.

Expert opinion

Camryn Berk, Gaurav Paul & Marwan Sabbagh† †

Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, Sun City, AZ, USA

Introduction: Alzheimer’s disease is a progressive neurodegenerative disorder affecting millions of people worldwide. Yet, this disease is presently incurable and treatable only in terms of modest delay of symptomatic progression. The need for more effective pharmacological intervention is becoming more pronounced as the patient population increases. Areas covered: This paper outlines and evaluates the current landscape of interventions in early phases of clinical study. Data and analysis for this review were procured from PubMed, clinicaltrials.gov, review of posters, abstracts and presentations from American Neurological Association, American Academy of Neurology meetings, Alzheimer’s Association International Conference and Clinical Trials on Alzheimer’s disease. Keywords and criteria searched included: Phase 0, I, and II trials related to Alzheimer’s disease, amyloid-b, anti-tau, monoclonal antibodies and metabolism. Expert opinion: The development of novel pharmacological interventions would be more fruitful if multitarget therapies were introduced, and unexplored mechanisms of action were expanded upon. Additionally, there is a rationale for intervening earlier in the disease, perhaps preceding or at the advent of symptoms. Keywords: Alzheimer’s disease, amyloid, clinical trials, drugs Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

Alzheimer’s disease is a progressive neurodegenerative disorder marked by a complex pathobiology, challenges in procuring an accurate diagnosis and distinct lack of a disease-modifying treatment. Pathologic signifiers of Alzheimer’s disease include aggregations of amyloid-b plaques and neurofibrillary tangles composed of highly phosphorylated tau proteins, but prior to end-stage illness, the defining characteristic is cognitive decline and associated dementia for a period ranging from years to decades before death. In the USA alone, thousands of new cases of Alzheimer’s disease are diagnosed each year with a projected increase to 13.2 million cases by 2050 [1]. In addition to dementia, other symptoms include erratic changes in mood, personality changes, increased agitation, psychosis, loss of circadian rhythm and physical wasting [2]. A suspected Alzheimer’s disease diagnosis is problematic not only for a patient but also for their families, caregivers and health communities in terms of the financial and social costs of managing the disease from diagnosis to end stage. At present, only symptomatic drug therapies have been approved by the FDA in the USA and the EMA in Europe for treating Alzheimer’s disease; patients with mild-to-moderate disease can be treated with cholinesterase inhibitors (ChEIs), and patients with moderate-to-severe disease can be treated with either memantine, an NMDA receptor agonist, or donepezil, a ChEI [3]. These are essentially symptomatic 10.1517/13543784.2014.905542 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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Many non-amyloid based approaches being developed there is increased interest in anti-tau and metabolic approaches. Novel anti-amyloid approaches being developed.


This box summarizes key points contained in the article.

treatments that neither stop decline nor repair neuronal damage. Because of the burgeoning population of afflicted patients, the significant burden this disease brings to their wider support networks, and the complete dearth of treatment options with any curative efficacy, the hunt for successful drugs to treat Alzheimer’s disease has never been more pressing. Compounding the issue of a lack of novel treatment options beyond ChEIs and memantine is the fact that the pathology of Alzheimer’s disease is insufficiently understood. Postmortem Alzheimer’s disease diagnosis generally relies on the presence of amyloid-b plaques aggregated in the brain and neurofibrillary tangles, and although it is definitive that a density of amyloid aggregates is associated with the presence of cognitive symptomology, there is a lack of strong clinical evidence for a causal relationship as opposed to amyloid deposits being the result of other causal factors. In addition to amyloid-b proteins, there are a variety of other biological indicators that are related to Alzheimer’s symptoms. Tau proteins are a category of microtubule-associated proteins that promote stability when functioning typically; defective tau proteins are correlated to neurological abnormalities. Antiamyloid and anti-tau approaches focus on the presence of potentially causal disease contributors, where the ideal therapy would remove them from the CNS into the periphery to be dissolved, whereas metabolic approaches focus on the decrease of absence of desirable biological actors such as glucose in the CNS that can precede cognitive decline. Estimating effects on biomarkers can be an indicator if a therapy is having any sort of physiological effect. Measuring for these targets in cerebrospinal fluid (CSF) can be an indicator of proteins being removed from the brain, but not necessarily that they are being degraded and removed from the body overall. Increasing the glucose in CSF could mean that more is crossing the blood--brain barrier to be metabolized. At present, part of the problem related to finding disease-modifying treatments for Alzheimer’s disease is the difficulty in specifying the relationships between disease corollaries, symptomatic effects, clear diagnostics in living patients and damage reversal. Because of all those factors, therapies that target more than one of the aforementioned pathways could be a faster way to an effective treatment than the single target drugs that have been most common in recent clinical trials. Until recently, the pharmacological focus for development was the amyloid-b hypothesis, or the idea that decreasing amyloid-b protein load in patients could have an ameliorating effect [4]. The high-profile failure of several amyloid clearance 2

therapies within the last 2 years has dramatically broadened the landscape of pathways that are under investigation and the therapeutic mechanisms therein. The focus of this paper is to examine both the novel pathological models currently being explored in early-stage clinical trials and the individual experimental treatment options designed to alter disease course by manipulating the aforementioned pathways in a variety of ways. 2.

Amyloid-based approaches

BMS-708163 BMS-708163, also known as Avagacestat, is a g-secretase inhibitor that was recently discontinued in Phase II. In Phase I trials, BMS-708163 decreased amyloid-b 40 and 42 in CSF by 30% for lower doses and 60% for higher doses; however, in a trial of 209 patients in 5 dosage groups (25, 50, 100, 125 mg/day and placebo) equal numbers of patients discontinued in the treatment cohorts compared with placebo. Additionally, patients on higher dosages indicated a faster cognitive decline compared with lower dosages and the placebo, causing the discontinuation of any development for this drug [5]. 2.1

EHT 0202 EHT 0202, also called Etazolate, is hypothesized to stimulate the a-secretase pathway while inhibiting amyloid-b-induced neuronal death. By redirecting amyloid precursor protein (APP) processing away from amyloid pathways, this is supposed to both reduce symptoms and slow down/stop disease progression. This drug showed only ‘precognitive’ properties in rodent trials but is undergoing human safety studies to investigate potential viability as a supplement to standard treatments, even though it is not suitable as a singular therapy in and of itself. This drug is currently in Phase II testing [6]. 2.2

MABT102A Also known as Crenezumab, MABT102A is a form of passive immunotherapy. MABT102A is a humanized monoclonal antibody designed to bind to human 1 -- 40 and 1 -- 42 amyloid-b in the brain and remove it to the periphery. In addition to Phase II testing, this drug will be evaluated in a trial against placebo for the prevention of cognitive decline in presymptomatic carriers of autosomal dominant genetic mutations. It was proven to be safe in Phase I trials, and Phase II trials have been completed for treatment of mild-to-moderate Alzheimer’s disease [7]. 2.3

Varenicline Nicotine agonists have been explained as potential treatments for Alzheimer’s disease because they represent good surrogates of acetylcholine and have good CNS penetration. Also known as Chantix, varenicline binds to a4b2 receptors; it was hypothesized that this drug could stimulate the receptor without acting as a total nicotine ligand producer, but in a 6-week 2.4

Expert Opin. Investig. Drugs (2014) 23(6)

Investigational drugs in Alzheimer’s disease: current progress

Phase II trial, it was found that varenicline does not improve cognition in nonsmokers and it does increase neuropsychiatric events, including suicidal ideation. This drug was discontinued in Phase II for Alzheimer’s disease treatment but is currently approved by the FDA to aid in smoking cessation [8]. ACC-001 This drug underwent multiple trials in Phase II. ACC-001 is an inactivated diphtheria toxin vaccine capable of crossing the blood--brain barrier. More specifically, it is a form of active immunotherapy, designed to recognize amyloid-b as an epitope and stimulate the immune system to recognize amyloidb as an antigen. It was hypothesized that ACC-001 would act directly on the CNS to clear plaques, but without also administering an adjuvant a strong antibody response was not observed. In late 2013, the manufacturer announced it was discontinuing development of this drug [9]. This is the latest attempt on active immunization, since AN-1792 was developed as an active immunotherapy and its development was halted because of adverse side effects, such as encephalitis [10].


2.5

Affitope AD02 This drug is a synthetic peptide composed of six amino acids designed to allow for the production of amyloid-b antibodies without triggering an inflammatory response. The Phase I safety study showed a favorable profile for both safety and tolerability after 1 year. Phase II trials of Affitope AD02 are currently underway, with results expected in 2014 [11].

Thalidomide Thalidomide is a TNF-a inhibitor. It is one of the main proinflammatory cytokines and is necessary to maintain an inflammatory response [15]. When inhibited by a drug-like thalidomide, the inflammatory response is limited. In animal models, thalidomide effectively suppresses the effects of amyloid-b related to memory, has a neuroprotective effect, reduces microglia numbers and increases neuronal viability in the dentate gyrus. Thalidomide has been approved to treat inflammatory diseases and multiple myeloma, and although its effect on neurodegenerative disorders is not yet clear, thalidomide apparently significantly reduces amyloid-b load and plaque formation in animal models. It is currently in Phase II trials [15]. 2.9

TC-6683 An a4b2 nicotinic receptor activator, this drug was hypothesized to activate the a4b2 nicotinic receptor to enhance the release of acetylcholine; although agonist binding to a4b2 nAChR has been shown to attenuate amyloid-b production in vitro, the Phase II trials for TC-6683 was terminated due to poor enrollment without results [16]. 2.10

2.6

CAD106 CAD106 is an active immunotherapy that recognizes the 1 -- 6 domain of amyloid-b. In animal studies, this antigen induces amyloid-b titers without activating amyloid-breactive T cells. Phase I results indicated that the therapy was well tolerated and allowed for antibody maturation. It is presently in Phase II trials [12]. 2.7

Simvastatin There are many statins on the market already approved for hypercholesterolemia and diabetic cardiomyopathy, but their potential for immunomodulatory effects warrants investigation for treatment of neurodegenerative disease as well. Hypothetically, the mechanism of action involves preventing g-cytokines from activating T cells and causing inflammation of neurons. Statins may also reduce myelin oxidation and decrease free radicals. The Cholesterol Lowering Agent to Slow Progression study was a research study to investigate the effectiveness of simvastatin to slow the progression of Alzheimer’s disease [13]. At the end of the study, simvastatin was no better than placebo in slowing the rate of cognitive decline; statins are in Phase II trials currently for Alzheimer’s disease [14]. 2.8

EVP-0962 Although technically an amyloid-related approach, EVP-0962 is a g-secretase modulator (in the same class as tarenflurbil) that decreases the generation of amyloid-b 42 in favor of shorter amyloid-b proteins while allowing for cleavage of the Notch substrate, preventing many of the toxic side effects typically associated with g-secretase inhibitors. In preclinical animal studies, this drug reduced amyloid-b 42, decreased neuroinflammation and lowered the hippocampal plaque load as well as reversed memory deficits in fear conditioning tests. At last report, EVP-0962 is in a single-center Phase II trial to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics [17]. 2.11

RO5313534 Also known as RG3487, RO5313534 is an a7 partial agonist with 5-HT3 receptor antagonist properties. In preclinical studies with age-impaired rats, RO5313534 improved object recognition, reversed spatial learning deficits and improved deficits in executive functioning tasks. Although RO5313534 was moved into a Phase II dose-ranging study with 389 mild-to-moderate patients to assess safety and efficacy, results were not made public and the study was discontinued. This drug was thereby rendered inactive in Phase II [18]. 2.12

TTP488 TTP488, formerly called PF-04494700, this drug is an inhibitor of receptor for advanced glycation endproducts (RAGE). Inhibiting RAGE from binding to ligands is an effective way to reduce toxic amounts of amyloid in the brain because amyloid would not be able to bind [19]. In a 2.13


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preclinical study done on mice, TTP488 was found to reduce the formation of amyloid-b plaque buildup [20]. In another preclinical study, which was done on mice that had excess APP, TTP488 was found to lower the amount of inflammatory markers and deposition of amyloid in the CNS after 3 months of treatment [21]. Phase I trials of TTP488 showed that in doses of 10 -- 60 mg, TTP488 was safe [21]. Phase IIa trials performed on individuals 50 years of age and older with an Mini Mental State Exam [22] between 12 and 26 showed that even after 10 weeks of treatment with TTP488, there was no significant reduction in the amount of amyloid-b found in the blood plasma [23]. Phase IIb trials performed on patients who had mild-to-moderate dementia used the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) as an efficacy measure, and at 18 months results showed that a low dose of TTP488 was statistically superior to the placebo group because the drop in ADAS-Cog was not as large [23]. High dosage of TTP488 was responsible for a large increase in cognitive decline with a significant drop in ADASCog, because those who stopped the high-dosage treatment showed a much slower rate of decline in the ADAS-Cog after [24]. FPS-ZM1 FPS-ZM1 targets the type V domain of RAGE, thereby not allowing amyloid to bind. In preclinical studies performed on mice, FPS-ZM1 was not toxic to mice and could cross the blood--brain barrier, thereby inhibiting the influx of amyloid-b proteins such as amyloid-b40 and amyloid-b42 by inhibiting RAGE [25]. By inhibiting these proteins, it allowed for suppression of microglia activation, which blocked a neuroinflammatory response [26]. By not allowing the neurofibrillary tangles to form, cognitive performance returned to normal and no toxic effects were reported in mice studies [27]. There have not been any clinical trials yet performed for FPS-ZM1. 2.14

3.

Metabolic approaches

Intranasal insulin Intranasal insulin is thought to have an effect on Alzheimer’s disease because of the various functions insulin has in the CNS. Insulin signaling is required for synaptic remodeling, and insulin also facilitates memory at high levels in normal metabolism. There is evidence that insulin dysregulation contributes to the onset of Alzheimer’s disease as insulin levels and activity is reduced in those who have Alzheimer’s disease [28]. Furthermore, insulin regulates the levels of amyloid-b in the brain and protects against the negative effects of amyloid-b oligomers on synapses [29]. By increasing insulin levels, all these processes should continue to work normally. Phase II trials showed that the levels of amyloid-b42 and amyloid-b40 did not change for the insulin-treated group, meaning results were inconclusive. Phase II trials are currently ongoing for intranasal insulin [30]. 3.1

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Deep brain stimulation Deep brain stimulation (DBS) is a therapy that targets various regions of the brain to try and halt the progression of memory impairment by implanting small electrodes that deliver electrical impulses. In preclinical studies, DBS was able to significantly increase nerve growth factor (NGF) levels in adult rats, meaning there could be a positive effect of DBS on Alzheimer’s disease. Phase II trials as of thus far have shown that using DBS in the hypothalamus/fornix area triggers the activation of neurons in the entorhinal and hippocampal areas, and positron emission tomography scans showed a reversal of the impaired glucose metabolism in the parietal and temporal lobes after 12 months of treatment with DBS. This means that DBS could be a possible treatment for patients with mild cognitive impairment. Phase II clinical trials are ongoing for DBS [31]. 3.2

Transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a therapy that uses electrodes to stimulate the CNS. It is a noninvasive, painless procedure in which an electromagnetic field that induces brain cortical excitability is created if applied repetitively. repetitive TMS (rTMS) has been thought to increase the plasticity of synapses in the brain. In preclinical studies, TMS helps the mechanisms that create memories work better. However, in Phase II clinical trials, high-frequency TMS elevates the amount of blood flow available to that part of the brain, whereas low-frequency TMS reduces the cortical excitability in that area. Therefore, high-frequency TMS shows promising results. Clinical trials are ongoing at present [32]. 3.3

CERE-110 CERE-110 is a gene therapy designed to circumvent the problem of the inability of NGF to cross the blood--brain barrier. This therapy targets basal forebrain cholinergic neurons to increase Ach production and prevent neuronal cell death. In preclinical studies, CERE-110 was shown to be effective in rats to both prevent cell death and reverse age-related cognitive decline. In addition to promising preclinical data regarding cognition, the safety profile for Phase I trials CERE-110 was excellent, with no adverse events reported. Currently, CERE-110 has moved into multi-centre Phase II testing with results expected in 2014 [33]. 3.4

Liraglutide Liraglutide is a glucagon-like peptide-1 agonist currently approved for the treatment of type 2 diabetes. The exact mechanism of action as a neurological agent is not clearly understood. Liraglutide could potentially act as a neurotrophic factor. This therapy could possess an NSAID-like capacity for reducing inflammation or facilitate neurogenesis or mitochondrial biogenesis. Although the exact channels through which it operates are not well understood, liraglutide has shown promising results in preclinical studies. When 3.5



peripherally injected, it can prevent memory impairments in animals, prevent synapse loss in the hippocampus and reduce soluble amyloid oligomers by 50 and 25%, respectively, as well as increase neuron numbers and decrease microglia. Because of the cognitive successes in the animal trials and a positive safety outcome in Phase I clinical trials, this drug is currently in Phase IIb testing for efficacy [34].


4.

Anti-tau approaches

Rember Also known by methylthioninium chloride, methylene blue or LMTX Rember is a drug that is believed to be an inhibitor of Tau protein aggregation. By being a tau aggregation inhibitor, Rember may be able to halt or reverse the progression of Alzheimer’s disease. Furthermore, it is able to enhance mitochondrial biochemical pathways and as such can activate and increase complex IV, which is correlated with Alzheimer’s disease when inhibited. In Phase IIB clinical trials, Rember was able to slow down the development of Alzheimer’s disease by 81% in patients. This drug is currently in Phase III trials [35]. 4.1

Epothilone D Also known as BMS-241027, epothilone D is presently undergoing Phase I trials for tolerability and efficacy following successful preclinical animal studies. BMS-241027 is unlike epothilone D compounds studied for application in oncology in that it can both cross the blood--brain barrier and is relatively safe. Epothilone D is a small-molecule microtubule stabilizer. Hyperphosphorylated tau dissociates from microtubules and is potentially related to neurodegeneration and cognitive decline, although no specific tau mutation is currently associated with Alzheimer’s disease. It is hypothesized that epothilone D will prevent this dissociation by stabilizing the microtubules [36], thus counteracting tau abnormalities. In animal experiments on mice expressing human mutant tau, epothilone D reduced hippocampal neuronal loss and restored spatial memory. In both young and old tauopathy animals wherein tau pathology was either developing or well established, epothilone D cleared tau pathology, curbed neuron loss and reversed behavioural as well as cognitive deficits. Additionally, epothilone D can be used in both preventative and interventional treatment depending on disease stage [37]. 4.2

T-817MA T-817MA is a Phase II neurotrophic/neuroprotective that prevents amyloid-b-induced cell loss in the dentate gyrus and increases hippocampal neurogenesis when intracerebroventricular ventricular infused. In animal studies with P301L mice displaying tau pathology, administration of T-817MA decreased spatial memory impairment, increased synaptic terminal density in the hippocampal gyrus, improved cognition and decreased tau-related neurodegeneration [38]. 4.3

5.

Multitarget approaches

Curcumin Currently in Phase IIb testing for Alzheimer’s disease, this therapy is a neuroprotective actor with anti-inflammatory, antioxidant and anti-amyloid mechanisms. In rats, curcumin decreased inflammation, oxidation rates, inhibited tau aggregation and was shown to clear AB plaques. Curcumin may also promote metal chelation and neurogenesis. Curcumin is a natural polyphenol that occurs in turmeric and has been used in traditional Eastern medicinal practice for centuries; as such, it has an unusually robust safety record [39]. 5.1

PBT2 PBT2 is a metal-protein attenuating compound in Phase II trials for Alzheimer’s disease but is also being investigated for applications treating Huntington’s disease. Potential mechanism of actions include oligomer formation inhibition, plaque disaggregation and AB toxicity neutralization. This drug is derived from a prior failure (PBT1) and showed significant improvement in decreased amyloid-b concentration and increased cognitive ability at the 12-week mark of a Phase IIa study. PBT2 is thought to reduce amyloid-b aggregation by reducing extracellular levels of metal ions associated with plaque formation [40]. 5.2

6.

Conclusion

Of the pathologies currently being investigated, amyloid-based approaches are the most numerous and consequently the most demonstrably likely to fail before reaching efficacy endpoints during clinical trial. Although anti-amyloid therapies are a well-established avenue for therapeutic experimentation, the relatively consistent failure to produce treatments that can influence disease pathology without significant toxicity indicates that the expansion of investigation into anti-tau and metabolic approaches is warranted. Because Alzheimer’s pathology is not clearly understood multitarget approaches that expand beyond the focus of merely decreasing amyloid-b protein loads increases the likelihood that an effective treatment can be found. 7.

Expert opinion

In recent years, the search for disease-altering drug therapy for Alzheimer’s disease has been typified by sensational Phase II trial results for treatments designed to ameliorate amyloid-b concentrations followed by a total lack of significant improvement over placebo control groups in Phase III trials. Among these high-profile failures are bapineuzumab, solanezumab, flurbiprofen and tramiprosate. Bapineuzumab exemplifies the trend; as a humanized monoclonal antibody that was designed to limit amyloid-b aggregation in the brain through passive immunotherapeutic binding and removal, bapineuzumab was extremely successful in Alzheimer’s disease model


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transgenic mice in terms of both decreasing amyloid-b accumulation and reversing cognitive decline [41]. During Phase II trials, ApoE4 noncarriers showed significant improvement in ADAS-Cog, NTB and CDR-SB scores, but the results of a broad-scale multi-centre Phase III trial showed no deviation from placebo for either ApoE4 carriers or noncarriers. In addition to having no statistically significant effect on any measure of cognition, there was no separation from placebo for any functional or behavioural performance [42]. Solanezumab is another example of an amyloid-affecting monoclonal antibody designed to bind amyloid-b monomers in the brain and allow it to be degraded in plasma and CSF. In Phase II studies, assay analysis showed that solanezumab effectively increased blood concentrations of amyloid-b 42, indicating that it was potentially removing peptides from the brain to increase the amount in the periphery [43]. In the Phase III trials that enrolled over 2000 subjects, which were randomized to monthly infusions of solanezumab or placebo, solanezumab was not significantly better than placebo on cognitive or functional endpoints and there was no evidence that peripheral amyloid-b was degraded even if cerebral concentrations were decreased. In prespecified post-hoc analyses, aggregating the studies and selecting mild cases of Alzheimer’s disease, solanezumab was significantly better than placebo on cognition at 18 months [44]. These data suggest solanezumab might be valuable as a therapeutic option, particularly because even when administered in very early disease stages, but the effect is likely to be modest. It is not clear that cerebral amyloid plaques are actually the cause of neuronal damage, but rather are just strongly associated with it. Immunotherapies are an avenue of research worth pursuing because of the possibility for manipulating the concentrations of disease-related peptides across the blood--brain barrier, which has been a problem for treatment. However, the recent failures of amyloid-related monoclonal antibodies highlight one of the most serious weaknesses in current Alzheimer’s research: the correlation between the pathological changes in the physicality of the diseased brain and actual effect on cognitive and functional abilities is not well understood. The presence of aggregated amyloid-b plaques is an undeniable hallmark of Alzheimer’s disease pathology, but what relation it has to disease course is elusive. The recent clinical focus on removal of amyloid-b aggregates in the brain is a reductive approach because, although it is known that patients who suffer cognitive decline and dementia as a result of Alzheimer’s disease have increased amyloid concentration, the role that amyloid-b plaques play in that process is not understood. Solanezumab was speculated as less robust because, although it could remove amyloid-b from the brain to the periphery, it made no difference in cognition. This indicates that perhaps instead of focusing research on a corollary to the effects of Alzheimer’s disease, more research should be done to determine what roles pathobiological changes in the brain actually play in disease onset and progression. Anti-amyloid treatments, such as immunotherapies, may have a future important role 6

in disease prevention, particularly with the availability of in vivo amyloid biomarkers. The ultimate goal for current Alzheimer’s research is to halt disease progression and restore cognitive function: essentially, to develop a cure. Curing a disease whose pathology is so poorly understood is a practically insurmountable challenge, so a more realistic goal is to isolate elements of disease progression that can be effected. To that end, instead of the recent trend of narrow focus on the amyloid hypothesis a broader investigation into multitarget approaches with various mechanisms of action is warranted. In addition to expanding the investigational target scope, the present difficulty in ameliorating cognitive decay once it has occurred suggests that developing treatments for presymptomatic stage disease would be a worthwhile investment of resources. Compared to amyloid-based approaches, clinical development for approaches targeting tau, metabolic actors such as insulin and NGF manipulators, and multitarget antiinflammatory agents and metal chelators are in the dawn of clinical development. Optimism in these areas may be largely based on the fact that there’s been fewer notable failures, because there have been fewer large-scale studies of nonamyloid drugs. Anti-tau approaches, in particular, are promising because clinically investigation of tau as it relates to Alzheimer’s disease is an unexplored frontier, but there is evidence of a correlation between tau abnormality and decreased cognition. Like amyloid-b, it is unknown what specific relationship tauopathy has to Alzheimer’s disease symptomology. Unlike amyloid-b aggregates, tau dysfunction has been positively correlated to other neurological diseases characterized by loss of cognitive function including Pick’s disease, Lytico-Bodig disease, ganglioglioma, Parkinson’s disease and frontotemporal dementia [45]. Additionally, high levels of tau aggregation in the brains of traumatic brain injury patients are positively correlated to poor recovery of cognitive and motor function [46]. Anti-tau approaches are also an attractive avenue for future research because of the large number of mechanisms of action that can affect tau morphology and thus can be tapped as therapeutic targets. Presently, there are more than 20 unique protein kinases that can each phosphorylate tau proteins, including but not limited to glycogen synthase kinase 3 b, cyclin-dependent kinase 5 and microtubule-affinity-regulating kinase. Hyperphosphorylation pathology allows for targeting multiple targets to potentially reduce protein aggregation, unlike amyloid-based approaches that primarily focus on either g-secretase manipulation or immunotherapies that pull amyloid-b out of the brain [47]. Among the experimental drugs discussed, epothilone D is particularly interesting because of its potential as a preventative agent as well as its ability to actually reverse, as opposed to merely slowing or stopping, neurodegeneration in animals. Additionally, epothilone D is unique among treatments currently in the pipeline for its multitarget mechanism of action; by acting as a microtubule stabilizer, it can




potentially counteract abnormal tau pathology regardless of the cause of that abnormality [37]. Although enthusiasm is high, it is too early to speculate on a robust clinical outcome. The value of epothilone D is not so much that it is guaranteed to have more of an effect than other drugs that started out with promise and failed in late stage trials but that it addresses challenges faced when experimenting with treatments focused on narrower mechanisms of action. It should be noted that the alternative avenues of research discussed here are in the position that the amyloid hypothesis was as of 15 years ago; they seem to have potential but are largely unexplored and could individually prove equally fruitless in terms of producing an effective treatment. However, because the amyloid hypothesis has been definitively shown not to yield results for patients, alternative mechanisms are by default the best new hope for meaningful treatment. Part of the problem related to amyloid-based treatment (and potentially other treatments related to the removal of individual proteins) is trying to undo what has been done; that is, even if it was possible to permanently decrease amyloid loads in the brain that would not fix the neuronal damage that had already occurred. There are hundreds of factors that affect the development of Alzheimer’s disease and the more of those that are investigated, the more likely it is to find a way to intervene in progression. To that end, every alternate target is worth being hopeful about, particularly when drugs are being developed that aim at more than one pathway at a time. Investigation into metabolic approaches allows for the possibility of disease prevention in a way that could benefit potential patients far more than attempting to reduce disease impact after indicators like amyloid plaques start developing. Currently, an effective presymptomatic therapy does not exist and the bulk of current research focuses on slowing and reversing loss of cognitive function. To date, the most frustrating difficulties in treating Alzheimer’s disease consist of determining causal relationships between pathologically relevant proteins and symptomatic expression and the difficulty of reversing neuronal damage once it has occurred. It would be almost impossible to overstate the value of a therapy that could prevent symptomatic onset or halt disease progression in its earliest stages and thus circumvent those difficulties. To that end, synthesis of treatments designed to target abnormal metabolism associated with early-stage Alzheimer’s disease is an area of research worth expanding upon. In particular, liraglutide and other drugs capable of supporting glucose metabolism deserve attention. In model mouse trials, liraglutide was able to prevent loss of cognitive function before disease onset and improve neuronal density following disease progression [34]. While caution should be exercised when considering remarkable results in preclinical studies, the possibility of a treatment that can effectively delay dementia when applied in early-stage disease and reverse course in later stages is exciting, particularly when compared to the minimal results offered by currently approved Alzheimer’s disease medications.

Therapeutic interventions targeting glucose metabolism could ameliorate this problem. It has long been understood that there is a significant decline in glucose metabolism prior to cognitive decline in Alzheimer’s patients [48]. Although metabolic therapies like liraglutide and internal insulin are valuable for their curative potential, a wider focus on the correlation between metabolism and neurological decay creates an opportunity to begin treating Alzheimer’s disease far earlier than is currently possible. By using decreased metabolism, which can be assessed in living patients, as a diagnostic tool instead of relying on the identification of amyloid-b plaques in late-stage disease, more modest goals of prolonged quality of life could be met for the growing population of patients who will develop Alzheimer’s disease in the coming decades. Among the barriers that have so far prevented a viable treatment option for Alzheimer’s disease is the relative uncertainty of diagnosis in living patients. Inquiry into anti-tau and metabolic treatments is imperative but pharmacological therapies are not the only research subjects that warrant attention. Implantation of brain pacemakers for DBS has been approved by the FDA to treat diseases with symptomologies similar to that of Alzheimer’s disease, including Parkinson’s disease among other neurological and psychological diseases and is currently undergoing clinical trials to investigate efficacy with regard to Tourette’s syndrome and major depression. DBS has been shown to increase brain cell glucose metabolism in patients exhibiting the metabolic decline typical of Alzheimer’s disease patients by 20% after 1 year [49]. Although the relationship between decreasing glucose metabolism and the onset of cognitive loss is poorly understood, the fact that metabolic decline precedes loss of function that indicates pursuit of both pharmacological and surgical approaches is critical. The present barriers to treating Alzheimer’s disease are complicated but not insurmountable so long as the current focus on amyloid clearance can be broadened to include manipulation of other pathological characteristics. Traditional clinical investigation for a disease such as Alzheimer’s is ultimately reductive; when the causality of a condition is so poorly understood and the symptoms so weakly correlated to physiological changes it is extremely unlikely that treatments operating on one specific mechanism of action will yield meaningful results, hence the current dearth of approved symptomatic treatments and utter lack of any curative treatments [50]. A more prudent investigational focus would be earlier interventions to prevent damage that is difficult to reverse. Part of the challenge regarding preventative treatment at present is determining who will eventually suffer from Alzheimer’s disease before the onset of loss of cognition, which is typically how patients come to be diagnosed in the first place. Increased clinical trials involving populations where prodromal Alzheimer’s disease is extremely likely, such as patients who also have a Down syndrome diagnosis, could be a viable option for finding useful application of therapies that have not been effective in later stages. However,


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that would not impact the issue of identifying patients who could benefit from extremely early intervention until diagnostic techniques for Alzheimer’s disease improve. Alternatively, broader therapeutic interventions that can operate on multiple targets such as those related to decreasing abnormal tau would increase the chances of finding a successful mechanism of action. It is also a possibility that the currently accepted process for evaluating experimental drugs is not the most streamlined method for determining which treatments have potential and which do not. Transgenic animals are not representative of the human population suffering from dementia. Although the integrity of clinical trials depends on homogeneity of animal disease symptoms and causes in preclinical testing, this does not account for the vast number of environmental, cultural and genetic variables that affect whether humans are afflicted with dementia or not. One benefit to a multitarget approach is that it accounts for the event that there is not one cause or cure for Alzheimer’s disease. In drugs that failed in recent late-phase trials, a common theme was success in regional Phase II trials only to not separate from placebo when expanded to global study [50]. In addition to expanding exploration of novel Bibliography

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Declaration of interest Supported by the NIA via grant P30 AG 019610 and the Banner Sun Health Research Institute. M Sabbagh has had clinical trial support from Pfizer, Genentech. Functional Neuromodulation, Avid, Neuronix, Eli Lilly & Co., Takeda Pharmaceuticals, Avanir, Navidea Biopharmaceuticals, Piramal, GE Healthcare and DART pharmaceuticals and is on the Advisory board of Piramal, Eli Lilly & Co., Avid and Biogen Idec. He receives royalties from Wiley and Tenspeed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

gamma-secretase inhibitor Avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012;69(11):1430-40

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

disease mechanisms, considering Alzheimer’s disease on a smaller scale related to a population’s specific risk factors could pave the way to more effective treatments being discovered even if on an international scale their efficacy was statistically insignificant.

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Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of abeta. J Neurosci 2012;32(28):9677-89

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Pfizer, Inc. Evaluation of the efficacy of varenicline on cognition, safety, tolerability and pharmacokinetics in subjects with mild-to-moderate Alzheimer’s disease. Available from: www.ClinicalTrials.gov (Identifier NCT00744978)

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Serrano-Pozo A, Vega GL, Lutjohann D, et al. Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers. Alzheimer Dis Assoc Disord 2010;24(3):220-6 Statins have been of theoretical interest for Alzheimer’s disease treatment. This investigates simvastatin’s effects on biomarkers.

Ryan JM, Grundman M. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J Alzheimers Dis 2009;17(2):243 Lambracht-Washington D, Rosenberg RN. Active DNA Abeta42 vaccination as immunotherapy for Alzheimer disease. Transl Neurosci 2012;2:307-13


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ameliorates amyloid-like pathology through inhibition of beta-secretase in a mouse model of Alzheimer’s disease. PLoS One 2013;8(2):e55091 An initial report of thalidomide as a BACE inhibitor. Mousavi M, Hellstrom-Lindahl E. Nicotinic receptor agonists and antagonists increase sAPPalpha secretion and decrease Abeta levels in vitro. Neurochem Int 2009;54(3-4):237-44 EnVivo Pharmaceuticals, Inc. Safety, tolerability, pharmacokinetics of EVP-0962 and effects of EVP-0962 on cerebral spinal fluid amyloid concentrations in healthy subjects and in subjects with mild cognitive impairment or early Alzheimer’s disease. Available from: www.clinicaltrials.gov/ct/show/ NCT01661673 (Identifier: NCT01661673) Wallace TL, Callahan PM, Tehim A, et al. RG3487, a novel nicotinic alpha7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. J Pharmacol Exp Ther 2011;336(1):242-53 Neugroschl J, Sano M. An update on treatment and prevention strategies for Alzheimer’s disease. Curr Neurol Neurosci Rep 2009;9(5):368-76 Rocken C, Kintsch-Engel R, Mansfeld S, et al. Advanced glycation end products and receptor for advanced glycation endproducts in AA amyloidosis. Am J Pathol 2003;162:1213-20

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McClean PL, Parthsarathy V, Faivre E, Holscher H. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2011;31(17):6587-94

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Zhang B, Carroll J, Trojanowski JQ, et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 2012;1432(11):3601-11

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De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 2009;106(6):1971-6

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Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol 2007;595:197-212

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Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012;69(1):29-38 An important study demonstrating the feasibility, proof of concept and efficacy signal using intranasal insulin as a treatment for Alzheimer’s disease.

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Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s disease: additional phase II analyses. J Alzheimers Dis 2010;20(2):509-16 PBT2 is a chelator, and this is the first proof of concept for a therapeutic benefit in the treatment for Alzheimer’s disease.

Hsiao K, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274(5284):99-102 An important early study linking amyloid accumulation with cognitive decline. Yan SD, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996;382(6593):685-91 An important early study demonstrating the RAGE is germane to Alzheimer’s disease pathophysiology. Deane R, Singh I, Sagare AP, et al. A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 2012;122:1377-92

Sabbagh MN, Agro A, Bell J, et al. PF04494700, an oral inhibitor of receptor for advanced glycation endproducts (RAGE), in Alzheimer disease. Alzheimer Disease Assoc Disord 2011;25(3):206-12 This is an early study demonstrating feasibility of RAGE inhibitor as a treatment for Alzheimer’s disease.

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Rinne JO, Brooks DJ, Rossor MN, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, doubleblind, placebo-controlled, ascending-dose study. Lancet Neurol 2010;9(4):363-72 This is a very important study demonstrating that a mAB for Alzheimer’s disease lowered amyloid by imaging. Imbimbo BP, Ottonello S, Frisardi V, et al. Solanezumab for the treatment of mild-to-moderate Alzheimer’s disease.

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reduced amyloid beta levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain 2011;135(4):1268-80

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Berk C, Sabbagh M. Successes and failures for drugs in late-stage


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development for Alzheimer’s disease. Drugs Aging 2013;30:783-92 This paper is of high interest because it clarifies reasons for failures for the heavily tested amyloid hypothesis and reasons why it is so difficult to make pharmacological progress in treating dementia.

Affiliation Camryn Berk BS, Gaurav Paul & Marwan Sabbagh† MD FAAN † Author for correspondence Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA Tel: +1 623 832 6500; Fax: +1 623 832 6504; E-mail: [email protected]

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