A pharmacoeconomic evaluation of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) results in progressively worsening cognitive decline, leading to loss of functional ability, behavior/mood disturbances, institutionalization, and death. Current pharmaceutical therapies only treat the symptoms of cognitive decline yet can be expensive for payers.

Areas covered: The authors undertook a systematic review of economic evaluations of pharmaceutical therapies for AD. The literature search encompassed English-language studies indexed in PubMed (Medline), Cochrane Library Current, and Web of Science. The search included articles published between 1 January 1995 and 10 February 2018. The literature suggested AD medications generally dominated comparator treatments (e.g. placebo).

Expert opinion: The authors noted several limitations of the included economic evaluations. These limitations suggest the results of the economic evaluations should be interpreted with caution. Many economic models were not transparent with respect to sources of probabilities and cost data, and data collected in certain jurisdictions were applied to other jurisdictions without considering the validity of such applications. Measuring health utilities in cognitively impaired populations raises questions about the validity of quality-adjusted life years, but this issue was unaddressed in the included studies. Most included studies were sponsored by industry and the results tended to overwhelmingly support the manufacturer’s product.     

An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer’s disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses.

Areas covered: The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more.

Expert opinion: These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.     

Progress in acetylcholinesterase inhibitors for Alzheimer’s disease

Current pharmacotherapy of Alzheimer’s disease (AD) involves drugs that are known as acetylcholinesterase inhibitors (AChEIs), which increase the acetylcholine concentration in the brain. Although effective in improving cognitive, behavioural and functional impairments, these drugs are not able to alter disease progression. In this review, the recent patent literature on AChEIs from 2002 to early 2005 will be discussed, focusing attention on the novel analogues of the approved drugs, as well as on the most important AD therapeutic advances. The clinical efficacy of AChEIs will probably be enhanced by their combination with other drugs acting through different pharmacological mechanisms. As the neuronal loss comprises more than the forebrain cholinergic system, the weak effectiveness of AChEIs is not surprising. Besides the ‘cholinergic hypothesis’ approaches, new treatments are emerging based on multipotent compounds able to target the underlying pathogenic mechanisms of AD; these treatments are summarised herein.     

Drug development for Alzheimer’s disease: review

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is considered as one of the most intractable medical problems with heavy social and economic costs. The current drugs for AD, including acetylcholinesterase inhibitors (AChEIs) and memantine, a NMDA receptor antagonist, only temporarily ameliorate cognitive decline, but are unable to stop or reverse the progression of dementia. This paper reviewed the recent advance in AD drug development. The drug discovery programs under clinical trials targeting cholinergic system, α7 nicotinic acetylcholine receptors (nAChRs), N-methyl-d-aspartate receptor (NMDAR), β-secretase, γ-secretase modulators, tau, inflammatory mediators and glucagon-like peptide-1 (GLP-1) were discussed. Though several drug discovery programs are ongoing, the high failure rate is an outstanding issue. Novel techniques and strategies are desperately needed to significantly accelerate this process.     

Old and new acetylcholinesterase inhibitors for Alzheimer’s disease

Introduction: To date, pharmacological treatment of Alzheimer’s disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.

Areas covered: On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.

Expert opinion: Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer’s disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.     

Protease inhibitors as potential disease-modifying therapeutics for Alzheimer’s disease

The current lack of an effective treatment for Alzheimer’s disease (AD) has fuelled an intense search for novel therapies for this neurodegenerative condition. Aberrant production or decreased clearance of amyloid-β peptides is widely accepted to be causative for AD. Amyloid-β peptides are produced by sequential processing of the β-amyloid precursor protein by the two aspartyl-type proteases β-secretase and γ-secretase. Because proteases are generally classified as druggable, these secretases are a centre of attraction for various drug discovery efforts. Although a large number of specific drug-like γ-secretase inhibitors have been discovered, progress towards the clinic has been slowed by the broad substrate specificity of this unusual intramembrane-cleaving enzyme. In particular, the Notch receptor depends on γ-secretase for its signalling function and, thus, γ-secretase inhibition produces distinct phenotypes related to a disturbance of this pathway in preclinical animal models. The main task now is to define the therapeutic window in man between desired central efficacy and Notch-related side effects. In contrast, most studies with knockout animals have indicated that β-secretase inhibition may have minimal adverse effects; however, the properties of the active site of this enzyme make it difficult to find small-molecule inhibitors that bind with high affinity. In most instances, inhibitors are large and peptidic in nature and, therefore, unsuitable as drug candidates. Thus, there are many issues associated with the development of protease inhibitors for AD that must be addressed before they can be used to test the ‘amyloid cascade hypothesis’ in the clinic. The outcomes of such trials will provide new directions to the scientific community and hopefully new treatment options for AD patients.     

Epigenetic drug discovery for Alzheimer’s disease

Introduction: It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer’s disease (AD).

Areas covered: This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs.

Expert opinion: Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.     

Clinically tested drugs for Alzheimer’s disease

Alzheimer’s disease poses a major health problem in developed countries and vigorous research is underway aimed at finding effective treatments. Acetylcholinesterase inhibitors are approved but give only temporary cognitive benefit to a percentage of patients. Their relative ineffectiveness is not surprising since the neuronal loss comprises much more than the forebrain cholinergic system. What is needed is a drug that will halt the neuronal death and thus progression of the disease. Avenues being explored are aimed at pathological features of the disease, i.e., drugs aimed at removing the amyloid burden which forms the plaques or reducing the neurotoxic neuroinflammation and oxidative stress which characterise the diseased brain regions. There are some promising leads, but more definitive clinical trials are required. Any agent designed to slow progression should clearly be used at an early stage of the disorder; therefore methods of early diagnosis are also essential.     

A review of the treatment options for Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant, inherited, neuropsychiatric disease which gives rise to progressive motor, cognitive and behavioural symptoms. Its core pathology involves degeneration of the basal ganglia, in particular, the caudate and putamen, and is caused by a single autosomal gene coding for a mutated form of the protein, huntingtin. At the present time, the only treatment options available in HD are symptomatic. There are several substances available today for the treatment of chorea. Other neurological symptoms, such as dystonia, can be treated, but treatment is associated with a high risk of adverse events. Psychiatric symptoms, on the other hand, are often amenable to treatment and relief of these symptoms may provide significant improvement in quality of life.     

Emerging drug targets for Aβ and tau in Alzheimer’s disease: a systematic review

Aims

Currently, treatment for Alzheimer’s disease (AD) focuses on the cholinergic hypothesis and provides limited symptomatic effects. Research currently focuses on other factors that are thought to contribute to AD development such as tau proteins and Aβ deposits, and how modification of the associated pathology affects outcomes in patients. This systematic review summarizes and appraises the evidence for the emerging drugs affecting Aβ and tau pathology in AD.

Methods

A comprehensive, systematic online database search was conducted using the databases ScienceDirect and PubMed to include original research articles. A systematic review was conducted following a minimum set of standards, as outlined by The PRISMA Group 1. Specific inclusion and exclusion criteria were followed and studies fitting the criteria were selected. No human trials were included in this review. In vitro and in vivo AD models were used to assess efficacy to ensure studied agents were emerging targets without large bodies of evidence.

Results

The majority of studies showed statistically significant improvement (P < 0.05) of Aβ and/or tau pathology, or cognitive effects. Many studies conducted in AD animal models have shown a reduction in Aβ peptide burden and a reduction in tau phosphorylation post-intervention. This has the potential to reduce plaque formation and neuronal degeneration.

Conclusions

There are many emerging targets showing promising results in the effort to modify the pathological effects associated with AD. Many of the trials also provided evidence of the clinical effects of such drugs reducing pathological outcomes, which was often demonstrated as an improvement of cognition.     

Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Introduction: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression.

Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment.

Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aβ are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Aβ alone and pay more attention to simultaneous clearance of tau and Aβ.     

Rodent models for Alzheimer’s disease drug discovery

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer’s disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals.

Areas covered: This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging.

Expert opinion: Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.     

Idalopirdine as a treatment for Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the serotonin 6 (5-HT₆) receptor, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT₆ receptors induces acetylcholine release, it became reasonable to consider that 5-HT₆ antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system.

Areas covered: This review discusses the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT₆ antagonists. The article is also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine.

Expert opinion: Idalopirdine is safe and well tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing Phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs.     

Diagnostic methods and biomarkers for Alzheimer’s disease

Alzheimer’s disease (AD) is the most frequently occurring and intensively investigated neurodegenerative disorder, which is associated with extracellular senile plaques and intracellular neurofibrillary tangles. In this review, AD related diagnostic strategies and the potential biomarkers of AD will be discussed. Several proteomics methods were developed for disease diagnosis, such as ELISA, MALDI-TOF, SELDI-TOF, and 2 D-electrophoresis. Imaging technologies, such as MRI and PET analyses, are also important, since they could directly show the changes in the brain, associated with dementia progression. MRI technologies might estimate the presence and degree of neurodegeneration by identification and quantification of atrophy. PET could reflect the metabolic changes in the brain by various radioactive molecules (tracers). Along with neuropsycoanalysis of behavioral changes, the progression of dementia can be characterized with biochemical changes in brain metabolisms, in addition to fluctuations in many inflammatory mediators in the cerebral spinal fluid (CSF), blood and in other bodily fluids. These biochemical changes in the brain and other body fluids can be initiated before the appearance of AD symptoms. There is no specific marker for AD along with other dementia, but the combination of different markers may predict the disease progression more accurately. Monitoring the changes in their levels in brain, CSF, blood and body fluids with biomarkers in early disease stages might improve the diagnosis and therapies. Several molecules were established as successful biomarkers for AD diagnosis. Ratio of Abeta42/40 became an important AD marker, which could reflect the disease-associated changes in the blood plasma and CSF. Additional markers were available in blood, such as apolipoprotein E or inflammatory molecules. In CSF, the Abeta42, Tau or phospho-tau could be the most successful biomarker for AD progression. Several new biomarkers and diagnostic approaches were developed for differentiating AD from other forms of dementia. It should be important to predict the AD progression prior to the development of clinical symptoms. Above all, the improvement of above strategies, especially with diverse biomarkers, should support the precise diagnosis of AD, greatly enhancing both AD therapies and preventative measures.