Quantitative Pharmacology Approach in Alzheimer’s Disease: Efficacy Modeling of Early Clinical Data to Predict Clinical Outcome of Tesofensine

Effective therapeutic options for Alzheimer’s disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For tesofensine, the dose concentration–effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.     

Measuring Study-Specific Heterogeneity in Meta-Analysis: Application to an Antecedent Biomarker Study of Alzheimer’s Disease

This article proposes several new indices that measure the heterogeneity for individual studies in a meta-analysis. These indices directly assess how inconsistent an individual study is compared to the rest of studies used in the meta-analysis, that is, how much impact the specific study has on the scientific conclusion of the meta-analysis and further on the generalization of the conclusion. The proposed indices can be intuitively interpreted as the proportion of total variance from all studies in a meta-analysis that can be accounted for by the heterogeneity from specific studies. Further, each proposed index over all the studies sums to the collective measure of heterogeneity for the meta-analysis. Therefore our proposed study-specific indices of heterogeneity can be regarded as a generalization of the collective index of heterogeneity in meta-analyses proposed by various authors. We examine the difference among the proposed study-specific measures of heterogeneity and assess the variation associated with each proposed index of heterogeneity through a large simulation study. Finally, we demonstrate the proposed methodology by assessing the effect of individual studies on the overall estimate to the difference of an antecedent biomarker of Alzheimer’s disease (AD) between different Apolipoprotein E (ApoE) genotypes.     

Biophysical Aspects of Alzheimer’s Disease: Implications for Pharmaceutical Sciences

An increasing amount of findings suggests that the aggregation of soluble peptides and proteins into amyloid fibrils is a relevant upstream process in the complex cascade of events leading to the pathology of Alzheimer’s disease and several other neurodegenerative disorders. Nevertheless, several aspects of the correlation between the aggregation process and the onset and development of the pathology remain largely elusive. In this context, biophysical and biochemical studies in test tubes have proven extremely powerful in providing quantitative information about the structure and the reactivity of amyloids at the molecular level. In this review we use selected recent examples to illustrate the importance of such biophysical research to complement phenomenological studies based on cellular and molecular biology, and we discuss the implications for pharmaceutical applications associated with Alzheimer’s disease and other neurodegenerative disorders in both academic and industrial contexts.     

Use of Benzodiazepines in Alzheimer’s Disease: A Systematic Review of Literature

Background:

Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited.

Methods:

Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific search terms in MEDLINE and PubMed Library according to the recommendations of The Strengthening the Reporting of Observational Studies in Epidemiology initiative.

Results:

Of the 657 articles found, 18 articles met predefined selection criteria and were included in this review (8 on frequency, 5 on cognitive functions, 5 on behavioral and sleep disturbances). The frequency of benzodiazepine use ranged from 8.5% to 20%. Five studies reported accelerated cognitive deterioration in association with benzodiazepine use. Two studies reported clinical efficacy for lorazepam and alprazolam to reduce agitation in Alzheimer’s disease patients. No evidence was found for an improvement of sleep quality using benzodiazepines.

Conclusion:

This systematic review shows a relatively high prevalence of benzodiazepine use but limited evidence for clinical efficacy in Alzheimer’s disease patients. However, there is a paucity of methodologically high quality controlled clinical trials. Our results underscore a need for randomized controlled trials in this area.     

Repurposing of Kinase Inhibitors to Target c-Abl as Potential Therapeutics for Alzheimer’s Disease

Alzheimer’s disease (AD) represents a major public health concern and has been considered as a research priority. Recently, the tyrosine kinase c-Abl has been shown as a new and potential target of AD therapy. In the current study, sophisticated molecular docking and empirical scoring functions were integrated to develop a bioinformatics predictor based on 52 kinase–inhibitor complexes with solved crystal structures and known biological activities. The predictor was then used to identify those potential c-Abl binders from a commercially available kinase inhibitor library. A total of 18 promising candidates with top scores were raised; their intermolecular interactions with c-Abl were further examined in detail by using molecular dynamics simulations and binding energy analysis. Seven out of the 18 candidates were selected and tested in vitro for their inhibitory activities against c-Abl, and, consequently, two compounds, namely S2882 and TAE684, were identified as high-activity agents (IC₅₀?=?28?±?5 and 12?±?3 nM, respectively). The two compounds possess long-chain structures with multiple rings that are structurally similar to the FDA-approved drugs imatinib and nilotinib. Visual examination of molded complex structures revealed that the S2882 and TAE684 can be readily bound within the active cleft of c-Abl kinase domain, exhibiting an extended conformation. In addition, an intensive network of nonbonded interactions across the complex interfaces of c-Abl with S2882 and TAE684 was also highlighted, which confers substantial stability and specificity for the complex systems.     

An update on the advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren’t effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn’t necessarily outweigh associated risks.

Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation.

Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.     

AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type

Introduction: Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death.

Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer.

Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan’s plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.     

Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer’s Disease

The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer’s disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain.     

Natural Products as Promising Drug Candidates for the Treatment of Alzheimer’s Disease: Molecular Mechanism Aspect

Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.Keyword: Alzheimer’s disease, Amyloid β, Apoptosis, Natural products, Neuroprotection, Tau protein.     

Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer’s Disease

Amyloid-β peptide (Aβ) is still best known as a molecule to cause Alzheimer’s disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. Thus, strategies on developing AD drugs have been focused on the reduc-tion of Aβ in the brain. Since accumulation of Aβ depends on the rate of its synthesis and clearance, the metabolic pathway of Aβ in the brain and the whole body should be carefully explored for AD research. Although the synthetic pathway of Aβ is equally important, we summarize primarily the clearance pathway in this paper because the former has been extensively reviewed in previous studies. The clearance of Aβ from the brain is accomplished by several mechanisms which include non-enzymatic and enzymatic pathways. Nonenzymatic pathway includes interstitial fluid drainage, uptake by microglial phagocytosis, and transport across the blood vessel walls into the circulation. Multiple Aβ-degrading enzymes (ADE) implicated in the clearance process have been identified, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II and others. A series of studies on Aβ clearance mechanism provide new insight into the pathogenesis of AD at the molecular level and suggest a new target for the development of novel therapeutics.     

Evaluation of memantine for the treatment of Alzheimer’s disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer’s disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda^?, Axura^®, Ebixa^®; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.     

Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer''s dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.Key Words: Alzheimer’s disease, neurodegeneration, inflammation, β-amyloid peptide, complement, complement regulators, CD59, complement therapeutics.     

Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far, the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable. The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ, hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction and deterioration of synaptic transmission. These factors together, accentuate changes in the CNS homeostasis, starting a complex process of interconnected physiological damage, leading to cognitive and memory impairment and neuronal death. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligand (MTDL) approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds acting simultaneously on diverse biological targets. This review aims to show some recent advances and examples of the exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.