Challenges In Drug Development Research Articles

Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development-A Drug Developer's Perspective.

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

A master protocol to investigate a novel therapy acetyl-l-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia

BackgroundThe lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients’ high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-l-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; “GM2”), and ataxia telangiectasia (A-T).Methods/designThe innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient’s functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient’s neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-l-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase.DiscussionThe novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients’ quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-l-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases.Trial registrationThe three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).

The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review.

Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.

A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling.

Osteosarcoma represents one of the most devastating cancersdue to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin,a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

Introduction to Special Issue on Ocular Pathology and Drug Development.

Dysfunction of the visual system remains a leading cause of human disability worldwide. Preclinical studies are a key component of efforts to develop drugs and devices to ameliorate visual impairment. Although new opportunities for the delivery of targeted ocular therapeutics have been created, clinical success has been confounded by unique challenges of drug development for the eye. This Special Issue brings together a broad range of articles that augment our current understanding of the visual system and highlight methods for assessing ocular toxicity and some of the current challenges in ocular drug development. Topics addressed include the anatomy, developmental anatomy, and/or immunobiology of the visual system and associated lymphoid tissues; animal models; methods for assessing ocular toxicity; spontaneous background and procedure-related microscopic findings and common artifacts in histologic sections of ocular tissues; and novel ocular drug delivery systems.

A universal CAR-NK cell approach for HIV eradication

<abstract> <p>No therapeutic drug has been able to completely eradicate HIV-infection so far, even after decades of research. A major challenge in HIV drug development is its immense diversity. NK cells are well-known for their anti-viral and anti-tumor functions. Since recently, NK cells have gained interest of researchers as they have paved the way for novel approaches in controlling HIV-infection supported by promising results observed in cancer immunotherapy trials. Here we report an anti-DNP CAR-NK cell approach introduced by Lim et al. capable of recognizing 2,4-dinitrophenyl tagged to anti-gp160 antibodies, which seemingly provides an effective solution to counteract HIV variability.</p> </abstract>

Photoaffinity labelling strategies for mapping the small molecule-protein interactome.

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping.

Human immunodeficiency virus (HIV) type 1 genetic diversity in HIV positive individuals on antiretroviral therapy in a cross-sectional study conducted in Teso, Western Kenya.

Introductionhigh HIV-1 infection rates and genetic diversity especially in African population pose significant challenges in HIV-1 clinical management and drug design and development. HIV-1 is a major health challenge in Kenya and causes mortality and morbidity in the country as well as straining the healthcare system and the economy. This study sought to identify HIV-1 genetic subtypes circulating in Teso, Western Kenya which borders the Republic of Uganda.Methodsa cross-sectional study was conducted in January 2019 to December 2019. Sequencing of the partial pol gene was carried out on 80 HIV positive individuals on antiretroviral therapy. Subtypes and recombinant forms were generated using the jumping profile hidden Markov model. Alignment of the sequences was done using ClustalW program and phylogenetic tree constructed using MEGA7 neighbor-joining method.Resultssixty three samples were successful sequenced. In the analysis of these sequences, it was observed that HIV-1 subtype A1 was predominant 43 (68.3%) followed by D 8 (12.7%) and 1 (1.6%) each of C, G and B and inter-subtype recombinants A1-D 3 (4.8%), A1-B 2 (3.2%) and 1 (1.6%) each of A1-A2, A1-C, BC and BD. Phylogenetic analysis of these sequences showed close clustering of closely related and unrelated sequences with reference sequences.Conclusionthere was observed increased genetic diversity of HIV-1 subtypes which not only pose a challenge in disease control and management but also drug design and development. Therefore, there is need for continued surveillance to enhance future understanding of the geographical distribution and transmission patterns of the HIV epidemic.

Design and Synthesis of Pyrano[3,2-b]indolones Showing Antimycobacterial Activity.

Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.

Challenges of drug development during the COVID‐19 pandemic: Key considerations for clinical trial designs

There is an urgent need for targeted and effective COVID-19 treatments. Several medications, including hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, tocilizumab and others have been identified as potential treatments for COVID-19. Bringing these repurposed medications to the public for COVID-19 requires robust and high-quality clinical trials that must be conducted under extremely challenging pandemic conditions. This article reviews translational science principles and strategies for conducting clinical trials in a pandemic and evaluates recent trials for different drug candidates. We hope that this knowledge will help focus efforts during this crisis and lead to the expedited development and approval of COVID-19 therapies.

Solubility enhancement of carvedilol using drug\u2013drug cocrystallization with hydrochlorothiazide

BackgroundIncreasing hydrophilicity of poorly water-soluble drugs is a major challenge in drug discovery and development. Cocrystallization is one of the techniques to enhance the hydrophilicity of such drugs. Carvedilol (CAR), a nonselective beta/alpha1 blocker, used in the treatment of mild to moderate congestive heart failure and hypertension, is classified under BCS class II with poor aqueous solubility and high permeability. Present work is an attempt to improve the solubility of CAR by preparing cocrystals using hydrochlorothiazide (HCT), a diuretic drug, as coformer. CAR-HCT (2:0.5) cocrystals were prepared by slurry conversion method and were characterized by DSC, PXRD, FTIR, Raman, and SEM analysis. The solubility, stability, and dissolution (in vitro) studies were conducted for the cocrystals.ResultsThe formation of CAR-HCT cocrystals was confirmed based on melting point, DSC thermograms, PXRD data, FTIR and Raman spectra, and finally by SEM micrographs. The solubility of the prepared cocrystals was significantly enhanced (7.3 times), and the dissolution (in vitro) was improved by 2.7 times as compared to pure drug CAR. Further, these cocrystals were also found to be stable for 3 months (90 days).ConclusionIt may be inferred that the drug–drug (CAR-HCT) cocrystallization enhances the solubility and dissolution rate of carvedilol significantly. Further, by combining HCT as coformer could well be beneficial pharmacologically too.

Machine learning with physicochemical relationships: solubility prediction in organic solvents and water

Solubility prediction remains a critical challenge in drug development, synthetic route and chemical process design, extraction and crystallisation. Here we report a successful approach to solubility prediction in organic solvents and water using a combination of machine learning (ANN, SVM, RF, ExtraTrees, Bagging and GP) and computational chemistry. Rational interpretation of dissolution process into a numerical problem led to a small set of selected descriptors and subsequent predictions which are independent of the applied machine learning method. These models gave significantly more accurate predictions compared to benchmarked open-access and commercial tools, achieving accuracy close to the expected level of noise in training data (LogS ± 0.7). Finally, they reproduced physicochemical relationship between solubility and molecular properties in different solvents, which led to rational approaches to improve the accuracy of each models.

PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?

Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intratumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate preclinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.

Therapeutic effect of disulfiram inclusion complex embedded in hydroxypropyl-β-cyclodextrin on intracranial glioma-bearing male rats via intranasal route

The unique environment of brain poses a huge challenge for drug development aimed at combatting glioblastoma (GBM) due to poor organ targeting. Intranasal administration is often considered as an attractive route directly into brain by not only circumventing the blood brain barrier and but also avoiding the hepatic first-pass effect. Disulfiram (DSF) is an old alcohol-aversion drug that has anti-tumor activities against diverse cancer types such as GBM in preclinical studies, especially when it is combined with cupper ion (Cu). In this study, DSF was embedded in hydroxypropyl-β-cyclodextrin (HP-β-CD) to prepare a DSF inclusion complex with the enhanced solubility, anti-GBM activity and high safety in vitro. The highest fluorescence signal of Cy5.5/HP-β-CD in the male rat brains showed the strong brain-targeting of nose-to-brain drug delivery. Therapeutic effects of DSF/HP-β-CD combined with Cu (DSF/HP-β-CD/Cu) on intracranial glioma-bearing male rats via different drug delivery routes were then investigated. DSF/HP-β-CD/Cu administrated by the intranasal route effectively inhibited tumor growth and migration, promoted apoptosis, and achieved 36.8% and 18.2% prolonged median survival time comparing to those of model rats by oral and intravenous administrations, respectively. Moreover, no obvious histopathological damage to normal tissues was observed by H&E staining. Overall, DSF/HP-β-CD/Cu could be a promising intranasal formulation for the effective GBM treatment.

Living with Advanced Hormone-Sensitive Prostate Cancer and Treatment with Abiraterone and Androgen Deprivation Therapy: The Patient, Nursing and Physician Perspective.

This article is co-authored by a patient with metastatic hormone-sensitive prostate cancer who is receiving abiraterone and androgen deprivation therapy treatment in Manchester, UK. The patient relates his personal experiences struggling with the diagnosis, his experience with treatment and the physical, emotional and psychosexual impact on his life. After his diagnosis, the patient has become an outspoken advocate and fundraiser for prostate cancer awareness and wants to ensure that novel treatments with proven efficacy and tolerability, such as abiraterone, are available for all men in his condition. The specialist nursing and physician perspectives, provided by healthcare professionals based in London who are not directly involved in this patient’s care, were written in response to the challenges and concerns highlighted by this patient. The role of the specialist nurse as a key healthcare professional in the cancer patient journey, particularly in managing the complex physical and emotional side effects of treatment, is highlighted in this perspective piece. The physician reviews the current difficulties of establishing an effective screening programme in prostate cancer, the common side effects of hormone treatment and the significant progress and challenges in novel drug development and prescription in metastatic hormone-sensitive prostate cancer. While written primarily from the perspective of a patient and healthcare professionals in England, many messages in this commentary would resonate with patients and professionals involved in the care of prostate cancer worldwide.

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell–Derived Organoids

Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution. We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline.

Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance in vivo, under zinc limitation, than in vitro Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.

Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development?

Translating basic biological knowledge into applications remains a key issue for effectively tackling neurodegenerative, neuroinflammatory, or neuroendocrine disorders. Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) still poses a demanding challenge for drug development targeting central nervous system diseases. Validated in vitro models of the BBB could facilitate effective testing of drug candidates targeting the brain early in the drug discovery process during lead generation. We here review the potential of mono- or (isogenic) co-culture BBB models based on brain capillary endothelial cells (BCECs) derived from human-induced pluripotent stem cells (hiPSCs), and compare them to several available BBB in vitro models from primary human or non-human cells and to rodent in vivo models, as well as to classical and widely used barrier models [Caco-2, parallel artificial membrane permeability assay (PAMPA)]. In particular, we are discussing the features and predictivity of these models and how hiPSC-derived BBB models could impact future discovery and development of novel CNS-targeting therapeutics. © 2020 The Authors.

1935P AI-driven big data analytics for effective response of cancer therapy (AIBERT drug discovery and development platform)

The traditional drug development process is driven by individual hypotheses, which is becoming less and less efficient. With the explosion of big cancer genomic data, the advancement of artificial intelligence, and the availability of cloud computing technologies, the era of data-driven drug development has arrived. However, there is still a large gap to put this vision into practice. We have collected and curated high-quality multi-omics data of patient and cell line samples from (i) several large cancer genomics consortium projects, (ii) published studies, and (iii) our in-house datasets. With cutting-edge bioinformatics pipelines, computational algorithms, and AI technologies, we have developed and implemented a big data analytics platform that aims to address the challenging questions in drug development. We have developed the analytics platform, AIBERT (AI-driven Big data analytics for Effective Response of cancer Therapy), to provide innovative, translational, data-driven service for pharmaceutical companies. AIBERT consists of the well-annotated, curated multi-omics datasets of large patient cohorts, dozens of best-practiced bioinformatics pipelines, and several AI technologies. Currently, the database includes the multi-omics data of more >20,000 cancer patients from about 40 cancer types, as well as about 2,000 cell lines and drug sensitivity data from >20,000 compounds. The main functional modules in this platform include (i) Target Discovery, (ii) Biomarker Identification, (iii) Drug Combination Prediction, and (iv) Clinical Trial Design. AIBERT focuses on clinically relevant signals with consistent patterns across different genotype-to-phenotype correlations and well balances the tradeoff between accuracy and robustness of data mining. This platform can effectively prioritize the candidate short lists for therapeutic targets, biomarkers, drug combinations or clinical investigations with high confidence and mechanistic insights. An AI-driven, big data analytic platform, AIBERT provides a creative solution to address the major challenges in drug development, facilitating the paradigm shift from “hypothesis-driven” to big “data-driven”.

Repositioning medication for cardiovascular and cerebrovascular disease to delay the onset and prevent progression of Alzheimer's disease.

Alzheimer's disease (AD) is a complex, progressive, neurodegenerative disorder. As with other common chronic diseases, multiple risk factors contribute to the onset and progression of AD. Many researchers have evaluated the epidemiologic and pathophysiological association between AD, cardiovascular diseases (CVDs), and cerebrovascular diseases (CBVDs), including commonly reported risk factors such as diabetes, hypertension, and dyslipidemia. Relevant therapies of CVDs/CBVDs for the attenuation of AD have also been empirically investigated. Considering the challenges of new drug development, in terms of cost and time, multifactorial approaches such as therapeutic repositioning of CVD/CBVD medication should be explored to delay the onset and progression of AD. Thus, in this review, we discuss our current understanding of the association between cardiovascular risk factors and AD, as revealed by clinical and non-clinical studies, as well as the therapeutic implications of CVD/CBVD medication that may attenuate AD. Furthermore, we discuss future directions by evaluating ongoing trials in the field.