A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease.
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ABSTRACT:
SUBMITTER: Karran E
PROVIDER: S-EPMC4204160 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease.
Annals of neurology 20140702 2
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Project description:The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
| S-EPMC8840505 | biostudies-literature
Project description:ObjectiveThe amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia.BackgroundAn ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits.Updated hypothesisIt is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies.Major challenges for the hypothesisKey challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late-onset AD.Linkage to other major theoriesThe amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.
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Project description:The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.
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Project description:Over the last decade Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) has been developed into a potent molecular biology tool used to rapidly modify genes or their expression in a multitude of ways. In parallel, CRISPR-based screening approaches have been developed as powerful discovery platforms for dissecting the genetic basis of cellular behavior, as well as for drug target discovery. CRISPR screens can be designed in numerous ways. Here, we give a brief background to CRISPR screens and discuss the pros and cons of different design approaches, including unbiased genome-wide screens that target all known genes, as well as hypothesis-driven custom screens in which selected subsets of genes are targeted (Fig. 1). We provide several suggestions for how a custom screen can be designed, which could broadly serve as inspiration for any experiment that includes candidate gene selection. Finally, we discuss how results from CRISPR screens could be translated into drug development, as well as future trends we foresee in the rapidly evolving CRISPR screen field.
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Project description:BackgroundThere has been limited progress in the development of novel therapeutics for the treatment of sarcomas. A review of phase I and II clinical trials for sarcomas may give insight into factors influencing sarcoma drug development.MethodsAn exhaustive analysis of phase I and II clinical trials testing drugs for human sarcoma patients between 1 January 2000 and 1 June 2018 was performed using the PubMed search engine, the Thomson Web of Science, and the National Clinical Trials registry. Recorded outcomes included tested drugs, tested histological subtypes, whether the drug was initially developed for sarcoma, reported funding sources, and whether studies led to phase III trials.ResultsOut of 238 studies meeting inclusion criteria, 87% (207 studies) reported funding sources. Of these, 59.9% (124/207) reported industry funding, 52.7% (109/207) reported government funding, and 27.5% (57/207) reported private funding. Only 5% (12/238) of phase I and II trials resulted in phase III trials, with 11 of 12 studies funded by industry. Approximately 90% (214/238) of studies tested drugs that were not initially tested in sarcoma, and 60.1% (143/238) of studies grouped different sarcoma histological subtypes together in the same study.ConclusionIndustry has funded the majority of phase I and II sarcoma clinical trials that have led to phase III trials. There was a high rate of drugs approved for other cancers and then secondarily tested in sarcoma. Most trials tended to group different sarcoma subtypes rather than studying each subtype separately.
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Project description:Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990-2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, β-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3β, NMDA receptors, and more than 70 other targets have been only marginally considered. These results might allow us to spot new design opportunities based on innovative target combinations to expand and diversify the repertoire of multitarget drug candidates and increase the likelihood of finding effective therapies for this devastating disease.
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