This article provides a brief overview of the processes of drug discovery and development. Our aim is to help scientists whose research may be relevant to drug discovery and/or development to frame ...their research report in a way that appropriately places their findings within the drug discovery and development process and thereby support effective translation of preclinical research to humans. One overall theme of our article is that the process is sufficiently long, complex, and expensive so that many biological targets must be considered for every new medicine eventually approved for clinical use and new research tools may be needed to investigate each new target. Studies that contribute to solving any of the many scientific and operational issues involved in the development process can improve the efficiency of the process. An awareness of these issues allows the early implementation of measures to increase the opportunity for success. As editors of the journal, we encourage submission of research reports that provide data relevant to the issues presented.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer’s disease (AD) dementia. The workgroup sought to ...ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds ...soluble forms of amyloid, did not improve cognition or functional status.
Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model
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; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .
In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than ...placebo, including skin cancers and infections.
Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro,
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but Notch and other transmembrane proteins are also substrates for γ-secretase,
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and studies have raised concern that the inhibition of γ-secretase could . . .
Objective:
This study compared the effects of duloxetine, 60 mg day, versus placebo on cognition, depression, and pain in elderly patients with recurrent major depressive disorder.
Method:
Patients ...were randomly assigned (2:1) to duloxetine, 60 mg day (N=207), or placebo (N=104) for 8 weeks in a double-blind study. The primary outcome measure was a prespecified composite cognitive score composed of four individual tests. Secondary measures included the Geriatric Depression Scale, the Hamilton Depression Rating Scale, the Visual Analogue Scale assessing pain, and standard safety and tolerability assessments.
Results:
Patients had a median age of 72 years (range=65-90). Duloxetine demonstrated significantly greater improvement in the composite cognitive score versus placebo (least-squares mean change from baseline to endpoint: 1.95 versus 0.76), driven by improved verbal learning and memory. Duloxetine treatment showed significantly greater baseline-to-endpoint reductions in both Hamilton depression scale (-6.49 versus -3.72) and Geriatric Depression Scale (-4.07 versus -1.34) total scores compared with placebo. Hamilton depression scale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were significantly higher for duloxetine than for placebo. Duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake versus placebo. Significantly fewer patients receiving duloxetine withdrew from the study because of lack of efficacy (2.9% versus 9.6%); the incidences of discontinuation due to adverse events were similar for duloxetine and placebo (9.7% versus 8.7%).
Conclusions:
Duloxetine improved cognition, depression, and some pain measures and was safe and well tolerated in elderly patients with recurrent major depressive disorder.
To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI).
Placebo group data were obtained from 2 National Institute on Aging ...(NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil. The data were collated for common measurement instruments. The performance of the placebo participants from these studies was tracked on the Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating-sum of boxes, and for progression on these measures to prespecified clinical study endpoints.
status, where available, was also analyzed for its effects.
The progression to clinical endpoints varied a great deal among the trials. The expected performances were seen for the participants in the 2 NIA trials, ADCS and ADNI, with generally worsening of performance over time; however, the industry-sponsored trials largely showed stable or improved performance in their placebo participants.
4 carrier status influenced results in an expected fashion on the study outcomes, including rates of progression and cognitive subscales.
In spite of apparently similar criteria for MCI being adopted by the 7 studies, the implementation of the criteria varied a great deal. Several explanations including instruments used to characterize participants and variability among study populations contributed to the findings.
Abstract The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of ...Alzheimer’s disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
INTRODUCTION
Alzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many ...are not amyloid positive. Use of blood‐based biomarkers may reduce screen failures.
METHODS
We recruited 755 non‐Hispanic White, 115 Hispanic, 112 non‐Hispanic Black, and 19 other minority participants across groups of cognitively normal (n = 417), mild cognitive impairment (n = 312), or mild AD (n = 272) participants. Plasma amyloid beta (Aβ)40, Aβ42, Aβ42/Aβ40, total tau, phosphorylated tau (p‐tau)181, and p‐tau217 were measured; amyloid PET/CSF (n = 956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated.
RESULTS
Greater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aβ42/Aβ40, p‐tau181, and p‐tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p‐tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power.
DISCUSSION
Blood‐based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites.
Highlights
Amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p‐tau)181, and p‐tau 217 blood‐based biomarkers predicted brain amyloid positivity.
P‐tau 217 was the strongest predictor of brain amyloid positivity.
Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity.
Community‐based populations have similar Alzheimer's disease (AD) biomarker levels as other populations.
A prescreen process with blood‐based assays may reduce the number of AD trial screen failures.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The health, well‐being, and financial security of Americans are greatly impacted by Alzheimer's disease. The forecast paints an upward trajectory with the number of Americans suffering from ...Alzheimer's disease and related dementia. To discuss the Alzheimer's crisis, The Senate Committee on Finance, Subcommittee on Health Care, held a hearing titled, “The Alzheimer's Crisis: Examining, Testing, and Treatment Pipelines and Fiscal Implications,” on December 16, 2020. Here, we summarize and expand on the discussion of the panel and its review of recent progress, ongoing challenges associated with Alzheimer's disease, and potential initiatives that promise to speed progress in developing treatments and improving care.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to ...show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.
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