SynthesisEuropean journal of clinical pharmacology2013
Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.
Synthesis in European journal of clinical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Applications of Model-Based Meta-Analysis in Drug Development.Pharmaceutical research · 2022Pooled it
- Use of Model-Based Meta-Analysis to Inform the Design of Early Clinical Trials of Anti-Amyloid Beta Therapies in Alzheimer's Disease.CPT: pharmacometrics & systems pharmacology · 2025Article
- Semimechanistic Population Pharmacokinetic Modeling to Investigate Amyloid Beta Trafficking and Accumulation at the BBB Endothelium.Molecular pharmaceutics · 2021Article
- Hexahydropyrrolo[2,3-ACS chemical neuroscience · 2019Article
- A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human.CPT: pharmacometrics & systems pharmacology · 2017Article
- Physiological and pathological roles of the γ-secretase complex.Brain research bulletin · 2016Review
- Aβ mediates Sigma receptor degradation via CaN/NFAT pathway.American journal of translational research · 2016Article
- The role and therapeutic targeting of α-, β- and γ-secretase in Alzheimer's disease.Future science OA · 2015Review
- γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
- Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig.Pharmaceutical research · 2014Article
- Evidence of a novel mechanism for partial γ-secretase inhibition induced paradoxical increase in secreted amyloid β protein.PloS one · 2014Article
- Modeling of age-dependent amyloid accumulation and γ-secretase inhibition of soluble and insoluble Aβ in a transgenic mouse model of amyloid deposition.Pharmacology research & perspectives · 2013Article
- Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor.The Journal of biological chemistry · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aβ in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aβ effects.
methodsA model-based-meta analysis on Aβ levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752).
resultsThe clinical data available did not show any significant or robust reduction of CNS Aβ over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aβ levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations.
conclusionsMore substantially, CNS Aβ-lowering drugs are needed to test whether inhibition of Aβ production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.