ArticleClinical pharmacology and therapeutics2020
Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies.
Article in Clinical pharmacology and therapeutics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 22 papers.
What it found
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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.
A Phase 1, Randomized, Double-blind, Sponsor-open, Placebo-controlled First-in-human Trial To Evaluate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Pf-06648671 After Administration Of Single Ascending Doses To Fasted And Fed Healthy Subjects
A Phase 1 Investigator-and-subject Blind, Randomized, Placebo Controlled, Parallel Study In Healthy Subjects To Evaluate The Pharmacodynamic Effects Of Single Oral Doses Of Pf-06648671 On Aβ Concentrations In Cerebrospinal Fluid Using Serial Sampling Methodology
An Investigator-and-subject Blind, Phase 1 Study To Characterize The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Repeat Doses Of Pf-06648671 In Healthy Adult Subjects And Healthy Elderly Subjects
Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.Journal of Alzheimer's disease : JAD · 2019Trial
- Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.Experimental neurobiology · 2026Review
- Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer's disease.Frontiers in pharmacology · 2026Article
- Targeting the awry Aβ pathway in Alzheimer's disease: hype and hurdles.Inflammopharmacology · 2025Review
- γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.Alzheimer's research & therapy · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Biomarkers and Target-Specific Small-Molecule Drugs in Alzheimer's Diagnostic and Therapeutic Research: From Amyloidosis to Tauopathy.Neurochemical research · 2024Review
- Early- and Late-Onset Alzheimer's Disease: Two Sides of the Same Coin?Diseases (Basel, Switzerland) · 2024Review
- Review on anti-alzheimer drug development: approaches, challenges and perspectives.RSC advances · 2024Review
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Synergistic activity of nootropic herbs as potent therapeutics for Alzheimer's disease: A cheminformatics, pharmacokinetics, and system pharmacology approach.Journal of Alzheimer's disease reports · 2024Article
- New Insights into Alzheimer's Disease: Novel Pathogenesis, Drug Target and Delivery.Pharmaceutics · 2023Review
- Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease.Frontiers in molecular neuroscience · 2023Review
- γ-Secretase in Alzheimer's disease.Experimental & molecular medicine · 2022Review
- Turning the tide on Alzheimer's disease: modulation of γ-secretase.Cell & bioscience · 2022Review
- Phenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer's disease.RSC medicinal chemistry · 2021Article
- Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.The Journal of experimental medicine · 2021Article
- Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders.International journal of molecular sciences · 2021Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.ACS medicinal chemistry letters · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials.
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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.