NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

Maria Z. Kounnas, Murat S Durakoglugil, Joachim Herz, William T. Comer

Research output: Contribution to journalArticle

Abstract

Introduction: Currently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease. Methods: Using amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ-secretase modulator, for the first time in human clinical trials. Results: Our preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects. Importantly, pharmacokinetic and pharmacodynamic parameters combined with safety outcomes indicate that NGP 555 penetrates the blood-brain barrier and increases the ratio of amyloid-β peptide Aβ37 and Aβ38 compared with that of Aβ42, establishing a proof of target engagement in humans in a 14 day, once-daily oral dosing trial. Discussion: In humans, NGP 555 has demonstrated a beneficial shift in the production of Aβ37 and Aβ38 versus Aβ42 biomarker levels in the cerebrospinal fluid while maintaining an adequate safety profile. The overall clinical goal is to achieve an optimal balance of efficacy for altering amyloid-β peptide (Aβ) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aβ42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

Original languageEnglish (US)
Pages (from-to)458-467
Number of pages10
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Volume5
DOIs
StatePublished - Jan 1 2019

Keywords

  • Alzheimer's
  • Amyloid
  • Biomarkers
  • Cerebrospinal fluid
  • Cognition
  • Dementia
  • Pathology
  • Pharmacodynamics
  • Pharmacokinetic
  • Prevention
  • Synapses
  • γ-secretase modulator

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health

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