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Overview

AbstractIntroductionCurrently, 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.MethodsUsing 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.ResultsOur 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.DiscussionIn 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.

01 Jan 2017·Alzheimer's & Dementia: Translational Research & Clinical Interventions

NGP 555, a γ‐secretase modulator, lowers the amyloid biomarker, Aβ_42, in cerebrospinal fluid while preventing Alzheimer's disease cognitive decline in rodents

Article

Author: Comer, William T. ; Kounnas, Maria Z. ; Nowakowski, Dan W. ; Herz, Joachim ; Lane‐Donovan, Courtney

AbstractIntroductionAlzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years.MethodsUsing amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques, we investigate the properties of NGP 555, a clinical‐stage γ‐secretase modulator.ResultsNGP 555 shifts amyloid peptide production to the smaller, nonaggregating forms of amyloid. Our preclinical studies show beneficial effects on amyloid biomarkers, pathology, and cognition. NGP 555 has successfully completed chemistry, pharmacology, toxicity, metabolism, and safety studies.DiscussionAbundant data support Aβ42 as a target for prophylactic or early‐stage intervention therapies in AD. The γ‐secretase modulator, NGP 555 is being actively developed in human clinical trials for the prevention of Alzheimer's disease with the overall aim to achieve an appropriate balance of potency/efficacy on reducing the toxic forms of amyloid versus safety.

2-Aminothiazoles derivatives as potent γ-secretase modulators

Author: Cheng, Soan ; Mao, Long ; Danks, Anne D. ; Comer, Dan ; Pleynet, David ; Wagner, Steven L. ; Kounnas, Maria Z. ; Yu, Chengzhi ; Comer, William T. ; Tyree, Curtis

Alzheimer′s disease (AD) is the major cause of dementia that affects 35 million people worldwide.Compelling genetic, biochem. and pathol. evidence indicate that fibrillar Aβ42 is the peptide species in the brain directly linked to the pathogenesis of Alzheimer′s Disease (AD).Using a cell based assay, we have identified a novel series of γ-secretase modulators that lowered Aβ42 levels without inhibiting NOTCH proteolytic processing (NICD generation).γ-secretase modulators shift the cleavage toward shorter Aβ peptides resulting in the selective inhibition of Aβ42 while increasing the production of shorter Aβ peptides (e.g. Aβ37, Aβ38).Starting from a weak hit identified from a high-throughput screen, we developed SAR and identified low nanomolar lead compounds with good in vitro and in vivo activity.Concurrent optimization of the drug properties have produced analogs that are orally bioavailable and achieve high concentrations in the brains of animals.The in vitro and in vivo γ-secretase modulating profiles of these 2-aminothiazoles derivatives and a review of the SAR which led to the clin. candidate NGP-328 will be presented.

100 Deals associated with NeuroGenetic Pharmaceuticals, Inc.

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100 Translational Medicine associated with NeuroGenetic Pharmaceuticals, Inc.

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Pipeline

Pipeline Snapshot as of 19 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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