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

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-ß peptide Aß37 and Aß38 compared with that of Aß42, 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 Aß37 and Aß38 versus Aß42 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-ß peptide (Aß) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aß42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

NGP 555, a γ-Secretase Modulator, Lowers the Amyloid Biomarker, Aß42, in Cerebrospinal Fluid while Preventing Alzheimer's Disease Cognitive Decline in Rodents.

INTRODUCTION: Alzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years. METHODS: Using amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques we investigate the properties of NGP 555, a clinical-stage γ-secretase modulator. RESULTS: NGP 555 shifts amyloid peptide production to the smaller, non-aggregating 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. DISCUSSION: Abundant data support Aß42 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.

Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Abeta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs).