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

Abstract

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 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.

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

“…Preclinical results demonstrate NGP 555 has favorable drug properties including good oral absorption, brain penetration, central nervous system activity, and specificity for a lipid-based membrane target (g-secretase) with limited metabolism [42,43]. In addition, we report beneficial activity of NGP 555 directed at synaptic function.…”

“…One such molecule is NGP 555, with previous studies demonstrating the ability to favorably alter amyloid biomarkers and pathology in the brain while preventing cognitive decline preclinically. Combined with the preclinical findings, this compound represents a new possibility for therapy to further advance a clinically safe molecule for AD [42–44]. To date, no GSM has gone the distance to confirm the translation of preclinical findings on Aβ biomarker reductions (Aβ 42 CSF levels and brain amyloid plaques) to prevention of cognitive decline (with an adequate safety margin) in humans.…”

“…Although GSMs represented a minority of the molecules tested in the clinic [16], to date most of these candidates have not succeeded because of compound toxicity based on structure or limited effectiveness to lower cerebrospinal fluid (CSF) amyloid biomarkers [32][33][34]. However, several GSMs are currently on the horizon and new discoveries of optimal chemical structures carry hope for the future of GSMs as therapeutics for AD [35][36][37][38][39][40][41][42][43][44]. One such molecule is NGP 555, with previous studies demonstrating the ability to favorably alter amyloid biomarkers and pathology in the brain while preventing cognitive decline preclinically.…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…We cite here two interesting compounds that have been discovered more recently as γ‐secretase allosteric modulators: NGP 555 ( 40 ) and compound 41 (Figure ). The former presents IC 50 =10 n m and lowers Aβ 42 levels in the cerebrospinal fluid of rodents, balancing its ratio in relation to smaller Aβ . Compound 41 is an azabicyclic fused pyrimidine derivative with Aβ 42 reduction expressed in terms of its potency: EC 50 =5 n m …”

“…The former presents IC 50 = 10 nm and lowers Ab 42 levels in the cerebrospinal fluid of rodents, balancing its ratio in relation to smaller Ab. [182,183] Compound 41 is an azabicyclic fused pyrimidine derivativew ith Ab 42 reduction expressed in terms of its potency: EC 50 = 5nm. [164] There are diverser eports of g-secretase modulators as being among the main strategies to treat AD.…”