Neuroprotective effects of fosgonimeton and amyloid‐β‐targeting monoclonal antibodies against amyloid‐β toxicity in primary neuron culture.

Background: We have previously reported the neuroprotective effects of fosgonimeton in amyloid‐β (Aβ)‐driven preclinical models of Alzheimer’s disease (AD). Fosgonimeton is an investigational small‐molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild‐to‐moderate AD (LIFT‐AD; NCT04488419). Given the recent approvals of Aβ‐targeting monoclonal antibodies (Aβ‐mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ‐mAbs.

Fosgonimeton attenuates amyloid‐β‐induced autophagic impairments in primary cortical neurons.

Background: Accumulating evidence highlights impairment of autophagy as a key pathological feature of neurodegenerative diseases including Alzheimer’s disease (AD). Autophagy is a highly dynamic, lysosome‐based degradation process that promotes the clearance of degenerative factors to maintain cellular functions, preserve metabolic integrity, and ensure survival. Impaired autophagic function leads to the abnormal accumulation of autophagic vesicles (i.

Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease.

Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action.

ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.

Introduction: Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system.

Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia.

All types of dementia, including Alzheimer's disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia.