The Silent Victory: Athira Pharma’s Quest Against Alzheimer’s

Athira Pharma presented a poster titled “Targeting Neurotrophic HGF Signaling for the Treatment of Neurodegenerative Disorders” at the recently, concluded American Academy of Neurology 2024 Annual Meeting, held in Denver, Colorado. It highlighted preclinical data supporting the development of Athira’s pipeline of small molecule candidates targeting the neurotrophic hepatocyte growth factor (HGF) system, including fosgonimeton for Alzheimer’s disease, ATH-1105 for amyotrophic lateral sclerosis (ALS), and ATH-1020 for Parkinson’s disease.

The current treatment regime for Alzheimer’s is mostly symptomatic with only one approved disease-modifying therapy, which is also marred with safety concerns. There exists a need for therapies that are safe and efficacious, and despite a robust pipeline, it is paradoxical that only a few pass the mid-stage of development. Incomplete knowledge of the molecular pathophysiology of the disease, and complex neurobiology complicate drug development. Fosgonimeton, potentially a first-in-class, disease-modifying small molecule, targeting the protection and repair of neuronal networks, is a beacon of hope.

A novel molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, MET, a naturally occurring repair mechanism for a healthy nervous system, fosgonimeton is currently being evaluated in individuals with mild-to-moderate Alzheimer’s disease, as a once-daily, easy to administer subcutaneous injection. 

Neurotrophic factor systems, including HGF, are expressed in neurons and glia and play crucial roles in maintaining neuronal survival, connectivity, metabolic stability, and regulating inflammation. By positively modulating the HGF signaling system, fosgonimeton has demonstrated neuroprotective, neurotrophic, and anti-inflammatory effects, countering mechanisms of amyloid-beta (Aβ)-induced toxicity both in vitro and in vivo.  It enhances neurite outgrowth, increases synaptic count, and promotes survival in primary neuron cultures, along with a decrease in oxidative stress, apoptotic signaling, pathological protein accumulation of pTau, α-synuclein, or TDP-43, and lysosomal dysfunction.

Various preclinical findings support the potential therapeutic benefit of fosgonimeton in modulating the neurotrophic HGF system and showed that the neuroprotective effects of fosgonimeton against glutamate toxicity, driven in part, by activation of pro-survival signaling pathways, help to counteract neurodegenerative hallmarks such as tau pathology and mitochondrial dysfunction, and improved cognitive performance.

A Phase II/III LIFT-AD trial of Fosgonimeton in Alzheimer’s disease is underway, and Athira has completed enrollment, with a topline data readout expected in the second half of 2024. There is much enthusiasm around the drug, due to its unique target that could potentially improve neuron function and be used in combination with an anti-amyloid or anti-tau therapy. It introduces the prospect of a safer, more tolerable treatment avenue for individuals with Alzheimer’s, potentially upending barriers that have impeded the progress of earlier therapeutic endeavors. The drug has the potential to address the current gaps in Alzheimer’s treatment, improving daily life, and offering a safer option than traditional treatments.