Preclinical Studies of ATH-1105 Highlight Therapeutic Potential in ALS
ATH-1105 protected various cell culture systems from glutamate-mediated toxicity and its pathological alterations, which include mitochondrial dysfunction, apoptotic signaling, and TDP-43 mis-localization, among others.
Kevin Church, PhD
Athira Pharma recently announced a new publication in Frontiers in Neuroscience that showcased consistent neuroprotective and anti-inflammatory effects of ATH-1105, an investigational agent designed to enhance the neurotrophic hepatocyte growth factor (HGF) system. All told, thesepreclinical data provided a rationale for therapeutic interventions like ATH-1105 that leverage the positive modulation of the HGF pathways as a treatment for amyotrophic lateral sclerosis (ALS).1,2
Led by Kevin Church, PhD, chief scientific officer at Athira, investigators evaluated the neurotrophic, neuroprotective, and anti-inflammatory impact of ATH-1105 treatment in primary neuron cultures exposed to neurotoxic insults consistent with the pathogenesis of ALS. Following that, the group of researchers assessed the preclinical efficacy of ATH-1105 in preserving neuromuscular function and extending survival in vivo using the Prp-TDP43A315T transgenic mouse model of ALS.
Of the findings, one of the greatest takeaways was that ATH-1105 enhanced neurotrophic HGF system signaling through the MET receptor. This was demonstrated in a HEK293 cell model where treatment with ATH-1105 1 uM led to a significant increase in phospho-ERK (pERK) or phospho-AKT (pAKT) compared with controls. Previous research has shown that the HGF system plays a critical role in nervous system maintenance and repair, including stimulation of cell survival, increase in neuronal outgrowth, and modulation of neuronal network repair.
Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. Here, these neurons were subjected to one of the following neurological toxins: glutamate, lipopolysaccharide (LPS), H2O2, and MPP+. All told, cortical neurons treated with ATH-1105 exhibited significant improvement in cell viability against neuronal damage by the aforementioned neurological toxins, suggesting the agent may protect against multiple cellular and molecular dysfunctions associated with ALS.
"These data demonstrate that ATH-1105 treatment results in significant, consistent beneficial effects both in cell culture and in vivo models of ALS. Through enhancement of the neurotrophic HGF system, ATH-1105 protects spinal motor neurons from ALS-relevant insults in vitro and in animal models of ALS, prevents the progressive decline of motor and nerve function, reduces inflammation, preserves body weight and extends survival," Church said in a statement.1
To determine whether ATH-1105 could provide protection from glutamate-induced damage, primary spinal motor neurons were exposed to glutamate in the presence or absence of ATH-1105 and immunoassayed to assess neuronal survival, neurite length, and extranuclear TDP-43. Results showed that these spinal neurons exhibited significant improvement in neuronal survival, preservation of neurite length, and decrease in TDP-43 cytoplasmic localization relative to cultures treated with glutamate and vehicle. Overall, these suggest that positive modulation of HGF by ATH-1105 may promote protective mechanisms that reduce or prevent excitotoxicity-mediated TDP-43 pathology.
Using a separate cohort of animals, the impact of ATH-1105 treatment on survival in male Prp-TDP43A315T ALS mic was assessed. In the analysis, animals received once-daily oral treatment with ATH-1105 or vehicle from 1 month of age until a maximum of 5 months of age. All told, Kaplan-Meier survival analyses over the study duration revealed a significant increase in survival probability in the ALS mice treated with daily ATH-1105. At 152 days of age, the final percentage survival rate was increased by 35% in the ALS + vehicle group vs 75% for the ALS + ATH-1105 20 mg/kg group.
In the same study, investigators assessed plasma biomarkers at multiple time points (2, 3, and 4 months of age). By the first follow-up, mice that underwent delayed treatment with ATH-1105 demonstrated reduced levels of markers of inflammation (interleukin-6, tumor necrosis factor) and neurodegeneration (neurofilament light) relative to those in vehicle-treated ALS mice, potentially indicating a slowing in the progression of the inflammatory phenotype. Notably, a robust decreases in plasma NfL levels was observed in response to delayed intervention with ATH-1105, which remained attenuated for the rest of the study, despite the continued increase in NfL concentrations in the ALS + vehicle group.
"There is an urgent need for new ALS treatment options, particularly those aimed at slowing or stopping neurodegeneration,” Mark Litton, PhD, president and chief executive officer at Athira, said in a statement.1 "The results reported in this peer-reviewed publication suggest that ATH-1105 demonstrated consistent translation of neuroprotective and anti-inflammatory effects from in vitro to in vivo models, which led to improved motor function and survival in an ALS animal model. These findings further support our plans to progress ATH-1105 into first-in-human studies in the first half of 2024."
