Potential ALS treatment ATH-1105 due to enter clinical testing this year

Therapy is designed to activate HGF system, a molecular signaling pathway

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
Mice are shown standing and sitting by bottles of medicine in a laboratory.

Treatment with the experimental oral therapy ATH-1105 significantly reduced nerve damage, improved motor function, and prolonged survival in preclinical models of amyotrophic lateral sclerosis (ALS), a study reports.

The work was funded by ATH-1105’s developer Athira Pharma, which plans to move the therapy into the first stages of clinical testing in the next few months.

The findings were first presented at last year’s American Academy of Neurology (AAN) Annual Meeting and are published now in “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,” in Frontiers in Neuroscience.

“The results reported in this peer-reviewed publication suggest that ATH-1105 demonstrated consistent translation of neuroprotective and anti-inflammatory effects … 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,” Mark Litton, PhD, president and CEO of Athira, said in a company press release.

ATH-1105 is designed to activate a molecular signaling pathway called the hepatocyte growth factor (HGF) system, which is important for the maintenance and health of nerve cells. By activating it, the therapy should counteract several processes that contribute to ALS.

Recommended Reading
Illustration shows mice climbing around beakers and vials in a lab.

ATH-1105 protects against common ALS, FTD disease mechanisms

ATH-1105 in cell, mouse models of ALS

Here, researchers at Athira assessed the impact of ATH-1105 in cell and animal models of the neurodegenerative condition.

In a battery of cell experiments, they demonstrated that ATH-1105 does activate the HGF system as designed. The experimental therapy was neuroprotective in nerve cell models, reducing cell damage from a range of cellular toxins and stressors. It also reduced the inflammatory activity of microglia, a type of immune cell in the brain.

After those proof-of-concept tests, ATH-1105 was tested in an ALS mouse model carrying mutations in TARDBP,  the gene responsible for producing TDP-43. In the first experiments, treatment was started at one month of age, which is before motor problems start developing in earnest in this model.

Mice given ATH-1105 maintained higher body weight, indicating better overall health, and better motor function, over untreated mice. ATH-1105 also lowered the severity of nerve dysfunction and reduced markers of inflammation and disease markers, including toxic TDP-43 levels in nerve fibers, a hallmark of ALS. ALS mice given ATH-1105 also lived longer than their untreated counterparts.

“Daily oral treatment with ATH-1105 in this model of ALS resulted in statistically significant and dose-dependent improvement across a battery of assessments for motor performance and nerve structure and function, ultimately resulting in prolonged survival,” the researchers wrote.

In separate experiments, mice were started on ATH-1105 at a later point after symptoms began developing to better mimic a clinical setting.

While the findings weren’t as dramatic, mice given the treatment maintained significantly better scores on several measures of motor function. ATH-1105 also reduced levels of neurofilament light chain (NfL), a marker of nerve damage.

“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. Also, the significant reduction in plasma neurofilament light chain (NfL) levels, an established biomarker of neurodegeneration in ALS, is highly encouraging,” said Kevin Church, PhD, chief scientific officer of Athira.

“Given these data and the critical unmet medical need and devastating disease progression of ALS, we are encouraged to continue the development of ATH-1105 as a potential therapeutic agent for people living with ALS,” the scientists said.