ATH-1105 prolongs survival in mouse model of ALS

Treatment reduced neurodegeneration, inflammation, TDP-43 protein buildup

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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ATH-1105, a treatment candidate by Athira Pharma, significantly prolonged survival in a mouse model of amyotrophic lateral sclerosis (ALS), according to a company update.

Consistent with previous analyses, the treatment also reduced neurodegeneration, inflammation, and the toxic buildup of the TDP-43 protein in nerve cells, which resulted in significant motor and nerve function improvements.

The findings were presented in a poster at the American Academy of Neurology (AAN) Annual Meeting last month.

Athira is completing preclinical studies so it can submit an investigational new drug application to conduct in-human studies of the therapeutic candidate. The company hopes to initiate clinical studies in 2024.

“We are encouraged by the compelling preclinical evidence with ATH-1105, which demonstrates statistically significant improvements on survival and nerve and motor function in an ALS animal model,” Kevin Church, PhD, Athira’s chief scientific officer, said in a press release announcing the presentation last month. “We are advancing IND-enabling studies with ATH-1105 and plan to begin clinical evaluation next year.”

ALS is marked by progressive neurodegeneration and inflammation. Nearly all patients exhibit abnormal clumps of the TDP-43 protein in nerve cells, which is thought to be a key driver of nerve cell damage in the disease.

ATH-1105 is an oral small molecule that activates the HGF/MET system, a signaling pathway involved in maintaining nerve cell health via its ability to counteract neurotoxicity, inflammation, and oxidative stress, a type of cell damage implicated in ALS.

A growing body of evidence indicates boosting the pathway’s activity may help treat neurodegenerative diseases like ALS.

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Prolonged survival with ATH-1105

Last year, the company presented data indicating nerve cells treated with ATH-1105 in cell cultures showed significantly better survival under toxic conditions than untreated cells.

ATH-1105 was also associated with higher body weight, lower levels of inflammatory markers, preserved nerve cell health, and better motor function in a mouse model of ALS. The model featured mutations in TARDBP,  the gene responsible for producing TDP-43, leading to ALS-like symptoms and TDP-43 buildup.

In the AAN poster “ATH-1105, a Small-Molecule Positive Modulator of Hepatocyte Growth Factor (HGF)/MET, Is Neuroprotective in a TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis,” researchers provided additional findings from this TDP-43 mouse model.

TDP-43 mice were treated with 20 mg/kg ATH-1105 or a placebo daily for four months to assess its effects on survival.

ATH-1105 significantly prolonged survival in the ALS model, delaying the time to a first death from 59 days in the placebo group to 101 days, results showed.

Two months of treatment also led to measures of motor function stabilizing, while untreated mice saw significant declines over time, which was consistent with previous analyses.

“Together, these behavioral data demonstrate that ATH-1105 helps to preserve balance, coordination, and muscle strength, which progressively decline in ALS mice,” Jewel Johnston, PhD, the director of in vivo pharmacology at Athira, said in the poster presentation.

The therapy was also associated with preserved muscle and nerve function, and it protected mice from nerve cell degeneration and loss of myelin, the fatty substance that surrounds and protects nerve cells.

Treated mice treated also had significant reductions in key inflammatory markers, as well as neurofilament light chain (NfL), a biomarker of nerve cell degeneration. The accumulation of TDP-43 in nerve cells was significantly reduced in ATH-1105-treated mice over those given the placebo.

Finally, mice given ATH-1105 saw increases in body weight that resembled those seen in healthy animals, indicating good general health, while untreated mice had consistently lower body weight.

“This study highlights the therapeutic potential of ATH-1105 in a mouse model of ALS and supports further investigation of ATH-1105 in this disease indication,” the researchers wrote.