Antioxidant actions of ATH434 may help to slow Parkinson’s advance

Data support iron modulating therapy in atypical parkinsonism Phase 2 trials

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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ATH434, an experimental therapy that’s currently in clinical trials for a type of atypical parkinsonism known as multiple system atrophy (MSA), has antioxidant activities that may protect mitochondria and contribute to its therapeutic effects.

Data supporting its actions were presented this month at the Society for Neuroscience in Washington, D.C., in the poster, “Potent Antioxidant and Mitochondrial-protectant Effects of ATH434, a Novel Inhibitor of [alpha]-Synuclein Aggregation with Moderate Iron-binding Affinity.”

The work was led by scientists at the University of Buffalo in New York, with contributions by a scientist at Alterity Therapeutics, the company developing ATH434.

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“These exciting new data underscore the potential of ATH434 as a treatment for neurodegenerative diseases, including Parkinson’s disease and related disorders,” David Stamler, MD, CEO of Alterity, said in a company press release.

ATH434 is an oral medication that has been shown in preclinical experiments to reduce the clumping of alpha-synuclein, a protein that forms toxic aggregates in the brains of people with Parkinson’s disease and some other types of parkinsonism.

An open-label biomarker trial of the therapy in people with moderate to advanced disease, called ATH434-202 (NCT05864365), began enrolling up to 15 MSA patients this year. A second and global Phase 2 trial (NCT05109091) is testing two doses of ATH434 against a placebo in about 77 adults in earlier MSA stages.

ATH434 is thought to mainly work by modulating levels of iron in the brain. Iron is a nutrient that plays key roles in regulating cellular activities and energy generation, but iron levels in the brain are dysregulated in diseases like Parkinson’s. Alterity expects that regulating brain iron levels may help to treat these disorders.

These new data suggest that ATH434 also has other effects beyond its ability to influence iron levels. Scientists conducted experiments with ATH434 and deferiprone, another drug that’s able to modulate iron levels.

Results indicated that ATH434 has antioxidant effects that were not seen with deferiprone. Antioxidants are molecules that can lower oxidative stress, a type of cellular damage that’s been implicated in the progression of Parkinson’s and many other neurological diseases. In these disorders, oxidative stress can contribute to problems in the workings of mitochondria, the cellular structures responsible for energy production.

“We have long known that ATH434 is able to reduce labile iron which, when elevated, can drive oxidative stress. The demonstrated mitochondrial protection may reveal additional mechanisms that augment its ability to slow disease progression,” Stamler said.

“These results suggest that antioxidant activity may be an important contributor to the efficacy of ATH434 in neurodegenerative disorders,” the researchers concluded.

“Future studies will focus on comparing mitochondrial activity in cells treated with 434 or [deferiprone],” they added.

The U.S. Food and Drug Administration and the European Commission granted orphan drug status to ATH434 for the treatment of MSA. This designation is given to investigational therapies with the potential to treat a disease for which there is a high unmet need.