Alterity Therapeutics Publishes New Mechanism for ATH434

Alterity Therapeutics, a biotech firm focused on developing treatments for neurodegenerative diseases, has announced a significant publication in the journal Metallomics. The paper, titled "ATH434, a promising iron-targeting compound for treating iron regulation disorders," explores the crucial role of iron and iron-targeting agents like ATH434 in addressing neurodegenerative disorders.

David Stamler, M.D., the CEO of Alterity, highlighted the impact of iron on neurodegeneration, emphasizing the importance of a suitable iron-targeting agent in treating such conditions. The publication presents a novel approach where ATH434 targets the labile, reactive form of iron, which can be harmful to cells when present in excess. Acting as an iron chaperone, ATH434 redistributes this reactive iron, reducing protein aggregation and oxidative stress in the brain, thereby improving neuronal function.

The research was led by Ashley Pall from the Department of Pharmaceutical Sciences at Wayne State University. It details the unique iron-binding properties of ATH434, which support its characterization as an iron chaperone. The compound targets the toxic form of iron associated with the pathology of Friedreich’s Ataxia, a rare neurodegenerative disease. This form of iron is also implicated in the pathogenesis of Parkinson’s disease and multiple system atrophy (MSA), which is the primary focus of Alterity’s research.

The study also compared ATH434 with iron chelators designed to irreversibly bind and remove the stored form of iron from the body. It specifically examined the binding affinity of ATH434 and iron chelators to ferric iron, the stored form, and ferrous iron, the active form necessary for essential cellular functions like energy production but toxic in excess. The findings revealed that ATH434 has a significantly lower affinity for ferric iron compared to approved iron chelators for systemic iron overload. Unlike these chelators, ATH434’s binding is reversible, which means it does not remove iron from the body.

Furthermore, the study confirmed that iron chelators often promote the conversion of ferrous to ferric iron, generating harmful free radicals. In contrast, ATH434 was much less likely to induce this reaction. These characteristics suggest that ATH434 can selectively target the harmful form of iron without disrupting normal cellular iron functions.

ATH434, the lead candidate from Alterity Therapeutics, is an oral agent designed to inhibit the aggregation of pathological proteins linked to neurodegeneration. Preclinical studies have shown that ATH434 can reduce α-synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain. The compound shows promise for treating Parkinson’s disease and various Parkinsonian disorders such as MSA.

ATH434 has successfully completed Phase 1 trials, demonstrating that it is well-tolerated and achieves brain levels comparable to those effective in animal models of MSA. Currently, ATH434 is undergoing two Phase 2 clinical trials. Study ATH434-201 is a randomized, double-blind, placebo-controlled trial for patients with early-stage MSA, while Study ATH434-202 is an open-label trial focusing on biomarkers in patients with more advanced MSA. ATH434 has been granted Orphan drug designation for the treatment of MSA by both the U.S. FDA and the European Commission.

Alterity Therapeutics, based in Melbourne, Australia, and San Francisco, USA, is committed to developing innovative treatments for neurodegenerative diseases. The company's primary asset, ATH434, holds the potential to address various Parkinsonian disorders and is currently being evaluated in clinical trials. Alterity also boasts a comprehensive drug discovery platform aimed at creating patentable compounds to treat the underlying pathology of neurological diseases.

The publication in Metallomics underscores the potential of ATH434 as a groundbreaking treatment for disorders related to iron regulation, providing a promising outlook for future therapies in neurodegenerative diseases.