Multiple System Atrophy Agent ATH434 Shows Promising Topline Efficacy in Phase 2 Trial

Daniel Claassen, MD, MS

(Credit: Vanderbilt University Medical Center)

New topline results from the randomized, double-blind, placebo-controlled phase 2 trial (NCT05109091) of Alterity Therapeutics’ ATH434 revealed that treatment with the investigational agent was well tolerated and demonstrated clinical as well as biomarker-based benefits, particularly at the 50 mg dose, among patients with early-stage multiple system atrophy (MSA).These findings support ATH434’s potential as a disease-modifying therapy for MSA to slow disease progression and reduce iron accumulation in key brain regions.¹

The study enrolled 77 participants across 23 sites in 6 countries, who received either 50 mg or 75 mg of ATH434 or placebo twice daily for 12 months. Findings showed that ATH434 was well tolerated and effectively reduced iron accumulation in brain regions impacted by MSA. The 50 mg dose demonstrated the greatest benefit, slowing clinical progression by 48% at 52 weeks compared with the placebo (P = 0.03). Additional analyses also suggested trends in improved motor function and preserved brain volume.

Coordinating investigator Daniel Claassen, MD, MS, professor of neurology at Vanderbilt University Medical Center, commented in a statement, “The findings from the study are compelling because ATH434 appears to have meaningfully slowed MSA progression and stabilized motor function. To date, no treatment has altered the progression of this devastating disease. The slowing of clinical progression in this study, particularly at 50 mg, is impressive. I look forward to continue working with Alterity to bring this therapy to patients, and I know the MSA community welcomes this exciting advancement.”¹

The primary end point of the trial assessed brain iron content via MRI. All told, ATH434 reduced or stabilized iron accumulation in affected brain regions, with the 50 mg dose showing significant reductions in the putamen at 26 weeks (P = 0.025) and approaching significance in the globus pallidus at 52 weeks (P = 0.08). Clinical efficacy was assessed using the Unified MSA Rating Scale Part I (UMSARS I), a common MSA assessment that measures disability and disease severity.² Overall, patients on the 50 mg dose experienced a 48% slower disease progression at 52 weeks (P = 0.03) compared with placebo, and the 75 mg dose slowed progression by 29% (P = 0.2). At 26 weeks, the 75 mg dose showed a 62% slowing of disease progression (P = 0.05).

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“We are thrilled that ATH434 has demonstrated significant slowing of clinical progression and an excellent safety profile in this rare, rapidly progressive disease,” David Stamler, MD, chief executive officer at Alterity, said in a statement.¹ “Currently, there are no approved treatments that slow the progression of MSA and these results show that ATH434’s targeted iron engagement may truly have a disease modifying effect.”

Additional secondary end points included improved motor performance, with the 50 mg dose showing significant benefit on the Clinical Global Impression of Severity scale (mean change, -0.81; P = 0.009). Wearable sensors also indicated increased step count, walking time, and standing time in treated patients. ATH434 was well tolerated, with adverse event rates comparable with placebo. Most adverse events were mild to moderate, and no treatment-related serious adverse events were reported. The 50 mg dose had the lowest rate of discontinuations because of adverse events (n = 0), compared to the 75 mg dose (n = 5) and placebo (n = 3).

“The fact that we achieved statistical significance on the UMSARS is extremely meaningful because it assesses the functional areas affected in MSA and is the endpoint needed to support drug approval by the U.S. Food and Drug Administration (FDA),” Stamler said in a statement.¹ “Based on the strength of these Phase 2 data, we look forward to engaging with the FDA as quickly as possible to discuss the path forward for accelerating the development of ATH434 given the tremendous unmet need for treating MSA. We are very grateful for the invaluable contributions of the study participants and the clinical sites who contributed to the study.”

Stamler concluded in a statement, “We now have evidence that targeting excess labile iron in neurodegenerative disease can be achieved. By redistributing this reactive form of iron that contributes to disease pathogenesis, not only can we target α‑synuclein aggregation, but we can also break the vicious cycle underlying disease progression. This has implications for developing disease modifying treatments for orphan diseases such as MSA and Friedreich’s ataxia as well as major neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease.”¹

REFERENCES
1. Alterity Therapeutics Announces Positive ATH434 Phase 2 Trial Results in Multiple System Atrophy Led By Robust Clinical Efficacy. News Release. Alterity Therapeutics. Published January 30, 2025. Accessed January 30, 2025. https://alteritytherapeutics.com/investor-centre/news/2025/01/30/alterity-therapeutics-announces-positive-ath434-phase-2-trial-results-in-multiple-system-atrophy-led-by-robust-clinical-efficacy/
2. Geser F, Wenning GK, Seppi K, et al. Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord. 2006;21(2):179-186. doi:10.1002/mds.20678