News|Articles|July 28, 2025
ATH434 Continues to Demonstrate Positive Efficacy in Latest Phase 2 Data Readout
Author(s)Marco Meglio
New trial data reveals ATH434 significantly improves symptoms and biomarkers in multiple system atrophy patients, paving the way for potential treatment advancements.
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Newly announced data from an open-label phase 2 trial (NCT05864365) showed that investigational ATH434 (Alterity Therapeutics) led to significant therapeutic impacts in patients with multiple system atrophy (MSA), including on biomarker end points and orthostatic function, over a 12-month period. The findings mark the second positive phase 2 study in MSA for ATH434, further adding to the agent’s treatment profile.1
Otherwise known as the ATH434-202 trial, this open-label study featured 10 patients with the disease who received 75 mg of ATH434 twice daily for 12 months. At the conclusion of the treatment period, study investigators recorded mean increases of 3.5 (SD, 4.7) points on Modified Unified MSA Rating Scale Part I (UMSARS I), with 3 of 7 (43%) patients who completed the study demonstrating stable UMSARS scores.
ATH434, an oral agent designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration, also demonstrated a positive impact on brain volume, the trial’s key biomarker. At 12 months, treated patients demonstrated a mean z-score of –0.44 (SD, 0.138) on MSA Atrophy Index (MSA-AI), which was consistent with that seen in the 75 mg treatment group of Study 201, a previously completed trial.
"These results are very helpful in establishing the clinical response to therapy. The consistent changes in UMSARS, along with quantitative measures in imaging, support the findings we noted in Study 201,” principal investigator Daniel Claassen, MD, MS, professor of neurology at Vanderbilt University Medical Center, said in a statement.1 "Currently, there are no disease modifying medications for the treatment of MSA, and these data encourage the continued development of ATH434 to treat this disease. We are indebted to the study participants and their families who contributed to this study."
MSA is associated with excess iron accumulation, particularly in the putamen, a region of the basal ganglia involved in movement regulation. All told, results from study 202 revealed reduced iron accumulation in the globus pallidus and putamen as compared with patients on placebo from the previously completed Study 201. In addition, iron accumulation in the substantia nigra over 12 months mirrored that seen in the 75 mg group from Study 201.
In terms of safety, there were no serious adverse events (AEs) related to ATH434 that were reported, and there were no evidence of AEs on hemoglobin or iron parameters. There were 3 discontinuations, 2 related to the progression of MSA and 1 due to an AE that was not related to ATH434. Overall, the safety profile was consistent with its previous study, with most AEs being mild to moderate in severity.
"I am very encouraged by the positive results from the ATH434-202 trial, as they reinforce the robust efficacy we observed in our double-blind study," David Stamler, MD, chief executive officer at Alterity, said in a statement.1 "The data from our Phase 2 studies are consistent and strongly support advancing our ATH434 program in MSA. With the favorable clinical and biomarker outcomes we have seen, we continue to believe that ATH434 has the potential to slow the progression of this devastating disease. We are committed to bringing this new therapy to patients as soon as possible."
Over a 12-month treatment period, 30% (3/10) of participants showed stabilization or improvement in overall neurological symptoms as assessed by both the clinician-rated Clinical Global Impression of Change (CGIC) and the patient-reported Patient Global Impression of Change (PGIC) scales. Additionally, symptoms of orthostatic hypotension, measured by the Orthostatic Hypotension Symptom Assessment (OHSA), remained stable on average throughout the study.
Study 201, announced earlier this year , featured 77 patients across 23 sites in 6 countries, who received either 50 mg or 75 mg of ATH434 or placebo twice daily for 12 months. In the trial, those in the 50 mg group demonstrated the greatest benefit, with clinical progression slowed by 48% at 52 weeks compared with placebo (P = .03). Once again, ATH434 showed reductions in brain iron content, with the 50 mg dose reaching significance in the putamen at 26 weeks (P = .025) and approaching significance in the globus pallidus at 52 weeks (P = .08).2
On UMSARS I, patients in the 50 mg dose cohort experienced a 48% slower disease progression at 52 weeks (P = .03) compared with placebo, while the 75 mg group showed slowed progression by 29% (P = 0.2). At 26 weeks, the 75 mg dose showed a 62% slowing of disease progression (P = .05). Secondary outcomes showed improved motor function with 50 mg, including a significant CGI-Severity score reduction (–0.81; P = .009) and increased activity on wearable sensors.
REFERENCES
1. Alterity Therapeutics Reports Positive Topline Data from Open-Label Phase 2 Clinical Trial of ATH434 in Multiple System Atrophy. News release. Alterity Therapeutics. July 28, 2025. Accessed July 28, 2025. https://alteritytherapeutics.com/investor-centre/news/2025/07/28/alterity-therapeutics-reports-positive-topline-data-from-open-label-phase-2-clinical-trial-of-ath434-in-multiple-system-atrophy/
2. 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 July 28, 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/
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