HONOLULU — A novel “moderate-affinity iron chaperone” known as ATH434 (Alterity Therapeutics) may slow disease progression in patients with multiple system atrophy (MSA), new research suggested.

The oral agent inhibits alpha-synuclein aggregation and reduces oxidative injury by redistributing excess labile iron in the central nervous system. ATH434 has received orphan drug designation for MSA from both the FDA and the European Commission and was granted FDA Fast Track Designation in May.

In a multicountry phase 2 trial, adults with MSA who received ATH434 for 12 months showed significantly greater improvement on the modified Unified Multiple System Atrophy Rating Scale Part I (UMSARS-I) than those given a placebo — a difference representing a 48% slowing of disease progression, investigators reported.

In addition, the 50 mg group showed a significant reduction in brain iron content at week 26 in the putamen and trends for reductions at week 52 in the substantia nigra and pallidum — all of which are areas of the brain known to be affected by MSA.

Adverse event (AE) rates were similar among the treatment groups, and there were no treatment-related serious AEs detected.

“I was pleasantly surprised to see not just statistically significant benefit with the study drug but also clinical significance,” Katie Longardner, MD, assistant clinical professor in the Department of Neurosciences, University of California, San Diego, and one of the site principal investigators, told Medscape Medical News.

The results were presented on October 8 at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2025.

No Approved Therapies

MSA is a rapidly progressive neurodegenerative disorder that affects several areas of the body, including the central nervous system, cardiovascular system, and autonomic system. There are currently no fully approved therapies that specifically target MSA.

The randomized, double-blind study included 77 adult patients from six countries. All participants (mean age, 63 years) had a clinical diagnosis of MSA, motor symptoms for at least 4 years, elevated plasma neurofilament light chain levels (mean, 33.1 pg/mL), and evidence of increased brain iron via MRI.

In the final analysis, 71 participants were randomly assigned to receive 12 months of treatment with ATH434 50 mg twice daily (n = 25), 75 mg of the drug twice daily (n = 24), or a matching placebo (n = 22).

Co-investigator David Stamler, MD, chief executive officer of Alterity Therapeutics, presented the results at an MDS oral platform presentation.

He noted that most baseline characteristics were similar between the three groups. However, the 75 mg group had higher rates of severe orthostatic hypotension (OH; 29%) than the 50 mg (4%) and placebo (4.5%) groups. Severe OH is “a predictor of rapid disease progression,” Stamler said.

Key study outcomes included the UMSARS-I, which rates functional ability in activities of daily living (mean baseline score, 15.5); the Clinical Global Impression-Severity (CGI-S) scale; brain iron content; and safety.

While the overall therapeutic approach was to reduce alpha-synuclein aggregation and oxidative injury in order to preserve neurons, the overall goal was to slow disease progression, Stamler said.

Potentially Disease-Modifying

Results showed that from baseline to week 52, the least square mean difference in UMSAR-I score was -3.8 for the ATH434 50 mg group vs placebo (P = .02), which represented a disease slowing of 48%.

Although the 75 mg group had a score change of -2.4 vs placebo, representing a 30% slowing of disease, it was not statistically significant (P = .16). 

However, Longardner said he would consider a difference of 2.5-3 points clinically significant.

Stamler added that the higher rate of severe OH at baseline in the 75 mg group may have contributed to its lower response.

The 50 mg group also had significantly greater change on the CGI-S scale from baseline to week 52 than the placebo group (P = .009), as well as significantly greater change in step count per day as measured via wearable sensors (P = .04). 

On neuroimaging, the 50 mg group had a significant reduction in iron content at week 26 in the putamen (P = .025). The group also showed reduction at 52 weeks in the substantia nigra and reduction at 26 weeks in the pallidum, with a trend towards significance at 52 weeks (P = .08). 

“ATH434 demonstrated target engagement and also showed trends in preserving brain volume,” Stamler reported.

Rates of any AE were similar among the 50 mg, 75 mg, and placebo groups (84%, 96%, and 92%, respectively). The most common AEs were urinary tract infections (40%, 27%, and 54%, respectively), falls (28%, 31%, and 31%), fatigue (4%, 19%, and 8%), and back pain (12%, 8%, and 4%). Although 20%, 27%, and 39% of the groups reported at least one serious AE, none of the events were found to be related to the study drug.

Characterizing the drug as “a potential disease-modifying treatment,” the investigators noted that ATH434 led to “robust efficacy” and stabilized or reduced iron content in MSA-affected areas.

Following the presentation, session co-moderator Edwin Jabbari, PhD, Department of Clinical and Movement Neurosciences, University College London, London, England, asked about possible next steps for the drug.

Stamler said the company is actively planning for stage 3 research and hoping to interact with the FDA in the near term. “That’s our goal,” he said.

‘Guarded Optimism’

Commenting for Medscape Medical News, Irene Malaty, MD, professor of neurology at the Norman Fixel Institute for Neurological Diseases at the University of Florida in Gainesville, Florida, said that any treatment for MSA, especially one with the potential to modify the disease, would meet a huge unmet need.

“It’s exciting to have any research into MSA with a suggestion of positive impact,” said Malaty, who was not involved with the study.

However, she noted that there have been several studies assessing modulators of alpha-synuclein aggregation in movement disorders that have shown early promise — and then didn’t ultimately pan out. “So we always have a guarded optimism,” she said.

For the current study, she said it’s important to question whether the imaging biomarkers were reliable indicators of clinically meaningful outcomes and whether the changes found in the imaging outcomes would truly affect people’s lives.

Malaty added that because the study population was in the first few years of the disorder, she’d like to see if the medication would have an impact on different stages of disease or even on different subtypes of MSA over time.

“Also, it would be interesting to see longer-term follow-up and if any potential changes hold,” she said.

“I think there’s reason for optimism, and this is an important start, but it will be great to see what we see in the phase 3 trials,” Malaty concluded.

The study was funded by Alterity Therapeutics. Longardner reported receiving some grants related to OH and minimal travel funds from Teva Pharmaceuticals. Stamler reported being an employee of Alterity Therapeutics. Malaty reported having no relevant financial relationships.