Alterity Therapeutics announced positive topline results from its Phase 2 clinical trial evaluating ATH434 in patients with early-stage multiple system atrophy (MSA). The randomized, double-blind, placebo-controlled study, known as ATH434-201, demonstrated clinically and statistically significant improvements in key measures of disease progression and target engagement.
The trial, conducted across 23 sites in six countries, enrolled 77 adults with early-stage MSA who were randomly assigned to receive either 50 mg or 75 mg of ATH434 or a placebo twice daily for 12 months. The primary objective was to assess the efficacy, safety, and pharmacokinetics of ATH434, along with its effects on neuroimaging and protein biomarkers.
Clinical Efficacy and Biomarker Results
The topline data revealed that ATH434 produced a clinically and statistically significant improvement on the modified Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, a functional rating scale assessing disability in activities of daily living affected by MSA. Specifically, the 50 mg dose of ATH434 demonstrated a 48% slowing of clinical progression (p=0.03) at Week 52 compared to placebo. The 75 mg dose showed a 29% slowing of clinical progression (p=0.2) at Week 52 and a 62% slowing of progression (p=0.05) at Week 26.
In addition to clinical improvements, biomarker analysis showed that the 50 mg dose of ATH434 reduced iron accumulation in MSA-affected brain regions, including the substantia nigra, putamen, and globus pallidus. The reduction in iron accumulation was significant at 26 weeks (putamen, P=0.025) and approached statistical significance at 52 weeks (globus pallidus, P=0.08). Trends in preservation of brain volume were also observed in both the 50 mg and 75 mg dose groups relative to placebo at both 26 and 52 weeks of treatment.
Safety and Tolerability
ATH434 was well-tolerated in the Phase 2 trial, with similar adverse event (AE) rates observed in the ATH434 treatment groups and the placebo group. Most AEs were mild to moderate in severity, and no serious adverse events (SAEs) related to ATH434 were reported. Discontinuations due to AEs were similar in the placebo (n=3) and 75 mg dose (n=5) groups and lowest in the 50 mg dose group (n=0).
Expert Commentary
"We are thrilled that ATH434 has demonstrated significant slowing of clinical progression and an excellent safety profile in this rare, rapidly progressive disease," said David Stamler, M.D., Chief Executive Officer of Alterity. "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."
Daniel Claassen, M.D., M.S., Professor of Neurology at Vanderbilt University Medical Center and Coordinating Investigator for the ATH434-201 Phase 2 study, commented, "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."
Future Directions
Based on the positive Phase 2 data, Alterity plans to engage with the U.S. Food and Drug Administration (FDA) to discuss the path forward for accelerating the development of ATH434 for the treatment of MSA. Currently, there are no approved disease-modifying therapies for MSA, a rapidly progressive and debilitating disease affecting an estimated 15,000 individuals in the U.S.
Dr. Stamler concluded, "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."
