ATH434 Slows Functional Decline in Multiple System Atrophy

MELBOURNE, Australia and SAN FRANCISCO, Oct. 05, 2026 /CourierPR/ -- Alterity Therapeutics, a biotechnology company dedicated to developing disease-modifying treatments for neurodegenerative diseases, presented new analyses from its Phase 2 clinical trial of ATH434 in Multiple System Atrophy (MSA) at the 2026 International Congress of Parkinson’s Disease and Movement Disorders in Seoul, Korea. The trial, a double-blind, placebo-controlled investigation of 12 months treatment with ATH434, enrolled 77 adults who were randomly assigned to receive 50 mg or 75 mg of the drug twice daily or matching placebo.

The analyses, which adjusted for baseline disease severity using cerebrospinal fluid neurofilament light chain (CSF NfL) as a covariate, revealed that ATH434 50 mg significantly slowed functional decline in MSA by approximately 52% versus placebo on the 11-item Unified Multiple System Atrophy Rating Scale (UMSARS) Part I at Week 52. The 75 mg dose also showed a trend towards slowing functional decline, with a −2.81-point difference versus placebo in change from baseline at Week 26 (p=0.072) and Week 52 (p=0.179).

Baseline CSF NfL, an established prognostic biomarker of clinical decline in MSA, was found to predict functional decline. Higher baseline CSF NfL predicted greater decline at Week 52: each 1,000 pg/mL increase was associated with approximately 0.9 additional points of worsening on UMSARS I1, a finding significant (p=0.033). This supports the use of CSF NfL as a covariate in future MSA trials, as adjusting for a known predictor of decline can produce a more precise measurement of treatment effect.

The analysis utilized a mixed model for repeated measures (MMRM) applied to the Modified Intent-to-treat (mITT) population (N=61). After adjustment for baseline CSF NFL, ATH434 50 mg significantly slowed functional decline on the 11-item UMSARS Part I at Week 52 with a −4.64-point difference versus placebo in change from baseline (p=0.032), roughly three-fold more improvement compared to the 1.5-point minimal clinically important difference.

The trial also reported advanced brain iron MRI imaging consistent with the ATH434 mechanism of action as an iron chaperone. While the primary endpoint of change in substantia nigra iron at Week 52 was not met, change from baseline in iron was numerically lower in the putamen and globus pallidus with ATH434 vs placebo. In the dentate nucleus, iron signal increased relative to placebo at Week 52 (50 mg: +0.016 ppm, p=0.021), which is hypothesized to reflect redistribution of mobilized iron through the brain’s glymphatic system. The regional differences may reflect region-specific iron handling because an MRI captures iron efflux but not the potential storage or buffering effects of ATH434.

The Phase 2 clinical trial, which was conducted as a double-blind, placebo-controlled investigation of 12 months treatment with ATH434, evaluated the efficacy, safety, and pharmacokinetics of ATH434 in participants with MSA. The study also assessed the effect of ATH434 on neuroimaging and protein biomarkers. Wearable sensors were employed to evaluate motor activities outside of the clinic. The data showed that, compared to placebo, ATH434 50 mg produced clinically and statistically significant slowing of decline on the 11-item UMSARS Part I, a functional rating scale that assesses disability on activities of daily living affected in MSA. Additional efficacy assessments demonstrated improvement consistent with the positive UMSARS Part I findings, including trends in improved motor performance on the Clinical Global Impression of Severity Scale, the Swallowing Disturbance Questionnaire, and the Orthostatic Hypotension Symptom Assessment. Wearable sensor data indicated that ATH434 also led to increased activity in an outpatient setting.

Biomarkers were used to evaluate potential drug effect and target engagement relative to placebo. Both dose levels reduced iron accumulation in MSA-affected brain regions with trends in preservation of brain volume. ATH434 was well tolerated with similar adverse event rates compared to placebo and no serious adverse events attributed to ATH434. The trial was found by ClinicalTrials.gov Identifier: NCT05109091.

Multiple System Atrophy (MSA) is a rare, neurodegenerative disease characterized by failure of the autonomic nervous system and impaired movement. The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord. It is a rapidly progressive disease and causes profound disability. MSA is a Parkinsonian disorder characterized by a variable combination of slowed movement and/or rigidity, autonomic instability that affects involuntary functions such as blood pressure maintenance and bladder control, and impaired balance and/or coordination that predisposes to falls. A pathological hallmark of MSA is the accumulation of the protein α-synuclein within glia, the support cells of the central nervous system, and neuron loss in multiple brain regions. MSA affects up to 50,000 individuals in the U.S., and while some of the symptoms of MSA can be treated with medications, currently there are no drugs that are able to slow disease progression and there is no cure.