Alterity presents new ATH434 Phase 2 analyses in multiple system atrophy at MDS Congress 2026
Alterity Therapeutics has presented additional analyses from its randomised, double-blind, placebo-controlled ATH434-201 Phase 2 trial in multiple system atrophy (MSA) at the 2026 International Congress of Parkinson’s Disease and Movement Disorders (MDS Congress) in Seoul, Korea.
The poster combined clinical, biomarker and imaging results from the trial after adjusting for baseline disease severity. Severity was measured by cerebrospinal fluid neurofilament light chain (CSF NfL), an established prognostic biomarker of clinical decline in MSA and a prespecified covariate in the trial.
CSF NfL predicts functional decline
Higher baseline CSF NfL predicted greater functional decline at Week 52. Each 1,000 pg/mL increase was associated with approximately 0.9 additional points of worsening on UMSARS Part I (p=0.033). The company said this supports using CSF NfL as a covariate in future MSA trials, because adjusting for a known predictor of decline allows a more precise measurement of treatment effect.
ATH434 50 mg slowed functional decline
After adjustment for baseline CSF NfL, ATH434 50 mg slowed functional decline on the 11-item UMSARS Part I by approximately 52% versus placebo at Week 52. This corresponded to a −4.64-point difference in change from baseline (p=0.032), around three times the 1.5-point minimal clinically important difference. The 75 mg dose also slowed decline, with a −2.81-point difference versus placebo at Week 26 (p=0.072) and Week 52 (p=0.179).
These results are consistent with the previously reported analysis, in which ATH434 50 mg slowed decline by 46% versus placebo (p=0.037). The difference between the two figures reflects distinct analysis populations and statistical models.
Brain iron imaging
ATH434 is an investigational iron chaperone designed to redistribute reactive (labile) iron that drives MSA pathology. Brain iron was measured using quantitative susceptibility mapping (QSM) MRI. The trial’s primary endpoint, change in substantia nigra iron at Week 52, was not met. However, iron was numerically lower in the putamen and globus pallidus with ATH434 than with placebo.
In the dentate nucleus, iron signal increased relative to placebo at Week 52 with the 50 mg dose (+0.016 ppm, p=0.021). The company hypothesises this reflects redistribution of mobilised iron through the brain’s glymphatic system. Because MRI captures iron leaving cells but not iron stored or buffered within them, regional differences may reflect region-specific iron handling.
“These additional analyses strengthen our confidence in ATH434 as a potential disease-modifying therapy for MSA,” said David Stamler, MD, CEO of Alterity. “When we account for differences in baseline disease severity using CSF NfL, ATH434 50 mg significantly slowed functional decline by more than 50% compared with placebo over one year.”
He added that the company would incorporate the NfL findings into its Phase 3 confirmatory trial.
About the trial
The ATH434-201 trial (NCT05109091) enrolled 77 adults with MSA. Participants were randomised to ATH434 50 mg or 75 mg twice daily or matching placebo for 12 months.
Beyond the UMSARS Part I findings, the trial showed supportive trends on the Clinical Global Impression of Severity Scale, the Swallowing Disturbance Questionnaire and the Orthostatic Hypotension Symptom Assessment. Wearable sensor data indicated increased activity in an outpatient setting with ATH434.
ATH434 was well tolerated, with adverse event rates similar to placebo and no serious adverse events attributed to treatment.
