Alterity Therapeutics has announced the presentation of multiple data sets at the International Congress of Parkinson’s Disease and Movement Disorders (MDS), showcasing the potential of its lead candidate, ATH434, in treating neurodegenerative diseases, particularly Multiple System Atrophy (MSA) and Parkinson's disease. The data, presented in both oral and poster formats, highlight ATH434's ability to modify disease progression and reduce disability in individuals with MSA.
ATH434-202 Phase 2 Interim Data
Interim data from the ATH434-202 Phase 2 open-label clinical trial in MSA demonstrated that 30% of participants experienced stable or improved clinical outcomes, defined as clinical responders. These responders also showed stability in key biomarkers, including brain iron levels and neurofilament light chain (NfL), a marker of nerve damage. Specifically, clinical responders had stable or reduced NfL levels, with average increases of 2.7% in CSF and 4.5% in plasma at 6 months, compared to 17.9% and 19.3% in Alterity’s bioMUSE natural history participants, respectively. These findings suggest that ATH434 may have a disease-modifying effect by modulating brain iron levels and reducing oxidative injury.
Dr. David Stamler, CEO of Alterity Therapeutics, stated, "In the open-label Phase 2 study, 30% of participants showed stable or improved clinical outcomes (clinical responders). In addition, the clinical responders demonstrated stability in objective biomarkers such as brain iron and a protein marker of nerve damage, when compared to non-responders. Taken together, these data suggest that ATH434 has potential as a disease modifying treatment."
The ATH434-202 trial is an open-label study evaluating the impact of 12 months of ATH434 treatment on brain volume and other biomarkers in individuals with advanced MSA. Final 12-month data from this trial are expected in the first half of 2025.
ATH434-201 Phase 2 Baseline Characteristics
Baseline characteristics from the ATH434-201 randomized, double-blind Phase 2 clinical trial were also presented. This trial enrolled 77 participants with early-stage MSA, selected using strict criteria to confirm the diagnosis. The presentation highlighted the use of multimodal approaches, including neuroimaging and fluid biomarkers, to improve the accuracy of diagnosing clinically probable MSA. Increased iron levels were evident in multiple subcortical brain regions, with increased levels being observed in the substantia nigra in nearly all subjects.
bioMUSE Natural History Study
Data from the bioMUSE natural history study, designed to track the progression of MSA, revealed significant brain volume reduction in MSA-relevant regions of interest (ROIs) over one year, as assessed by novel MRI imaging techniques and deep learning segmentation. Specifically, MSA patients exhibited significant volume reductions in the cerebellum, globus pallidus, and brainstem, while MSA-P patients showed significant volume loss in the putamen. These results correlated with worsening clinical scores, providing a visual representation of disease progression.
ATH434 in Parkinson's Disease Model
Preclinical data in a Parkinson's disease model in macaques demonstrated that ATH434 treatment led to lower iron levels in the substantia nigra and improved motor performance and general function. At week 12, all 5 ATH434-treated macaques had stable or improving scores from Baseline while two of three vehicle-treated macaques did not demonstrate improvement. These favorable outcomes were associated with increased levels of striatal synaptophysin, a protein marker reflecting functional connections between neurons, suggesting functional recovery of nerve endings. These results support further investigation of ATH434 for the treatment of Parkinson’s disease.
About ATH434
ATH434 is an oral agent designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration. Preclinical studies have shown that ATH434 reduces α-synuclein pathology and preserves neuronal function by restoring normal iron balance in the brain. It is currently being evaluated in two Phase 2 clinical trials in MSA: ATH434-201 in early-stage MSA and ATH434-202 in more advanced MSA. ATH434 has been granted Orphan Drug Designation for the treatment of MSA by the U.S. FDA and the European Commission.
Topline data from the ATH434-201 trial is expected in January 2025, and 12-month data from ATH434-202 is anticipated later in 2025. These trials aim to evaluate the effect of ATH434 on neuroimaging and protein biomarkers, as well as clinical endpoints, to demonstrate efficacy and assess safety and pharmacokinetics.
