Positive Interim Phase 2 Data Reported for Multiple System Atrophy Agent ATH434
After 6 months of treatment, nearly half of the small-scale cohort demonstrated enhancements on the Unified MSA Rating Scale, an assessment of activities of daily living.
Daniel Claassen, MD, MS
Newly announced interim data from a phase 2 open-label study (NCT05864365) showed that treatment with investigational ATH434 (Alterity Therapeutucs) was safe, with noted improvements in disability and biomarker assessments after 6 months in patients with multiple system atrophy (MSA). Final, 12-month data from the trial are expected in the first half of 2025.1
Within the small-scale trial, which included 10 participants with MSA, interim data comprised of 7 patients who completed 6 months of treatment with ATH434, 3 of whom who also completed 12 months of treatment. ATH434, an oral agent designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration, was considered well tolerated by patients, with most adverse events (AEs) mild to moderate in severity. Notably, no serious AEs related to the study drug were reported during the trial.
After 6 months of treatment with ATH434 75 twice daily, 43% (3 of 7) of patients had lowered scores on the Unified MSA Rating Scale (UMSARS), an assessment of MSA activities of daily living. Overall, among these patients, UMSARS scores increased by 1.7 (SD, 5.1) points at 6 months, a favorable outcome in comparison with historical data in a similar MSA population. In addition, 29% (2 of 7) of participants were stabilized or improved on the Clinical Global Impression of Change scale and Patient Global Impression of Change scales.
"I am gratified to see that the work we have done over the last several years is bearing fruit as we enhance our understanding of MSA. This has led to improved patient selection and optimized biomarker endpoints in the Alterity Phase 2 trials,” principal investigator Daniel Classen, MD, MS, a professor of neurology at Vanderbilt University Medical Center, said in a statement. “The clinical observations in the ATH434-202 study are supported by the objective biomarkers of brain volume, brain iron, and NfL."
He added, "These early data increase our confidence that we have chosen the right biomarker and clinical endpoints to evaluate the potential effect of ATH434 in individuals with MSA. I am grateful to the study participants and their family members for their contributions to the study."
In terms of biomarker assessments, treated patients showed similar declines in brain volume after 6 months, as assessed by the MSA-atrophy index (MSA-AI); however, in the clinical responders, brain volume was stable between month 6 and month 12. Among clinical responders, iron content in the substantia nigra was stable over 12 months. Additionally, treatment with the agent led to smaller increases in myoinositol, a biomarker of glial cell pathology in MSA, in clinical responders relative to those who worsened.
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Among 5 patients with available data, clinical responders demonstrated stable levels in spinal fluid neurofilament light (NfL) whereas those who declined clinically had increased spinal fluid NfL levels. NfL, a biomarker of neuroaxonal damage, has been used as a diagnostic tool to distinguish early MSA from healthy individuals as well as those with Parkinson disease. To date, there have been questions as to whether changes in NfL in MSA correlate with progression of clinical markers over a longitudinal period of time.
"I am very encouraged by these positive interim data in advanced patients with MSA," David Stamler, MD, chief executive officer at Alterity, said in a statement.1 "As MSA is a rapidly progressive and unremitting disease, we expected to see decline in all participants. Instead, we saw favorable clinical and biomarker outcomes in some patients suggesting that ATH434 has the potential to modify the course of this devastating condition. We were also very pleased to see that the clinical responders had biomarker evidence of stable disease as this provides an objective indication of potential efficacy."
ATH434 is also being evaluated in a phase 2, randomized, double-blind, placebo-controlled trial (NCT05109091) of MSA. Dubbed ATH434-201, the trial assesses the treatment’s effect on neuroimaging and protein biomarkers to demonstrate target engagement and clinical end points to demonstrate efficacy, in addition to assessment s of safety and pharmacokinetics. This global study is fully enrolled, with 77 participants from sites spanning across the US, Europe, Australia, and New Zealand.2
In the study, patients are randomly assigned 1:1 to either ATH434 or placebo for a 12-month treatment period. The hope is that the time of the study will allow for investigators to detect changes in efficacy end points that will ultimately optimize the design of a definitive phase 3 study.
