Alterity Therapeutics released topline results from its Phase 2 trial of ATH434-201 in patients with early-stage multiple system atrophy (MSA). MSA is a debilitating and rapidly progressing disease for which no disease-modifying treatments currently exist.
A key gap in knowledge about the development of neurodegenerative diseases like MSA is a clear mechanism that leads to neuronal dysfunction. Treating diseases like MSA requires such mechanisms to modify disease course. Recent studies have demonstrated that patients with MSA exhibit more iron dysregulation, which likely is correlated with neuronal atrophy. In a separate, foundational study, increased levels of iron were found in the striatum in individuals with Parkinson’s disease (PD) when compared to healthy controls. A 2019 review describes how this iron accumulation is believed to be correlated with neurodegeneration via oxidative stress and the aggregation of phosphorylated α-synuclein, a protein implicated in MSA pathology.
ATH434 is an oral small molecule that targets the accumulation of alpha-synuclein by restoring normal iron balance in settings of neurodegeneration. In preclinical trials, researchers demonstrated that patients treated with ATH434 experienced improved motor function and reduced iron levels in the brain.
The randomized, double-blind placebo-controlled Phase 2 trial assigned 77 adults with MSA to either 50 mg or 75 mg of ATH434 or placebo twice daily. The primary endpoint was the change in brain iron measured my MRI.
The reduction in accumulation of iron in the putamen at 26 weeks (P=0.025) was significant with the 50 mg dose and approached significance in the globus pallidus at 52 weeks (P=0.08).
Slowing of clinical, symptomatic progression by 26% to 62% was represented by decreases in UMSARS Part I, a functional rating scale that assesses disability and disease severity in MSA.
Mean Change From Baseline in UMSARS I Score
| Week 26 | Week 52 | |
| Placebo | -4.5 | -8.2 |
| ATH434 50 mg | — | -4.3 (P=0.03) |
| ATH434 75 mg | -1.8 (P=0.05) | -5.8 (P=0.02) |
A significant reduction in Clinical Global Impression of Severity score (-0.81, P=0.009) was demonstrated with the 50mg dose. Both doses demonstrated clinical benefit on Parkinson Plus total motor score and showed increases in step count and standing time as measured by wearable sensors.
ATH434 was well tolerated. No serious adverse events were reported, and no adverse events leading to discontinuation were due to treatment.
“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. The fact that we achieved statistical significance on the UMSARS is extremely meaningful because it assesses the functional areas affected in MSA and is the endpoint needed to support drug approval by the U.S. Food and Drug Administration (FDA),” said David Stamler, MD, CEO of Alterity. Alterity hopes to discuss accelerating the development of ATH434 with the FDA.
References:
Lee J-H and Lee M-S (2019) Brain iron accumulation in atypical parkinsonian syndromes: in vivo MRI evidences for distinctive patterns. Front. Neurol. 10:74. doi: 10.3389/fneur.2019.00074
