Oral ATH434 improved motor function in monkeys

Alterity's investigational therapy also is in ongoing clinical trials for MSA

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Alterity Therapeutics‘ ATH434 improved motor performance and overall function in non-human primates with induced Parkinson’s disease, according to data presented at the recent Future of Parkinson’s Disease Conference 2023.

The investigational therapy is currently undergoing evaluation in an open-label biomarker study called ATH434-202 (NCT05864365), which has begun enrolling 15 adults, ages 30-75 years, with multiple system atrophy (MSA), a form of atypical parkinsonism.

“These new data are exciting because we have shown for the first time that ATH434 can reduce Parkinson’s symptoms in a higher order animal — the monkey,” David Stamler, MD, CEO of Alterity, said in a press release.

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“The data from this study improve our ability to predict clinical outcomes and increases our confidence level in our ongoing Phase 2 clinical trials in Multiple System Atrophy, a parkinsonian disorder with similar underlying pathology to Parkinson’s disease,” Stamler said.

Although its early stages are similar to Parkinson’s disease, MSA patients may experience blood pressure and bladder control problems, a sign of dysfunction of the autonomic nervous system that controls involuntary bodily functions. A loss of muscle coordination, or ataxia, is another feature of MSA.

ATH434 is a small molecule that can access the brain and bind to iron, which is thought to play a role in the formation of toxic clumps of alpha-synuclein protein in the brain. The buildup of this protein is a hallmark feature of both MSA and Parkinson’s.

According to Alterity, ATH434’s moderate iron-binding affinity prevents it from interfering with healthy iron trafficking processes, unlike high-affinity iron chelators tested previously in Parkinson’s.

Normalized iron levels in the brains of mice

In mouse models, the candidate therapy helped normalize iron levels in the brain, prevented cell death, and restored motor skills. In Phase 1 clinical studies, ATH434 was well tolerated, and brain levels similar to those reported in MSA animal models were achieved.

This study, “Effects of ATH434, a Clinical-Phase Small Molecule with Moderate Affinity for Iron, in Hemiparkinsonian Macaques” is supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research. It tested ATH434 in macaque monkeys with induced Parkinson’s on one side of the body (hemiparkinsonian). The goal was to determine whether oral ATH434 improved motor function after symptom onset.

After neurotoxin-induced parkinsonian symptoms were evident, monkeys were given daily oral doses of ATH434 (3 or 10 mg/kg) or a placebo for 12-14 weeks. Motor symptoms, either side-specific or general, as well as overall behavior, were assessed using the Parkinson Behavior Rating Scale (PBRS) before (baseline) and after treatment.

After 12 weeks (about three months), all evaluable monkeys treated with ATH434 had stable or improving PBRS scores, either on the affected body side or overall, compared with baseline. By contrast, two of the three placebo-treated macaques showed no change or worsened, “as expected from the progressive nature of the Parkinson model,” the company noted in its release.

Individual PBRS components indicated that ATH434 improved general functions such as balance, posture, activity, and gait. General behavior scores also improved and correlated significantly with reduced motor impairment.

These favorable outcomes seen in each of the ATH434-treated monkeys were associated with lower iron levels in the substantia nigra, the brain region affected in Parkinson’s and MSA patients.

In addition, macaques with improved PBRS scores had higher levels of brain synaptophysin protein, a sign of recovery in motor pathway synapses, which are the gaps between nerve cells that allow the cells to communicate via impulses. Reductions in iron levels significantly correlated with increases in synaptophysin.

“Importantly, the improvements in motor skills and general functioning that parallel human parkinsonism were associated with reductions in iron in affected brain regions, validating the approach we are using in our ongoing clinical trials,” Stamler said.

ATH434 has orphan drug status

ATH434 has been granted orphan drug status by the U.S. Food and Drug Administration and the European Commission. This designation encourages the development of treatments for rare and serious diseases for which there is a high unmet need.