Effects of ATH434, a Clinical-phase Small Molecule with Moderate Affinity for Iron, in a Parkinson’s Disease Model in Macaques
Margaret Bradbury1, Megan Aumann2, Daniel Claassen2, David Finkelstein3
1Alterity Therpeutics, 2Vanderbilt University Medical Center, 3Florey Institute of Neuroscience and Mental Health
Objective:
(1) Determine whether oral ATH434 improves motor performance in a non-human primate hemiparkinasonian model when administered after symptom onset. (2) Relate observations to changes in brain iron, preservation of substantia nigra (SN) tyrosine hydroxylase positive (TH+) neurons, and nigrostriatal integrity.
Background:
ATH434 is a novel iron binding drug candidate currently in Phase 2 clinical trials for Multiple System Atrophy (MSA). In Parkinson’s disease and MSA mouse models, ATH434 reduced disease-related excess iron, oxidative stress markers, and aggregated alpha-synuclein. ATH434 also improved nigrostriatal pathway integrity and motor performance. ATH434 is postulated to redistribute excess labile cellular iron, facilitating export. Unlike high-affinity iron chelators approved for iron overload, ATH434’s moderate iron affinity precludes it from interfering with endogenous iron trafficking proteins such as transferrin.
Design/Methods:
Young male macaques received single right carotid MPTP infusion (Day 0) followed by daily oral doses of vehicle or ATH434 (3mg/kg/day or 10 mg/kg/day) from Day 3 to Weeks 12-14 (final n=2-3/group). Parkinson Behavior Rating Scale (PBRS) scores were recorded pre-treatment (Day 2), and during Weeks 4, 8, and 12. Terminal endpoints included SN iron (mass spectrometry), TH+ SN neurons (immunocytochemistry), dorsal striatal dopamine transporter (DAT) density (PET), and synaptophysin (western blot).
Results:
Pre-treatment left side specific, generalized motor, and generalized behavior scores of the PBRS indicated significant parkinsonism in all macaques. Striatal DAT confirmed similar lesion sizes across groups. At Week 12, all ATH434-treated and 1 vehicle-treated macaque had improved or stabilized scores; the remaining 2 vehicle-treated macaques demonstrated worsening symptoms. Changes in TH+ SN neuron counts were not significant. Reduced parkinsonian indices clustered with increased right-side striatal synaptophysin and reduced right-side SN iron.
Conclusions:
ATH434 improved motor performance in MPTP-injured primates in this small study. Efficacy is thought to be mediated by reducing excess labile iron in areas of pathology and by enhancing synaptic connectivity in the nigrostriatal pathway.