Abstract Details

Title Effects of ATH434, a Clinical-phase Small Molecule with Moderate Affinity for Iron, in a Parkinson’s Disease Model in Macaques

Topic Movement Disorders

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-010

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.

Authors/Disclosures
Margaret Bradbury (Alterity Therpeutics) PRESENTER	Margaret Bradbury has received personal compensation for serving as an employee of Alterity Therapeutics. The institution of Margaret Bradbury has received research support from Alterity Therapeutics.
Megan Aumann	No disclosure on file
Daniel O. Claassen, MD, FAAN (Vanderbilt University Medical Center)	Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for AskBio. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Michigan. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cognition Therapeutics . Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from CHDI.
David Finkelstein (Florey Institute of Neuroscience and Mental Health & The University of Melbourne)	No disclosure on file

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