Abstract Details

Title A Phase 1 Study of PBT434, a Novel Small Molecule Inhibitor of a-Synuclein Aggregation, in Adult and Older Adult Volunteers

Topic Movement Disorders

Presentation(s) S41 - Parkinson's Disease Interventions and Clinical Trials (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

Objective Evaluate the safety, tolerability and pharmacokinetics of PBT434 in healthy adult and older adult volunteers.

Background

PBT434 is a novel, brain penetrant small molecule inhibitor of α-synuclein aggregation. In transgenic mouse models of Parkinson disease (PD;A53T) and Multiple System Atrophy (MSA;PLP-α-Syn), PBT434 reduced α-synuclein aggregation and markers of oxidative stress, preserved neurons, improved motor function and reduced glial cell inclusions (PLP-α-Syn). PBT434 is thought to act by redistributing labile iron across membranes in the CNS. The affinity of PBT434 for iron is lower than for iron trafficking proteins, e.g., transferrin.

Design/Methods In this randomized, double-blind, placebo-controlled study, adult subjects received oral single doses (8/cohort) 50-600 mg or 8 days dosing (10/cohort) at 100, 200 or 250 mg bid. Older adults (≥65 years) received 250 mg bid. Serial blood samples were collected post-dose and CSF was sampled at 1.5 or 11 hours post-dose at 200-250 mg bid at steady state. Safety was assessed with physical examination, adverse events (AEs), laboratory tests and 12-lead ECGs.

Results PBT434 was rapidly absorbed with a T_max of 0.5-2 hours and demonstrated dose-dependent pharmacokinetics after single and multiple doses. Mean elimination half-life up to 9.3 hours was observed independent of dose. CSF concentrations near T_max were 102.5 to 229.5 ng/mL. AE rates were similar for PBT434 and placebo. All AEs were mild to moderate in severity. There were no serious AEs or AEs leading to discontinuation. The AE profile was similar for adult and ≥65 year-old volunteers. There were no clinically significant vital sign, laboratory or 12-lead ECG findings.

Conclusions

PBT434 is an orally bioavailable, brain penetrant, small molecule inhibitor of α-synuclein aggregation. CSF concentrations at doses ≥200 mg bid were greater than those associated with efficacy in animal models of PD and MSA. PBT434 was safe and well tolerated at all doses. PBT434 has potential to treat synucleinopathies.

Authors/Disclosures
David A. Stamler, MD (Alterity Therapeutics) PRESENTER	Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has stock in Alterity Therapeutics.
	No disclosure on file
Cynthia Wong	Cynthia Wong has received personal compensation for serving as an employee of Alterity Therapeutics. An immediate family member of Cynthia Wong has received personal compensation for serving as an employee of RefleXion Medical. Cynthia Wong has stock in Teva. An immediate family member of Cynthia Wong has stock in 10x Genomics.
	No disclosure on file

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