A Phase 1 Study of PBT434, a Novel Small Molecule Inhibitor of α-Synuclein Aggregation, in Adult and Older Adult Volunteers (4871)

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.

Disclosure: Dr. Stamler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Former employee of Teva Pharmaceuticals; salary and benefits from Auspex Pharmaceuticals. Patents pending: US20160346270, US20160287574.. Dr. Bradbury has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alterity Therapeutics. Dr. Wong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alterity. Dr. Offman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alterity Therapeutics.