A First in Human Study of PBT434, a Novel Small Molecule Inhibitor of α-Synuclein Aggregation (S4.001)

Objective: To evaluate the safety, tolerability and pharmacokinetics of PBT434 in healthy volunteers. Background: PBT434 is a novel, brain-penetrant, small molecule inhibitor of α-synuclein aggregation. In transgenic animal models of Parkinson disease (A53T) and MSA (PLP-α-Syn), PBT434 reduced α-synuclein aggregation, preserved neurons and improved motor function. Glial cell inclusions were also reduced in a murine MSA model. PBT434 is thought to act by redistributing reactive iron across membranes, thereby blocking intracellular protein aggregation and oxidative stress. The affinity of PBT434 for iron is greater than that of α-synuclein but lower than that of iron trafficking proteins, e.g., ferritin. Design/Methods: In this randomized, double-blind, placebo-controlled first in human study, subjects received oral single ascending doses (SAD; n=8) or multiple ascending doses (MAD; n=10) of PBT434. Serial plasma samples were collected over 72 hour post-dose in the SAD and over 12 and 96 hours post-dose on Days 1 and 8, respectively, in the MAD portions of the study. Safety was assessed between cohorts with physical examination, vital signs, adverse events, laboratory tests and 12-lead ECGs. Results: PBT434 demonstrated approximately proportional pharmacokinetics over the dose range studied based on dose normalized PK parameters. The mean(CV%) AUCinf was 896.7(27.8), 1587(19.0) and 6494(35.9) ng•hr/mL and the mean(CV%) Cmax was 493.3(33.3), 802.7(28.1) and 2978(46.5) ng/mL for 50, 100 and 300 mg, respectively. PBT434 was rapidly and extensively absorbed after oral administration with a median Tmax of 1 to 1.25 hours. PBT434 was well tolerated following single doses up to 300 mg with infrequent AEs that were mild. No serious adverse events were reported. No laboratory or ECG abnormalities were detected. Conclusions: PBT434 demonstrated approximately proportional pharmacokinetics up to 300 mg and was well tolerated in healthy volunteers. PBT434 is an oral small molecule drug candidate with potential for treating synucleinopathies such as Parkinson disease and MSA. Disclosure: Dr. Stamler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Auspex Pharmaceuticals. Dr. Bradbury has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Prana Biotechnology and Teva. Dr. Wong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Prana. Dr. Offman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Prana.