Stamler's poster in the ANA 2020 meeting

This poster is presented next Friday>




483. Safety and Pharmacokinetics of ATH434 (PBT434),
a Novel Small Molecule Inhibitor of α-Synuclein
Aggregation, in Adult and Older Adult Volunteers
David A. Stamler, MD1
, Margaret Bradbury, PhD1
, Cynthia
Wong, MPH1
, Elliot Offman, PhD2
. 1
Alterity Therapeutics,
Newark, CA, USA, 2
Certara Strategic Consulting, Montreal,
QC, Canada.
Objective: Evaluate the safety, tolerability, cardiac repolarization, and pharmacokinetics of ATH434.
Background: ATH434 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), ATH434 reduced α-synuclein aggregation and markers of oxidative stress, preserved
neurons, and improved motor function. ATH434 reduced
glial cell inclusions (PLP-α-Syn). ATH434 is thought to act
by redistributing labile iron across neuronal membranes. The
affinity of ATH434 for iron is lower than for iron trafficking
proteins, such as transferrin and ferritin.
Design/Methods: In this randomized, double-blind, placebo-controlled study, adult subjects received single oral
doses (8/cohort) at 50, 100, 300 or 600 mg or 8 days dosing
(10/cohort) at 100, 200 or 250 mg bid. Older adults
(≥65 years) received 250 mg bid for 8 days. 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. A concentration-effect
analysis was performed to estimate the effect of ATH434 on
the QT interval using ATH434 plasma levels and ECGs
extracted from continuous Holter monitoring at pre-specified
timepoints.
Results: ATH434 was readily absorbed with a Tmax of
0.5-2 hours and demonstrated dose-dependent pharmacokinetics after single and multiple doses. Mean elimination halflife up to 9.3 hours was observed independent of dose. CSF
concentrations near Tmax were 102.5 to 229.5 ng/mL, comparable to free ATH434 concentrations in plasma. AE rates
were similar for ATH434 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. A linear
mixed-effects model predicted the placebo-corrected, baseline-adjusted change in QTcF to be <2 ms (upper bound of
90%CI <4 ms) at the anticipated steady state Cmax.
Conclusions: ATH434 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. ATH434 was safe and well tolerated at all doses and
has no evidence of cardiac liability