A Phase 1 Study of PBT434, a Novel Small Molecule Inhibitor of α-Synuclein Aggregation, in Adult and Older Adult Volunteers (4871)
Citation Manager Formats
Make Comment
See Comments

Abstract
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 Tmax 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 Tmax 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.
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Hemiplegic Migraine Associated With PRRT2 Variations A Clinical and Genetic Study
Dr. Robert Shapiro and Dr. Amynah Pradhan
Related Articles
- No related articles found.