Category: Parkinsonism, Atypical: MSA
Objective: Evaluate potential cardiac liability of PBT434 using concentration-response and outlier analyses of ECG and pharmacokinetic (PK) data from a Phase 1 study of PBT434
Background: PBT434 is a novel, brain penetrant small molecule inhibitor of α-synuclein aggregation with an iron binding affinity competitive for α-synuclein but not for endogenous iron trafficking proteins. In Parkinson disease and MSA mouse models, PBT434 reduced α-synuclein aggregation and markers of oxidative stress, preserved neurons, improved motor function and reduced glial cell inclusions. A phase 1 study that evaluated the safety and PK of PBT434 complied with current ICH guidelines that allow for modeling to assess QTc effects of novel drugs. ECG and PK data from a phase 1 study of PBT434 were used to rule out significant (> 10 ms) QTcF prolongation at the Cmax of projected clinical doses.
Method: In a randomized, double blind, placebo-controlled (n=2/cohort) single- and multiple-ascending dose (SAD, MAD) study of PBT434, healthy adults received oral single doses of PBT434 at 50, 100, 300 or 600 mg (n=6/dose) or 8 days dosing at 100, 200 or 250 mg BID (n=8/dose). Older adults (≥65 y) also received 250 mg (n=8) BID for 8 days.
Continuous 12-lead digital ECGs were recorded pre-dose through 24 hours post-dose in the SAD; 17 post-dose ECG timepoints were assessed (3-10 ECGs/timepoint). ECG intervals were measured with high precision methods. QT intervals were corrected with Fridericia’s formula (QTcF). Outlier analyses were performed by timepoint on QTcF, ΔQTcF, PR and QRS intervals. A linear mixed effects model was developed and tested with ΔQTcF and PBT434 concentration data. 21 plasma samples were collected over 72 hours post-dose in the SAD and 17 were collected over 96 hours post-dose on Day 8 in the MAD for measuring PBT434 levels by validated methods.
Results: A linear mixed-effects model predicted the effect of PBT434 on cardiac intervals. At the anticipated clinical Cmax (2979 ng/mL), the baseline-adjusted, placebo-corrected QTcF (∆∆QTcF) was <2 ms (upper bound of 90% CI <5 ms). No subject had a QTcF >450 ms or a ∆QTcF >30 ms. There was no signal on PR or QRS intervals using modeling or outlier analyses. PBT434 was well tolerated at all tested doses with no signal for cardiac AEs.
Conclusion: PBT434 was safe and well tolerated at projected clinical doses and has no evidence of cardiac liability.
To cite this abstract in AMA style:D. Stamler, M. Bradbury, C. Wong, E. Offman. Cardiac Safety of PBT434, an Inhibitor of Alpha-Synuclein Aggregation for the Treatment of Multiple System Atrophy (MSA) [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/cardiac-safety-of-pbt434-an-inhibitor-of-alpha-synuclein-aggregation-for-the-treatment-of-multiple-system-atrophy-msa/. Accessed December 5, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/cardiac-safety-of-pbt434-an-inhibitor-of-alpha-synuclein-aggregation-for-the-treatment-of-multiple-system-atrophy-msa/