Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose.

Abstract

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile. C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5mg bid) or placebo over 52weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6ms (upper bound 90% CI, 8.0ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. At the 45mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.