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

INTRODUCTION: 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 ar...

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Autores principales: Darpo, Borje, Geva, Michal, Ferber, Georg, Goldberg, Yigal Paul, Cruz-Herranz, Andres, Mehra, Munish, Kovacs, Richard, Hayden, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Healthcare 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10043059/
https://www.ncbi.nlm.nih.gov/pubmed/36811812
http://dx.doi.org/10.1007/s40120-023-00449-w
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author Darpo, Borje
Geva, Michal
Ferber, Georg
Goldberg, Yigal Paul
Cruz-Herranz, Andres
Mehra, Munish
Kovacs, Richard
Hayden, Michael R.
author_facet Darpo, Borje
Geva, Michal
Ferber, Georg
Goldberg, Yigal Paul
Cruz-Herranz, Andres
Mehra, Munish
Kovacs, Richard
Hayden, Michael R.
author_sort Darpo, Borje
collection PubMed
description INTRODUCTION: 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 45 mg 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. METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks 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). RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109–0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. CONCLUSIONS: At the 45 mg 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. TRIAL REGISTRATION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40120-023-00449-w.
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spelling pubmed-100430592023-03-29 Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose Darpo, Borje Geva, Michal Ferber, Georg Goldberg, Yigal Paul Cruz-Herranz, Andres Mehra, Munish Kovacs, Richard Hayden, Michael R. Neurol Ther Original Research INTRODUCTION: 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 45 mg 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. METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks 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). RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109–0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. CONCLUSIONS: At the 45 mg 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. TRIAL REGISTRATION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40120-023-00449-w. Springer Healthcare 2023-02-22 /pmc/articles/PMC10043059/ /pubmed/36811812 http://dx.doi.org/10.1007/s40120-023-00449-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research
Darpo, Borje
Geva, Michal
Ferber, Georg
Goldberg, Yigal Paul
Cruz-Herranz, Andres
Mehra, Munish
Kovacs, Richard
Hayden, Michael R.
Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title_full Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title_fullStr Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title_full_unstemmed Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title_short Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose
title_sort pridopidine does not significantly prolong the qtc interval at the clinically relevant therapeutic dose
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10043059/
https://www.ncbi.nlm.nih.gov/pubmed/36811812
http://dx.doi.org/10.1007/s40120-023-00449-w
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