PMID- 36811812
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230628
IS  - 2193-8253 (Print)
IS  - 2193-6536 (Electronic)
IS  - 2193-6536 (Linking)
VI  - 12
IP  - 2
DP  - 2023 Apr
TI  - Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically 
      Relevant Therapeutic Dose.
PG  - 597-617
LID - 10.1007/s40120-023-00449-w [doi]
AB  - 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 (DeltaQTcF) 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 DeltaQTcF (DeltaDeltaQTcF) 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.
CI  - (c) 2023. The Author(s).
FAU - Darpo, Borje
AU  - Darpo B
AD  - ERT/Clario, Philadelphia, PA, USA.
FAU - Geva, Michal
AU  - Geva M
AUID- ORCID: 0000-0002-6949-0963
AD  - Prilenia Therapeutics B.V., Naarden, The Netherlands. michal.geva@prilenia.com.
FAU - Ferber, Georg
AU  - Ferber G
AD  - Statistik Georg Ferber GmbH, Riehen, Switzerland.
FAU - Goldberg, Yigal Paul
AU  - Goldberg YP
AD  - Prilenia Therapeutics B.V., Naarden, The Netherlands.
FAU - Cruz-Herranz, Andres
AU  - Cruz-Herranz A
AD  - Prilenia Therapeutics B.V., Naarden, The Netherlands.
FAU - Mehra, Munish
AU  - Mehra M
AD  - Biometrics Department, Tigermed-BDM Inc., Somerset, NJ, USA.
FAU - Kovacs, Richard
AU  - Kovacs R
AD  - Krannert Institute of Cardiology, Indiana University School of Medicine, 
      Indianapolis, IN, USA.
FAU - Hayden, Michael R
AU  - Hayden MR
AD  - Prilenia Therapeutics B.V., Naarden, The Netherlands. mrh@cmmt.ubc.ca.
AD  - Department of Medical Genetics, CMMT, University of British Columbia, Vancouver, 
      BC, Canada. mrh@cmmt.ubc.ca.
LA  - eng
SI  - ClinicalTrials.gov/NCT02006472
SI  - ClinicalTrials.gov/NCT00724048
SI  - ClinicalTrials.gov/NCT00665223
PT  - Journal Article
DEP - 20230222
PL  - New Zealand
TA  - Neurol Ther
JT  - Neurology and therapy
JID - 101637818
PMC - PMC10043059
OTO - NOTNLM
OT  - Concentration-QTc analysis
OT  - Huntington's disease (HD)
OT  - Pridopidine
OT  - QT prolongation
EDAT- 2023/02/23 06:00
MHDA- 2023/02/23 06:01
PMCR- 2023/02/22
CRDT- 2023/02/22 16:00
PHST- 2022/12/23 00:00 [received]
PHST- 2023/01/27 00:00 [accepted]
PHST- 2023/02/23 06:01 [medline]
PHST- 2023/02/23 06:00 [pubmed]
PHST- 2023/02/22 16:00 [entrez]
PHST- 2023/02/22 00:00 [pmc-release]
AID - 10.1007/s40120-023-00449-w [pii]
AID - 449 [pii]
AID - 10.1007/s40120-023-00449-w [doi]
PST - ppublish
SO  - Neurol Ther. 2023 Apr;12(2):597-617. doi: 10.1007/s40120-023-00449-w. Epub 2023 
      Feb 22.