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Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial
SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excelle...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926/ https://www.ncbi.nlm.nih.gov/pubmed/33207828 http://dx.doi.org/10.3390/jcm9113682 |
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author | Brownstein, Michael J. Simon, Neal G. Long, Jeffrey D. Yankey, Jon Maibach, Hilda T. Cudkowicz, Merit Coffey, Christopher Conwit, Robin A. Lungu, Codrin Anderson, Karen E. Hersch, Steven M. Ecklund, Dixie J. Damiano, Eve M. Itzkowitz, Debra E. Lu, Shifang Chase, Marianne K. Shefner, Jeremy M. McGarry, Andrew Thornell, Brenda Gladden, Catherine Costigan, Michele O’Suilleabhain, Padraig Marshall, Frederick J. Chesire, Amy M. Deritis, Paul Adams, Jamie L. Hedera, Peter Lowen, Kelly Rosas, H. Diana Hiller, Amie L. Quinn, Joseph Keith, Kellie Duker, Andrew P. Gruenwald, Christina Molloy, Angela Jacob, Cara Factor, Stewart Sperin, Elaine Bega, Danny Brown, Zsazsa R. Seeberger, Lauren C. Sung, Victor W. Benge, Melanie Kostyk, Sandra K. Daley, Allison M. Perlman, Susan Suski, Valerie Conlon, Patricia Barrett, Matthew J. Lowenhaupt, Stephanie Quigg, Mark Perlmutter, Joel S. Wright, Brenton A. Most, Elaine Schwartz, Guy J. Lamb, Jessica Chuang, Rosalind S. Singer, Carlos Marder, Karen Moran, Joyce A. Singleton, John R. Zorn, Meghan Wall, Paola V. Dubinsky, Richard M. Gray, Carolyn Drazinic, Carolyn |
author_facet | Brownstein, Michael J. Simon, Neal G. Long, Jeffrey D. Yankey, Jon Maibach, Hilda T. Cudkowicz, Merit Coffey, Christopher Conwit, Robin A. Lungu, Codrin Anderson, Karen E. Hersch, Steven M. Ecklund, Dixie J. Damiano, Eve M. Itzkowitz, Debra E. Lu, Shifang Chase, Marianne K. Shefner, Jeremy M. McGarry, Andrew Thornell, Brenda Gladden, Catherine Costigan, Michele O’Suilleabhain, Padraig Marshall, Frederick J. Chesire, Amy M. Deritis, Paul Adams, Jamie L. Hedera, Peter Lowen, Kelly Rosas, H. Diana Hiller, Amie L. Quinn, Joseph Keith, Kellie Duker, Andrew P. Gruenwald, Christina Molloy, Angela Jacob, Cara Factor, Stewart Sperin, Elaine Bega, Danny Brown, Zsazsa R. Seeberger, Lauren C. Sung, Victor W. Benge, Melanie Kostyk, Sandra K. Daley, Allison M. Perlman, Susan Suski, Valerie Conlon, Patricia Barrett, Matthew J. Lowenhaupt, Stephanie Quigg, Mark Perlmutter, Joel S. Wright, Brenton A. Most, Elaine Schwartz, Guy J. Lamb, Jessica Chuang, Rosalind S. Singer, Carlos Marder, Karen Moran, Joyce A. Singleton, John R. Zorn, Meghan Wall, Paola V. Dubinsky, Richard M. Gray, Carolyn Drazinic, Carolyn |
author_sort | Brownstein, Michael J. |
collection | PubMed |
description | SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. |
format | Online Article Text |
id | pubmed-7696926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76969262020-11-29 Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial Brownstein, Michael J. Simon, Neal G. Long, Jeffrey D. Yankey, Jon Maibach, Hilda T. Cudkowicz, Merit Coffey, Christopher Conwit, Robin A. Lungu, Codrin Anderson, Karen E. Hersch, Steven M. Ecklund, Dixie J. Damiano, Eve M. Itzkowitz, Debra E. Lu, Shifang Chase, Marianne K. Shefner, Jeremy M. McGarry, Andrew Thornell, Brenda Gladden, Catherine Costigan, Michele O’Suilleabhain, Padraig Marshall, Frederick J. Chesire, Amy M. Deritis, Paul Adams, Jamie L. Hedera, Peter Lowen, Kelly Rosas, H. Diana Hiller, Amie L. Quinn, Joseph Keith, Kellie Duker, Andrew P. Gruenwald, Christina Molloy, Angela Jacob, Cara Factor, Stewart Sperin, Elaine Bega, Danny Brown, Zsazsa R. Seeberger, Lauren C. Sung, Victor W. Benge, Melanie Kostyk, Sandra K. Daley, Allison M. Perlman, Susan Suski, Valerie Conlon, Patricia Barrett, Matthew J. Lowenhaupt, Stephanie Quigg, Mark Perlmutter, Joel S. Wright, Brenton A. Most, Elaine Schwartz, Guy J. Lamb, Jessica Chuang, Rosalind S. Singer, Carlos Marder, Karen Moran, Joyce A. Singleton, John R. Zorn, Meghan Wall, Paola V. Dubinsky, Richard M. Gray, Carolyn Drazinic, Carolyn J Clin Med Article SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. MDPI 2020-11-16 /pmc/articles/PMC7696926/ /pubmed/33207828 http://dx.doi.org/10.3390/jcm9113682 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Brownstein, Michael J. Simon, Neal G. Long, Jeffrey D. Yankey, Jon Maibach, Hilda T. Cudkowicz, Merit Coffey, Christopher Conwit, Robin A. Lungu, Codrin Anderson, Karen E. Hersch, Steven M. Ecklund, Dixie J. Damiano, Eve M. Itzkowitz, Debra E. Lu, Shifang Chase, Marianne K. Shefner, Jeremy M. McGarry, Andrew Thornell, Brenda Gladden, Catherine Costigan, Michele O’Suilleabhain, Padraig Marshall, Frederick J. Chesire, Amy M. Deritis, Paul Adams, Jamie L. Hedera, Peter Lowen, Kelly Rosas, H. Diana Hiller, Amie L. Quinn, Joseph Keith, Kellie Duker, Andrew P. Gruenwald, Christina Molloy, Angela Jacob, Cara Factor, Stewart Sperin, Elaine Bega, Danny Brown, Zsazsa R. Seeberger, Lauren C. Sung, Victor W. Benge, Melanie Kostyk, Sandra K. Daley, Allison M. Perlman, Susan Suski, Valerie Conlon, Patricia Barrett, Matthew J. Lowenhaupt, Stephanie Quigg, Mark Perlmutter, Joel S. Wright, Brenton A. Most, Elaine Schwartz, Guy J. Lamb, Jessica Chuang, Rosalind S. Singer, Carlos Marder, Karen Moran, Joyce A. Singleton, John R. Zorn, Meghan Wall, Paola V. Dubinsky, Richard M. Gray, Carolyn Drazinic, Carolyn Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title | Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title_full | Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title_fullStr | Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title_full_unstemmed | Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title_short | Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington’s Disease Patients—A Randomized Phase 2 Clinical Trial |
title_sort | safety and tolerability of srx246, a vasopressin 1a antagonist, in irritable huntington’s disease patients—a randomized phase 2 clinical trial |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926/ https://www.ncbi.nlm.nih.gov/pubmed/33207828 http://dx.doi.org/10.3390/jcm9113682 |
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