Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

Journal: Journal Of Clinical Medicine

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.

Michael Brownstein, Neal Simon, Jeffrey Long, Jon Yankey, Hilda Maibach, Merit Cudkowicz, Christopher Coffey, Robin Conwit, Codrin Lungu, Karen Anderson, Steven Hersch, Dixie Ecklund, Eve Damiano, Debra Itzkowitz, Shifang Lu, Marianne Chase, Jeremy Shefner, Andrew Mcgarry, Brenda Thornell, Catherine Gladden, Michele Costigan, Padraig O'suilleabhain, Frederick Marshall, Amy Chesire, Paul Deritis, Jamie Adams, Peter Hedera, Kelly Lowen, H Rosas, Amie Hiller, Joseph Quinn, Kellie Keith, Andrew Duker, Christina Gruenwald, Angela Molloy, Cara Jacob, Stewart Factor, Elaine Sperin, Danny Bega, Zsazsa Brown, Lauren Seeberger, Victor Sung, Melanie Benge, Sandra Kostyk, Allison Daley, Susan Perlman, Valerie Suski, Patricia Conlon, Matthew Barrett, Stephanie Lowenhaupt, Mark Quigg, Joel Perlmutter, Brenton Wright, Elaine Most, Guy Schwartz, Jessica Lamb, Rosalind Chuang, Carlos Singer, Karen Marder, Joyce Moran, John Singleton, Meghan Zorn, Paola Wall, Richard Dubinsky, Carolyn Gray, Carolyn Drazinic
Relevant Conditions

Dementia, Huntington Disease