Citation

Brownstein MJ, Simon NG, Long JD, Yankey J, Maibach HT, Cudkowicz M, Coffey C, Conwit RA, Lungu C, Anderson KE, Hersch SM, Ecklund DJ, Damiano EM, Itzkowitz DE, Lu S, Chase MK, Shefner JM, McGarry A, Thornell B, Gladden C, Costigan M, O'suilleabhain P, Marshall FJ, Chesire AM, Deritis P, Adams JL, Hedera P, Lowen K, Diana Rosas H, Hiller AL, Quinn J, Keith K, Duker AP, Gruenwald C, Molloy A, Jacob C, Factor S, Sperin E, Bega D, Brown ZR, Seeberger LC, Sung VW, Benge M, Kostyk SK, Daley AM, Perlman S, Suski V, Conlon P, Barrett MJ, Lowenhaupt S, Quigg M, Perlmutter JS, Wright BA, Most E, Schwartz GJ, Lamb J, Chuang RS, Singer C, Marder K, Moran JA, Singleton JR, Zorn M, Wall PV, Dubinsky RM, Gray C, Drazinic C. J. Clin. Med. 2020; 9(11): 1-14.

Copyright

(Copyright © 2020, MDPI: Multidisciplinary Digital Publishing Institute)

DOI

10.3390/jcm9113682

PMID

unavailable

Abstract

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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Language: en

Keywords

Safety; adult; human; female; male; aged; suicidal ideation; aggression; randomized controlled trial; suicide attempt; suicidal behavior; fatigue; Tolerability; controlled study; clinical article; unclassified drug; double blind procedure; headache; somnolence; falling; drug safety; placebo; drug tolerability; nausea; multicenter study; irritability; apathy; muscle weakness; drug dose reduction; liver enzyme; Article; Huntington chorea; bilirubin; bilirubin blood level; phase 2 clinical trial; angina pectoris; Staphylococcus infection; kidney tumor; drug dose escalation; hypertransaminasemia; problem behavior; ankle fracture; Huntington’s disease; vasopressin antagonist; srx 246; staphylococcal skin infection; Unified Huntington Disease Rating Scale; Vasopressin 1a receptor antagonist