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
Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, USA.
Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, USA.
J Clin Med. 2020 Nov 16;9(11):3682. doi: 10.3390/jcm9113682.
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.
SRX246是一种能穿越血脑屏障的血管加压素（AVP）1a受体拮抗剂。在动物模型中，它可减轻冲动性攻击、恐惧、抑郁和焦虑，在一项实验性医学功能磁共振成像研究中，它能阻断鼻内AVP对攻击/恐惧回路的作用，并且在1期多剂量递增临床试验中显示出极佳的安全性。本研究是一项针对早期有易怒症状的亨廷顿舞蹈症（HD）患者的3组、多中心、随机、安慰剂对照、双盲、为期12周的剂量递增研究，旨在探究SRX246的疗效。我们的目标是确定鉴于SRX246在治疗有问题的神经精神症状方面的潜在用途，其在这些HD患者中是否安全且耐受性良好。参与者被随机分配接受安慰剂，或递增至每日两次、每次120毫克或每日两次、每次160毫克的SRX246剂量。评估包括标准安全性测试、统一亨廷顿舞蹈症评定量表（UHDRS）以及问题行为的探索性测量。各组在人口统计学、HD特征和基线易怒程度方面具有可比性。106名随机分组的受试者中有82名按指定药物剂量完成了试验。采用单侧精确方法置信区间检验来拒绝每个剂量组相对于安慰剂耐受性或安全性较差的原假设。无动于衷和自杀倾向不受SRX246影响。活性组中的大多数不良事件被认为不太可能与SRX246有关。该化合物在HD患者中安全且耐受性良好，可作为治疗易怒和攻击行为的候选药物进一步研究。
