Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s 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 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\u27s 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\u27s 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

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 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

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: A phase 2, randomised, double-blind, placebo-controlled trial

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited