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

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.

The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington’s Disease

“…Baseline: The primary and secondary endpoints of the STAIR study were the tolerability and safety of SRX246. These results have been reported earlier [ 15 ]. Between 2016 and 2018, 106 patients and their study partners were enrolled at 22 US study sites.…”

“…The compound is orally available, CNS penetrant, and highly specific for the V1a receptor [ 13 , 14 ]. The drug candidate had an excellent safety profile in animals, and based on clinical studies, including the STAIR study (NCT 02507284), it was safe and well-tolerated in human subjects as well [ 15 ].…”

Current and Possible Future Therapeutic Options for Huntington’s Disease

“…It showed safety, tolerability and validity as a treatment candidate in the near future. 301 Varenicline is a nicotinic acetylcholine receptor agonist targeting cognitive improvements in early HD patients who smoke. HD patients treated with varenicline showed significant executive function and emotional recognition improvements, without clinically significant adverse events.…”

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

“…V1A receptors have been initially been linked to autism spectrum disorder (ASD) 12, 13 , Huntington’s disease 14, 15 , cerebral vasospasm 4 and brain edema 16 , primary aldosteronism 17 and dysmenorrhea 18 . As such, strenuous drug discovery efforts led to the discovery of several potent antagonists, of which some have entered the clinical arena ( Figure 1 ).…”

“…[16, 25] Further, SRX246 was tested for the treatment of Huntington disease in a clinical phase II study. [14, 15] A CNS-targeted V1A antagonist, RG7713 (RO5028442) [26], exhibited beneficial effects in the treatment of abnormal affective speech recognition, olfactory identification and social communication in adult ASD patients. [27] Further, the triazolobenzodiazepine, balovaptan (RG7314) showed encouraging results for the treatment of ASD in a clinical phase II study, which led to a Breakthrough Therapy Designation by the U.S. FDA in January 2018.…”