SRX246 / Azevan - LARVOL DELTA

Molecular basis of antagonism of the dimeric human arginine vasopressin receptor 1A. (PubMed, Nat Commun) - "Here, we present structures of human V1aR in its apo state and in complexes with antagonists: atosiban, balovaptan, and SRX246. Antagonist-bound structures, combined with mutagenesis and radioligand binding assays, uncover distinct binding modes and key determinants for antagonism and selectivity. These findings provide a comprehensive understanding of V1aR assembly and dynamic regulation, offering valuable insights for structure-guided development of new antagonists targeting dimeric V1aR for CNS disorders."

Journal • CNS Disorders

Inhibition of Aggressive Behavior in Participants With Fragile X Syndrome (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Azevan Pharmaceuticals

New P2 trial • Fragile X Syndrome • Genetic Disorders

Radiosynthesis and Evaluation of a 18F-labeled PET ligand for Imaging the Peripheral Vasopressin 1A Receptor (SNMMI 2025) - "The signal intensities significantly reduced upon co-incubation with V1A antagonists PF184563, balovaptan and SRX246, while vasopressin 2 receptor antagonist Lixivaptan and the V1B receptor antagonist TASP325 led to minimal signal reduction, confirming high specific binding of [18F]8 with V1A receptor (Figure 1C-D). Compound 8 was synthesized in a yield of 19% over five steps and compound 10 was prepared in 8% yield over five steps (Figure 1A–B). The LogD value of compound 8 was measured as 1.89. Compound 8 demonstrated nanomolar potency and high affinity for the hV1A receptor (IC50 = 6.22 nM and Ki = 1.23 nM)."

Autism Spectrum Disorder • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Mood Disorders • Nephrology • Psychiatry • Renal Disease

Radiosynthesis and Evaluation of a 18F-labeled PET ligand for Imaging the Peripheral Vasopressin 1A Receptor (SNMMI 2025) - "The signal intensities significantly reduced upon co-incubation with V1A antagonists PF184563, balovaptan and SRX246, while vasopressin 2 receptor antagonist Lixivaptan and the V1B receptor antagonist TASP325 led to minimal signal reduction, confirming high specific binding of [18F]8 with V1A receptor (Figure 1C-D). Compound 8 was synthesized in a yield of 19% over five steps and compound 10 was prepared in 8% yield over five steps (Figure 1A–B). The LogD value of compound 8 was measured as 1.89. Compound 8 demonstrated nanomolar potency and high affinity for the hV1A receptor (IC50 = 6.22 nM and Ki = 1.23 nM)."

Autism Spectrum Disorder • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Mood Disorders • Nephrology • Psychiatry • Renal Disease

The utility of the irritability scale in Huntington's disease patients with evidence of irritability or aggression. (PubMed, Parkinsonism Relat Disord) - "The proposed 5-item SF IS provided a reliable measure of the full scale and may be less burdensome for use in a clinical setting."

Journal • Huntington's Disease • Movement Disorders • Psychiatry

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder. (PubMed, Drugs) - "Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders."

Journal • Review • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD: Design, methods, and recruitment. (PubMed, Contemp Clin Trials Commun) - "An 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted...This study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors."

Journal • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

A Comparison of Self-Report and Informant-Report Irritability Scale in Huntington’s Disease Patients with Evidence of Irritability or Aggression (HSG 2022) - " Baseline irritability was characterized with IS in patients with confirmed irritability in the STAIR (Safety, Tolerability, and Activity of SRX246 in Irritable Subjects with Huntington’s Disease) trial... Substantial variability in item performance suggests that future research may be better served through development of an abridged IS."

Clinical • Huntington's Disease • Movement Disorders • Psychiatry

The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington's Disease. (PubMed, J Pers Med) - "The exploratory analyses showed that SRX246 reduced aggressive acts. Readily observed behaviors should be used as trial endpoints."

Journal • Huntington's Disease • Movement Disorders

The role of Angiotensin II in Fear Memory and therapeutic opportunities for PTSD (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Sex-opposite effects of the neurokinin 3 receptor neuropeptide in memory consolidation (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Clinical translation of oxytocin neuroscience to the treatment of anxiety and posttraumatic stress disorders (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

Clinical • CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Chair (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Co Chair (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

A proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist for PTSD (Neuroscience 2021) - "These preliminary findings suggest SRX246 may be an effective treatment for PTSD. If confirmed through additional clinical studies, SRX246 would represent a breakthrough in pharmacotherapy for PTSD.; Grant Support: NIH UL1TR002384; US Department of Defense grant W81XWH-15-1-0645 to NGS; Azevan Pharmaceuticals, Inc."

Clinical • CNS Disorders • Depression • Major Depressive Disorder • Post-traumatic Stress Disorder • Psychiatry • Substance Abuse

Chair (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Stress-enhanced fear learning, violence, and the neuropeptide Tac2 (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Oxytocin facilitates fear memory to predictable threats by inhibiting output neurons of the bed nucleus of the stria terminalis (BNST). (Neuroscience 2021) - "We will also show that Neurokinin 3 receptor (Nk3R) neuropeptide antagonist osanetant enhances memory consolidation in female mice whereas it impairs memory consolidation in males. Finally, we will present data from human subjects showing that highly selective vasopressin 1A receptor antagonist SRX246 reduces anxiety but not fear-potentiated startle in male and female participants. This mini-symposium will address sex-specific effects of limbic neuropeptides in both rodents and humans and the importance of sex-specific pharmacotherapies for PTSD."

CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Proof-of-concept Study to Assess the Efficacy and Safety of SRX246 in Adults With PTSD (clinicaltrials.gov) - P2; N=33; Terminated; Sponsor: Azevan Pharmaceuticals; N=52 ➔ 33; Suspended ➔ Terminated; funding

Clinical • Enrollment change • Trial termination • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study. (PubMed, Psychopharmacology (Berl)) - "As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target."

Clinical • Journal • Mood Disorders • Psychiatry

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial. (PubMed, J Clin Med) - "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."

Clinical • Journal • P2 data • CNS Disorders • Depression • Huntington's Disease • Mood Disorders • Movement Disorders • Psychiatry

Proof-of-concept Study to Assess the Efficacy and Safety of SRX246 in Adults With PTSD (clinicaltrials.gov) - P2; N=52; Suspended; Sponsor: Azevan Pharmaceuticals; Trial completion date: Jun 2020 ➔ Jun 2021; Recruiting ➔ Suspended; Trial primary completion date: Jun 2020 ➔ Jun 2021

Clinical • Trial completion date • Trial primary completion date • Trial suspension • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Tolerability, Safety, and Activity of SRX246 in Irritable Subjects With Huntington's Disease (clinicaltrials.gov) - P2; N=108; Not yet recruiting; Sponsor: Azevan Pharmaceuticals; Initiation date: Jan 2016 ➔ Apr 2016; Trial primary completion date: Oct 2017 ➔ Apr 2018

Trial initiation date • Trial primary completion date • Biosimilar

AVN009: Safety, Tolerability and Activity of SRX246 in Adults With Intermittent Explosive Disorder (clinicaltrials.gov) - P2; N=96; Active, not recruiting; Sponsor: Azevan Pharmaceuticals; Recruiting ➔ Active, not recruiting

Enrollment closed • Biosimilar

Effects of SRX246, a Vasopressin 1a Receptor (V1a) Antagonist, on an Experimental Model of Phasic and Sustained Threat in Humans (SOBP 2020) - "SRX246 reduced APS, but not FPS, in participants with high reactivity to unpredictable-threat. This dissociation may help inform clinical indications for this first-in-class drug. Funding Source: Intramural Research Program of the National Institute of Mental Health, ZIAMH002798"

CNS Disorders • Mood Disorders • Psychiatry