PS-04-004 The pharmacological profile of IX-01, a selective oxytocin receptor antagonist being developed to treat men with premature ejaculation

Few treatments are available for men with premature ejaculation (PE). Oxytocin receptor (OTR) antagonism in the central nervous system (CNS) is a potential new approach. To determine if IX-01 selectively inhibits human OTR, effects ejaculatory physiology, and has the clinical properties to potentially treat PE. Experiments complied with UK legislation and were subject to local ethical review. In vitro potency and selectivity of IX-01 was assessed using recombinant and native OT and vasopressin receptor assays systems. IX-01 was evaluated in two anaesthetised rat models - the electromyography (EMG) model of ejaculatory physiology and a model of OT-mediated CNS neuronal firing. Human pharmacokinetics, toleration and safety were assessed in 3 completed Phase I studies. IX-01 is a potent OTR antagonist, with a KB of 5.7 nM against native human uterine smooth muscle cell OTR. IX-01 displays similar antagonistic potency against human recombinant and rat native OTRs, demonstrates >100-fold selectivity over human V1A and >500-fold selectivity over human V1B and V2 vasopressin receptors. In the EMG model, IX-01 (0.9mg/kg, iv bolus) reduced the bulbospongiosum burst pattern and contraction amplitude associated with ejaculation. IX-01 did not impair erectile function. In the anaesthetised CNS neuronal firing model, IX-01 (0.9mg/kg, iv bolus) modulated the OT-mediated response in the nucleus tractus solitarius. In clinical studies single doses up to 2400 mg were well tolerated with no maximal tolerated dose identified. IX-01 showed rapid absorption when administered without food. Terminal elimination half-life was approximately 12 hours. IX-01 was present in cerebrospinal fluid obtained by lumbar puncture of healthy volunteers.