SAT-LB073 SJX-653, a Novel Selective NK3 Antagonist, Demonstrates Activity on Pharmacodynamic Markers of NK3 Target Engagement

Background: NK3 antagonism is a clinically validated mechanism of action for treating menopausal vasomotor symptoms (“hot flashes”). In men, reductions of LH and T are sensitive pharmacodynamic markers of central NK3 antagonism, due to the known inhibitory effect of NK3 antagonists on GnRH pulsatility. Here we present results of a first-in-human study with SJX-653, a novel and selective NK3 antagonist, in healthy adult men. Objective: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity (as measured by LH and T reductions) of single ascending oral doses of SJX-653 in healthy adult men. Methods: The study was a randomized, placebo-controlled, double-blind, single ascending dose study of orally administered SJX-653 in healthy adult men. Seven cohorts of 6 men were enrolled (4 SJX-653: 2 placebo). Subjects were confined to a Phase 1 unit from Day -1 to Day 3 with a follow-up visit on Day 8. Safety assessments (labs, ECG, vitals) and serial PK/PD samples were collected pre- and post-dose at multiple timepoints. Results: 42 male subjects were randomized and completed the study. Dose levels of 0.5 to 90 mg SJX-653 were evaluated. The median ages of subjects in the SJX-653 and placebo groups were 32.0 and 27.0 years, respectively. Subjects receiving SJX-653 and placebo had comparable mean height, weight, and BMI measurements. There were no serious adverse events (SAEs) or clinically meaningful changes in clinical laboratory values, vital sign measurements, or ECG parameters. AEs were mostly mild and the incidence of adverse events (AEs) was similar between subjects treated with SJX-653 and placebo. Across the 180-fold dose range (0.5 to 90 mg) mean C(max) and AUC(0-24) values increased in a dose‑proportional manner with 175-fold and 143-fold increases, respectively. The mean terminal elimination half-life for SJX-653 was 10 to 13 hours. Reductions in LH and T levels were reversible and dose-dependent. LH reductions preceded T reductions by 2-3 hours, as expected. Statistically significant reductions in LH and T from baseline were observed at doses ≥15 mg SJX-653. The maximum mean LH reduction of 70% at 6 hours was in subjects treated with 30 mg SJX-653, versus 10% in placebo-treated subjects at the corresponding timepoint (p = 0.0006). The maximum mean T reduction of 68% at 8 hours was in subjects treated with 60 mg SJX-653, versus 18% in placebo-treated subjects at the corresponding timepoint (p < 0.0001). Conclusions: Single ascending doses of SJX-653 were well tolerated in healthy adult men. There were no SAEs and the incidence of AEs was similar between subjects treated with SJX-653 and placebo. The plasma half-life for SJX-653 was 10-13 hours, consistent with once-daily (QD) dosing. SJX-653 demonstrated clinical proof-of-mechanism as a central NK3 antagonist by causing statistically significant, dose-dependent, and reversible reductions in LH and T. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.