Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men

• Published in: The journal of clinical endocrinology and metabolism 2020-12, Vol.105 (12), p.e4857-e4865
• Main Authors: Anderson, Richard A, Cormier, Jennifer, Thieroff-Ekerdt, Ruth, Boyce, Malcolm, van den Berg, Frans, Grau, Daniel, Turnquist, David, Corzo, Deya, Graham, Philip
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Clinical s; Clinical trials; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Gonadotropin-releasing hormone; Gonadotropins; Healthy Volunteers; Hormone Antagonists - administration & dosage; Hormone Antagonists - adverse effects; Hormone Antagonists - pharmacokinetics; Humans; Luteinizing hormone; Male; Middle Aged; Neurokinin NK3 receptors; Organic Chemicals - administration & dosage; Organic Chemicals - adverse effects; Organic Chemicals - pharmacokinetics; Pharmacodynamics; Pharmacokinetics; Pituitary (anterior); Receptors, Neurokinin-3 - antagonists & inhibitors; Statistical analysis; Testosterone; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa657

Abstract Context SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism. Objective To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men. Design A randomized, placebo-controlled, double-blind, single ascending dose study. Setting Phase 1 unit. Patients or Other Participants Seven cohorts of 6 healthy men 18–45 years of age (4:2 randomization to SJX-653/placebo per cohort). Intervention(s) Single oral doses of 0.5–90 mg SJX-653. Main Outcome Measure(s) Safety assessments and serial pharmacokinetic (PK)/PD measurements. Results SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ± 7% (mean ± sd) at 6 hours after 30 mg SJX-653 versus 10 ± 43% for placebo (P = 0.0006); maximal T reduction was of 68 ± 5% at 8 hours after 60 mg SJX-653 versus 18 ± 11% for placebo (P