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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 < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL. Conclusions These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.

In a previous 52-wk trial, treatment with alglucosidase alfa markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alfa at either 20 mg/kg biweekly ( n = 8) or 40 mg/kg biweekly ( n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alfa at the age of 36 mo. Cox regression analyses showed that over the entire study period, alglucosidase alfa treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, compared with an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy.

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 Cmax and AUC0-24 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.

In a previous 52-wk trial, treatment with alglucosidase alpha markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alpha at either 20 mg/kg biweekly (n = 8) or 40 mg/kg biweekly (n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alpha at the age of 36 mo. Cox regression analyses showed that over the entire study period, alglucosidase alpha treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, compared with an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alpha treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy.