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Clinical Trial
. 2020 Dec 1;105(12):e4857-e4865.
doi: 10.1210/clinem/dgaa657.

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

Richard A Anderson  1 , Jennifer Cormier  2 , Ruth Thieroff-Ekerdt  2 , Malcolm Boyce  3 , Frans van den Berg  3 , Daniel Grau  2 , David Turnquist  2 , Deya Corzo  2 , Philip Graham  2
Affiliations
Clinical Trial

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

Richard A Anderson et al. J Clin Endocrinol Metab. .

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.

Keywords: KNDy neuron; LH; NK3 antagonist; neurokinin; pharmacodynamics; testosterone.

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Figures

Figure 1.
Figure 1.
SJX-653 plasma concentration by cohort for doses 0.5–90 mg, over 48 hours, following single oral administration. Data are mean ± SD, n = 4 per cohort. Abbreviation: SD, standard deviation.
Figure 2.
Figure 2.
Effects of single doses of SJX-653 on LH (A, B), testosterone (C, D), and FSH (E, F). Doses as indicated on figure. Data are time profiles for changes from baseline calculated as a ratio of mean value for each time point to the mean baseline value, which was calculated as the average of 4 predose time points collected over 1.5 hours before dosing. Mean ± SD, n = 4 subjects per dose; placebo cohorts were pooled, n = 14. Abbreviations: FSH, follicle stimulating hormone; LH, luteinizing hormone; SD, standard deviation.
Figure 3.
Figure 3.
Maximum observed percentage reductions in LH (A) and FSH (B) at 6 hours and testosterone (C) at 8 hours from baseline. Mean ± SD, n = 4 per group except placebo, n = 14. Significance indicated as * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 versus placebo. Abbreviations: FSH, follicle stimulating hormone; LH, luteinizing hormone; SD, standard deviation.
Figure 4.
Figure 4.
Reduction in LH (6 hours) and testosterone (8 hours) versus plasma concentration of SJX-653 (6 hours): individual subject responses at doses of 1.5 to 90 mg SJX-653. Blue circles: LH at 6 hours; red triangles: testosterone at 8 hours after drug administration. Abbreviation: LH, luteinizing hormone.
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