MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
Sojournix, Inc., Waltham, Massachusetts.
J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4857-65. doi: 10.1210/clinem/dgaa657.
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.
To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men.
A randomized, placebo-controlled, double-blind, single ascending dose study.
Phase 1 unit.
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.
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.
These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.
SJX-653 是一种新型的神经激肽 3 受体（NK3R）拮抗剂。NK3 途径是促性腺激素释放激素（GnRH）分泌的中枢调节剂，并且与热潮红的发生也有关。因此，男性黄体生成素（LH）和睾酮的减少可作为中枢 NK3 拮抗作用的敏感药效学（PD）标志物。
描述 SJX-653 在健康男性中的安全性、耐受性、药代动力学和药效学活性。
一项随机、安慰剂对照、双盲、单次递增剂量研究。
1 期单位。
7 个队列，每个队列有 6 名年龄在 18-45 岁的健康男性（4：2 随机分配接受 SJX-653/安慰剂）。
单次口服 0.5-90 mg SJX-653。
安全性评估和连续药代动力学（PK）/药效学（PD）测量。
SJX-653 在所有剂量水平均耐受良好。Cmax 和 AUC0-24 呈剂量比例增加。终末消除半衰期在 9.8 至 12.5 小时之间，与剂量无关。观察到 LH 和睾酮呈剂量依赖性、可逆性降低，在 15 mg 时接近最大效应，在 4.5 mg 时几乎没有影响。SJX-653 30 mg 给药后 6 小时，LH 最大降低 70%±7%（平均值±标准差），安慰剂组为 10%±43%（P=0.0006）；SJX-653 60 mg 给药后 8 小时，T 最大降低 68%±5%，安慰剂组为 18%±11%（P<0.0001）。LH 降低的血浆 IC50 为 33 ng/mL。
这些数据为 SJX-653 作为一种有效的中枢作用 NK3R 拮抗剂提供了临床机制证据。
