Pavinetant

Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect.

Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed.

By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, −81.3 to −63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, −46.1 to −29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, −47.5 to −30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, −79.1 to −43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to −44%, −50%, and −70%, respectively by day 28, all P < 0.0001 compared with placebo).

NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.

Objectives: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. Methods: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. Results: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, <i>p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, <i>p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. Conclusions: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.