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Menopause. 2018 Aug;25(8):862-869. doi: 10.1097/GME.0000000000001090.

Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action.

Author information

1
Department of Investigative Medicine, Imperial College London, United Kingdom.
2
Millendo Therapeutics, Inc., Ann Arbor, MI.
3
TPS Pharmaceutical Consulting, Saline, MI.
4
Department of Gynaecology, Queen Charlotte's & Chelsea Hospital and Chelsea & Westminster Hospital, London, United Kingdom.
5
Institute of Reproductive and Development Biology, Imperial College London, United Kingdom.
6
Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom.
7
Emerging Innovations Unit, Scientific Partnering and Alliances, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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

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