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

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 7HF/24hours 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.