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

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.

Conflict of interest statement

Financial disclosure/conflicts of interest: JKP is funded by the UK MRC. RER and SC are funded by the NIHR. CNJ is an inventor on a patent application 14762086.8-1453, which is registered to Imperial Innovations. PM and VHL are employees of Millendo Therapeutics. NP has lectured for and acted in an advisory capacity for Abbott, Bayer, Besins, Consilient, Meda, MSD, Mylan, Novo Nordisk, Pfizer, and Shionogi. LCW is an employee of AstraZeneca UK. AstraZeneca licensed the compound and associated patents to Millendo Therapeutics (WO2014170648A1, pending; US9475773 B2, granted). WSD is funded by the NIHR, is an inventor on a patent application 14762086.8-1453, which is registered to Imperial Innovations, and was previously an investigator for a separate study of MLE4901 in polycystic ovarian syndrome, for which a consultancy fee was paid. Millendo Therapeutics provided some financial support for an administrative assistant for the study of MLE4901 in menopausal flushing. TPS worked as a statistical consultant for Millendo Therapeutics. ANC and MSH declare no competing interests.

Figures

FIG. 1

Summary of protocol: baseline period: participants underwent a 2-week period to gather baseline data on hot flush (HF) frequency, HF severity, HF bother, and perceived HF interference (Hot Flash-Related Daily Interference Scale). If the inclusion criteria regarding HF frequency and severity were met at the end of this period, then they were assigned to the active phase of the study after randomization (black circle). Intervention 1 (double-blind): all participants randomized to either 4 weeks of treatment with oral, 40 mg twice daily MLE4901 or exact-match placebo. Washout period: all participants underwent a 2-week washout period after intervention 1 (half-life of MLE4901 is 8.5 h). Intervention 2 (double-blind): all participants then switched to receive either four weeks treatment with oral twice daily exact-match placebo or oral 40 mg twice daily MLE4901 depending on which intervention they received first. Monitoring period: a subsequent 2-week period to complete safety monitoring. Figure available under the terms of the CC BY licence from http://dx.doi.org/10.1016/S0140-6736(17)30823-1 (Prague et al, Lancet, 2017).

FIG. 2

Hot flash frequency (A), severity (B), bother (C), and interference (D) outcomes: results are presented as percentage change with 95% CIs from baseline at each time point during the treatment period (ie, on day 3 of treatment, and then weekly mean total for each week (wk) of the 4-week treatment period for both placebo (white) and MLE4901 (gray). Minimum n = 33; maximum n = 37. ∗P < 0.0001, #P = 0.0006, ^P = 0.0011, +P = 0.0001. Week 4 data adapted from Prague et al, Lancet, 2017.