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

Julia K. Prague; Rachel E. Roberts; Alexander N. Comninos; Sophie Clarke; Channa N. Jayasena; Pharis Mohideen; Vivian H. Lin; Theresa P. Stern; Nicholas Panay; Myra S. Hunter; Lorraine C. Webber; Waljit S. Dhillo

doi:10.1097/GME.0000000000001090

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

Julia K. Prague, Rachel E. Roberts, Alexander N. Comninos, Sophie Clarke, Channa N. Jayasena, Pharis Mohideen, Vivian H. Lin, Theresa P. Stern, Nicholas Panay, Myra S. Hunter, Lorraine C. Webber, Waljit S. Dhillo

Research output: Contribution to journal › Editorial › peer-review

51 Citations (Scopus)

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.

Original language	English
Pages (from-to)	862-869
Number of pages	8
Journal	Menopause (New York, N.Y.)
Volume	25
Issue number	8
DOIs	https://doi.org/10.1097/GME.0000000000001090
Publication status	Published - 1 Aug 2018

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Prague, J. K., Roberts, R. E., Comninos, A. N., Clarke, S., Jayasena, C. N., Mohideen, P., Lin, V. H., Stern, T. P., Panay, N., Hunter, M. S., Webber, L. C., & Dhillo, W. S. (2018). Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause (New York, N.Y.), 25(8), 862-869. https://doi.org/10.1097/GME.0000000000001090

@article{408359968d5549ca8f28061972072e88,

title = "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.",

author = "Prague, {Julia K.} and Roberts, {Rachel E.} and Comninos, {Alexander N.} and Sophie Clarke and Jayasena, {Channa N.} and Pharis Mohideen and Lin, {Vivian H.} and Stern, {Theresa P.} and Nicholas Panay and Hunter, {Myra S.} and Webber, {Lorraine C.} and Dhillo, {Waljit S.}",

year = "2018",

month = aug,

day = "1",

doi = "10.1097/GME.0000000000001090",

language = "English",

volume = "25",

pages = "862--869",

journal = "Menopause (New York, N.Y.)",

issn = "1072-3714",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "8",

}

TY - JOUR

T1 - Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action

AU - Prague, Julia K.

AU - Roberts, Rachel E.

AU - Comninos, Alexander N.

AU - Clarke, Sophie

AU - Jayasena, Channa N.

AU - Mohideen, Pharis

AU - Lin, Vivian H.

AU - Stern, Theresa P.

AU - Panay, Nicholas

AU - Hunter, Myra S.

AU - Webber, Lorraine C.

AU - Dhillo, Waljit S.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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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U2 - 10.1097/GME.0000000000001090

DO - 10.1097/GME.0000000000001090

M3 - Editorial

C2 - 29533369

SN - 1072-3714

VL - 25

SP - 862

EP - 869

JO - Menopause (New York, N.Y.)

JF - Menopause (New York, N.Y.)

IS - 8

ER -

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

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