Effects of NT-814, a dual neurokinin 1 and 3 receptor antagonist, on vasomotor symptoms in postmenopausal women: a placebo-controlled, randomized trial

Mike Trower, Richard A Anderson, Elizabeth Ballantyne, Hadine Joffe, Mary Kerr, Steve Pawsey, Mike Trower, Richard A Anderson, Elizabeth Ballantyne, Hadine Joffe, Mary Kerr, Steve Pawsey

Abstract

Objectives: To evaluate the safety, pharmacokinetics, and preliminary efficacy of NT-814, a dual neurokinin 1,3 antagonist, in postmenopausal women with vasomotor symptoms (hot flashes).

Methods: We completed a double-blind, randomized, placebo-controlled trial in three US clinical research units in 76 postmenopausal women with moderate/severe hot flashes. Participants were randomized to 14 days of once-daily NT-814 or placebo within each of four sequential dose cohorts; 50, 100, 150, and 300 mg. Participants completed diaries of hot flash frequency and severity and waking due to night sweats before (baseline) and during treatment.

Results: All prespecified efficacy parameters (24-h hot flash frequency and severity, frequency of waking due to night sweats) decreased in all groups (including placebo). Mean reduction from baseline at week 2 in moderate/severe hot flash frequency was 37% in the placebo group and, respectively, 24% (P = 0.048 vs placebo), 59% (P = 0.155), 84% (P < 0.001) and 66% (P = 0.022) in the 50 mg, 100 mg, 150 mg, and 300 mg NT-814 groups; in waking due to night sweats reduction was 20% (P = 0.059), 55% (P = 0.135), 81% (P < 0.001), and 63% (P = 0.031) in the NT-814 groups and 32% in the placebo group. The improvement with NT-814 ≥150 mg was also evident in the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, more frequently in the 300 mg group. Safety monitoring identified no concerns.

Conclusions: Once-daily NT-814 (≥150 mg/d) resulted in a rapid, marked improvement in hot flashes and waking due to night sweats. No safety concerns were identified. Doses up to 300 mg were well tolerated.

Trial registration: ClinicalTrials.gov NCT02865538.

Conflict of interest statement

Financial disclosure/conflicts of interest: MT, MK, EB, and SP report holding stock in NeRRe Therapeutics, Ltd. and KaNDy Therapeutics, Ltd. (the current developer of NT-814). RAA reports receipt of personal fees from NeRRe, KaNDy, and Sojournix, Inc. for consultancy. HJ reports receipt of research grant support from NeRRe, KaNDy, Merck, QUE Oncology, Pfizer, and the US National Institutes of Health; receipt of personal fees from NeRRe, KaNDy, Eisai Co., Ltd., Sojournix, Inc., and Mitsubishi Tanabe Pharma for consultancy or service on advisory board; and a spouse who is an employee of Merck Research Laboratories, has equity in and received personal fees from Arsenal Biosciences, and has equity in Tango Therapeutics.

Figures

FIG. 1
FIG. 1
Disposition of participants.
FIG. 2
FIG. 2
Daily frequency of: moderate and severe hot flashes (A), Severity of hot flashes (B), daily hot flash severity scorea (C), and waking at night due to night sweats (D), by day. Data shown are mean ± standard error (aseverity score = [number of mild hot flashes × 1] + [number of moderate hot flashes × 2] + [number of severe hot flashes × 3]).
FIG. 3
FIG. 3
Exposure-response model of % change from baseline in frequency of moderate and severe hot flashes versus plasma concentration (area under the curve during the dose interval (AUC0-tau in ng∗h/mL) on day 14 of treatment. (the red circles show individual actual values; the blue line shows the predicted (modelled) response).

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