Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial

Abstract

Context The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). Objective To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. Design Twelve-week, double-blind, randomized, placebo-controlled study. Setting Eight Belgian centers from September 2015 to October 2016. Participants Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. Interventions Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. Main Outcome Measures Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability. Results Of 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (−26.5 vs −12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6). Conclusions Fezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms

“…These change dramatically in postmenopausal women, in whom they can generate hot flushes [39]. In this subpopulation of neurons, in particular, neurokinin B and its receptor NK3R have been implicated in the induction of hot flushes in healthy women that are typical in location and duration of postmenopausal hot flushes [40,41]. In order to gain more insights into the mechanism of action of Serelys V R on neurons, the effect of PureCyTonin V R on the uptake of [ 3 H]-serotonin into rat cortical synaptosomes was analyzed.…”

Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men

“…Elegant opticogenetic labeling experiments have shown that the stimulation of these thermoregulatory neurons by KNDy neurons is mediated by neurokinin B acting though NK3 receptors ( 15 ). Three compounds with NK3R antagonist activity have now been shown to have striking efficacy in reducing menopausal VMS ( 9 , 16–18 , 21 ), supporting the development of NK3R antagonists as a highly effective nonhormonal class of medicine. In relation to the possible therapeutic potential in a range of sex hormone–dependent conditions through the inhibition of GnRH secretion, it is noteworthy that the suppression of LH and testosterone was maximal at about 6 to 12 hours, with recovery thereafter, even with higher doses, despite the continuing presence of effective serum concentrations of SJX-653 for at least 48 hours.…”

Fezolinetant in the treatment of vasomotor symptoms associated with menopause

“…Fezolinetant was next evaluated in patients with VMS associated with menopause in phase II studies. These included a 12week double-blind proof-of-concept phase IIa study conducted in eight Belgian clinics from September 2015 to October 2016 (EudraCT 2015-002578-20), in which healthy postmenopausal women 40-65 years of age with moderate/severe VMS (≥49 episodes/week) were randomized 1:1 to fezolinetant 90 mg BID or placebo [62]. In addition, a 12-week, randomized, placebocontrolled, double-blind dose-ranging phase IIb study (VESTA; [ClinicalTrials.gov NCT03192176]) was conducted at 51 sites in the US from July 2017 to September 2018 in postmenopausal women 40-65 years of age with moderate/severe VMS (≥50 episodes/week) who were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo [63].…”

“…In the phase IIa study, at peak drug levels (3 h postdose), fezolinetant decreased plasma LH by 49.8% relative to baseline vs 16.4% with placebo [62]. Fezolinetant showed little impact on plasma levels of estradiol, FSH, and sex hormonebinding globulin (SHBG).…”