Dataset Information

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1).

ABSTRACT:

Objective

Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life.

Methods

Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life.

Results

Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: -3.93 [SE, 1.02], P < 0.001; week 12: -2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (-2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated.

Conclusions

Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS.

SUBMITTER: Simon JA

PROVIDER: S-EPMC9970022 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1).

Simon James A JA Anderson Richard A RA Ballantyne Elizabeth E Bolognese James J Caetano Cecilia C Joffe Hadine H Kerr Mary M Panay Nick N Seitz Christian C Seymore Susan S Trower Mike M Zuurman Lineke L Pawsey Steve S

Menopause (New York, N.Y.) 20230130 3

<h4>Objective</h4>Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life.<h4>Methods</h4>Postmenopausal ...[more]

PMID: 36720081

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Project description:Abstract Vasomotor symptoms (VMS; eg, hot flashes, night sweats) are caused by a loss of thermoregulatory control. The thermoregulatory center in the brain is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. The activity of KNDy neurons is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen negative-feedback. Declining estrogen levels at menopause disturb this balance, leading to VMS. Fezolinetant is an antagonist at NK3R that acts to moderate KNDy neuron function for the treatment of VMS (1). The aim of the current trial was to evaluate fezolinetant dose levels and treatment regimen in VMS. In this phase 2b, double-blind trial (NCT03192176), menopausal women age >40−65 y with moderate/severe VMS (≥50/wk) were randomized to one of the following: fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo (PBO). Coprimary efficacy outcomes were frequency and severity of moderate/severe VMS at wk 4 and 12. Secondary efficacy outcomes included changes in moderate/severe VMS frequency and severity by study wk. Of 356 women randomized, 352 received ≥1 dose study drug (safety population; mean [SD] age: 54.6 [4.7] y; 73% white) and 287 (81%) completed the study: PBO: 37/44 (84%); fezolinetant: 250/312 (80%). The most common reasons for discontinuation were withdrawal of consent (6.7%) and AEs (5.9%). All fezolinetant dose groups demonstrated reductions in VMS frequency and severity at wk 4 and 12. Significant dose responses were observed in all coprimary efficacy endpoints. The differences from PBO in least squares (LS) mean changes from baseline in moderate/severe VMS frequency per day at wk 4 were −1.9, −3.0, −2.8, and −3.5 for 15, 30, 60, and 90 mg BID, respectively, and −2.3, −3.0, and −2.4 for 30, 60, and 120 mg QD, respectively, with a common SE of 0.8 (all P<.05). The differences from PBO in LS mean change from baseline in moderate/severe VMS frequency per day at wk 12 were −1.8, −2.1, −2.3, and −2.6 for 15, 30, 60, and 90 mg BID, respectively, and −2.1, −2.6, and −2.1 for 30, 60, and 120 mg QD, respectively, with a common SE of ~0.7 (all P<.05). Dose response was apparent in frequency and severity as early as at wk 1. The majority of TEAEs were mild or moderate in severity. There were no deaths or serious treatment-related TEAEs. This study demonstrates that fezolinetant is a safe and effective nonhormonal treatment for rapid reduction of moderate/severe menopausal VMS. 1Fraser GL, et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes [abstract OR16-5]. Endocr Rev. 2017;38(3).

Project description:ObjectiveIn the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs).MethodsIn this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs).ResultsOf 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6).ConclusionsOral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.

Project description:ObjectiveTo evaluate the safety, tolerability, and effect of fezolinetant on endometrial health over 52 weeks.MethodsWe conducted a phase 3, randomized, double-blind, 52-week safety study (SKYLIGHT 4 [Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause]) of placebo, fezolinetant 30 mg, and fezolinetant 45 mg once daily (1:1:1). Participants were postmenopausal and seeking treatment for vasomotor symptoms associated with menopause. Primary endpoints were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia, and percentage with endometrial malignancy. Endometrial hyperplasia or malignancy was evaluated according to U.S. Food and Drug Administration guidance (point estimate of 1% or less with an upper bound of one-sided 95% CI of 4% or less). Secondary endpoints included change in bone mineral density (BMD) and trabecular bone score. A sample size of 1,740 was calculated to enable observation of one or more events (≈80% probability for events with background rate of less than 1%).ResultsA total of 1,830 participants were randomized and took one or more medication dose (July 2019-January 2022). Treatment-emergent adverse events occurred in 64.1% (391/610) of the placebo group, 67.9% (415/611) of the fezolinetant 30-mg group, and 63.9% (389/609) of the fezolinetant 45-mg group. Treatment-emergent adverse events leading to discontinuation were similar across groups (placebo, 26/610 [4.3%]; fezolinetant 30 mg, 34/611 [5.6%]; fezolinetant 45 mg, 28/609 [4.6%]). Endometrial safety was assessed in 599 participants. In the fezolinetant 45-mg group, 1 of 203 participants had endometrial hyperplasia (0.5%; upper limit of one-sided 95% CI 2.3%); there were no cases in the placebo (0/186) or fezolinetant 30 mg (0/210) group. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI 2.2%) with no cases in the other groups. Liver enzyme elevations more than three times the upper limit of normal occurred in 6 of 583 placebo, 8 of 590 fezolinetant 30 mg, and 12 of 589 fezolinetant 45 mg participants; no Hy's law cases were reported (ie, no severe drug-induced liver injury with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal and total bilirubin more than two times the upper limit of normal, with no elevation of alkaline phosphatase and no other reason to explain the combination). Changes in BMD and trabecular bone score were similar across groups.ConclusionResults from SKYLIGHT 4 confirm the 52-week safety and tolerability of fezolinetant and support its continued development.Funding sourceAstellas Pharma Inc.Clinical trial registrationClinicalTrials.gov , NCT04003389.

Dataset Information

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1).

Objective

Methods

Results

Conclusions

Publications

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1).

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