Elinzanetant Improves Sleep Through VMS-Independent Mechanisms, According to New Pooled Analysis

The novel dual neurokinin-1,3 (NK-1,3) receptor antagonist elinzanetant improves menopausal sleep disturbances through mechanisms found to extend beyond vasomotor symptom (VMS) relief, according to research findings presented during The Menopause Society 2025 Annual Meeting, October 21-25, 2025, in Orlando, FL.

Coauthor Pauline Maki, PhD, professor of psychiatry, psychology and obstetrics and gynecology at the University of Illinois College of medicine Chicago, and colleagues analyzed pooled data from 1,345 postmenopausal women across 4 clinical trials and found that elinzanetant reduced sleep disturbance scores, as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) by 4.92 points compared with placebo over 12 weeks. Remarkably, 54.3% of this improvement occurred independently of reductions in nighttime vasomotor symptoms, challenging the prevailing assumption that sleep problems in menopause result primarily from hot flashes and night sweats disrupting sleep.

Elinzanetant has demonstrated efficacy in reducing both VMS and sleep disturbances in postmenopausal women. This distinction carries clinical importance, study authors noted: if sleep benefits derive entirely from VMS reduction, any effective VMS treatment should produce equivalent sleep improvements. Conversely, if elinzanetant improves sleep through additional pathways, this would position the compound as uniquely beneficial for women experiencing both symptoms.

Maki and colleagues designed this analysis to quantify how much of elinzanetant's sleep benefit operates independently of nighttime VMS reduction vs through VMS reduction.

The Pooled Analysis

The research team pooled 12-week data from the elinzanetant 120 mg and placebo arms of 3 phase 3 trials (OASIS-1, -2, -3) and a single phase 2 trial (NIRVANA). The OASIS cohorts enrolled postmenopausal women with moderate-to-severe VMS (50 or more per week for OASIS-1 and -2, with no minimum requirement for OASIS-3) but there were no requirements imposed for sleep disturbances. NIRVANA enrolled postmenopausal women with VMS (20 or more per week) and sleep disturbances.

Participants documented VMS frequency twice daily via morning diary (recalling nighttime VMS) and evening diary (recalling daytime VMS). Researchers assessed sleep disturbances using PROMIS SD SF 8b T-scores at weeks 1, 2, 3, 4, 8, and 12.

The team employed longitudinal causal mediation analysis to partition treatment effects into 3 components:

• Total treatment effect (overall impact of elinzanetant versus placebo)
• Natural direct effect (NDE: sleep improvement independent of nighttime VMS reduction)
• Natural indirect effect (NIE: sleep improvement mediated by nighttime VMS reduction)

Nighttime moderate-to-severe VMS frequency served as the mediator variable, with analyses adjusted for baseline scores and confounders.

Findings

The pooled analysis included 1,345 women (668 receiving elinzanetant, 677 receiving placebo). At baseline, mean nighttime moderate-to-severe VMS frequency was 4.83, while PROMIS SD SF 8b T-scores averaged 59.58, according to the study abstract.

The total effect of elinzanetant versus placebo was −4.92 points (95% CI −5.73 to −4.12). The natural direct effect accounted for −2.67 points (95% CI −3.28 to −2.07), while the natural indirect effect contributed −2.25 points (95% CI −2.81 to −1.69). The researchers calculated that the proportion of total effect attributable to direct effects of elinzanetant on sleep was 54.3% (95% CI 45.8 to 62.8).

Maki et al emphasize that their findings highlight the potential for elinzanetant to improve sleep through mechanisms beyond VMS alleviation and support the notion that sleep disturbances in menopause are not solely caused by VMS. "Further research is warranted to elucidate the pathways through which elinzanetant exerts its direct effects on sleep," they concluded.

Source: Maki P, Trigg A, Joffe H, et al. Elinzanetant improves sleep disturbances in menopausal women partially independently of reductions in vasomotor symptoms. Abstract presented at: The Menopause Society’s 2025 Annual Meeting; October 21-25, 2025; Orlando, FL. Accessed October 21, 2025.