Over half of elinzanetant's sleep benefit is VMS-independent

A post-hoc causal mediation analysis pooling data from 4 clinical trials found that elinzanetant (Lynkuet) improved sleep disturbances in postmenopausal women through 2 distinct pathways—reduction of nighttime vasomotor symptoms (VMS) and a direct, VMS-independent mechanism—with more than half of the total sleep benefit attributable to the direct effect. The findings were presented as a poster at the SLEEP 2026 Annual Meeting in Baltimore, Maryland.¹

The research was conducted by investigators led by Pauline Maki, PhD, a professor of Psychiatry, Psychology and Obstetrics & Gynecology; director of Women’s Mental Health Research Program; and senior director of Research, Center for Research on Women and Gender at the University of Illinois College of Medicine in Chicago.

Background

VMS and sleep disturbance are among the most frequent symptoms of the menopause transition, reported by up to 80% and 69% of women, respectively.^2,3 Up to 40% of women report disruptive, moderate-to-severe VMS.² Sleep disturbance encompasses poor sleep quality, frequent awakenings, obstructive sleep apnea, restless legs syndrome, and insomnia. Although nighttime VMS (night sweats) are widely presumed to drive much of menopausal sleep disruption, the extent to which sleep disturbance in this population is independent of VMS has not been well characterized.

Elinzanetant is a selective dual neurokinin-1 (NK1) and NK3 receptor antagonist that targets receptors in the hypothalamus and skin to help restore balance to temperature regulation and sleep.^4,5 In the pivotal OASIS-1 (NCT05042362) and OASIS-2 (NCT05099159) trials, elinzanetant significantly and rapidly reduced the frequency of moderate-to-severe VMS from as early as week 1 and significantly reduced Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF 8b) total scores compared with placebo at week 12.⁶ This post-hoc analysis was designed to determine whether those sleep improvements occurred solely as a downstream consequence of VMS reduction or whether elinzanetant also acts on sleep through independent mechanisms.

Methods

Pooled data from the elinzanetant 120 mg and placebo arms of 4 randomized, placebo-controlled trials were analyzed: the pivotal 26-week OASIS-1 and OASIS-2 studies (n=796 women with at least 50 moderate-to-severe VMS per week),⁶ the 52-week OASIS-3 study (NCT05030584) (n=628 women with moderate-to-severe VMS, no minimum frequency requirement),⁷ and the 12-week phase 2 NIRVANA trial (NCT06112756) (n=110 women with at least 30 moderate-to-severe VMS per week and baseline sleep disturbance).⁸ The OASIS studies had no eligibility requirements related to sleep disturbances, whereas NIRVANA specifically required baseline sleep disturbance, allowing the pooled analysis to capture a broad range of sleep impairment at entry.

Sleep disturbances were assessed using the PROMIS SD SF 8b total T-score at weeks 1, 2, 3, 4, 8, and 12, with higher scores indicating greater disturbance. Nighttime VMS frequency was documented via a morning diary recalling hot flashes from the prior night and served as the mediator variable.

A longitudinal causal mediation analysis using linear mixed-effects models⁹ was applied to measurements at all prespecified time points. A treatment-mediator interaction term was included to allow the effect of nighttime VMS on sleep disturbance to vary by treatment arm. Analyses were adjusted for plausible confounders including baseline body mass index, smoking history, and clinical trial. The total treatment effect of elinzanetant vs placebo on sleep was partitioned into the natural indirect effect (NIE)—the component mediated through nighttime VMS reduction—and the natural direct effect (NDE)—sleep improvement occurring independently of any effect on nighttime VMS.

Results

A total of 1345 women were included in the analysis (elinzanetant: n=668; placebo: n=677). At baseline, the mean nighttime moderate-to-severe VMS frequency was 4.83 (standard deviation [SD], 4.84) per week, and the mean PROMIS SD SF 8b total T-score was 59.58 (SD, 7.26), consistent with a moderately to severely sleep-disturbed population.

The total treatment effect of elinzanetant on sleep disturbance relative to placebo was -4.92 (95% CI, -5.73 to -4.12), indicating a clinically meaningful reduction. Of this total, the NDE accounted for -2.67 (95% CI, -3.28 to -2.07) and the NIE for -2.25 (95% CI, -2.81 to -1.69). The proportion of the total treatment effect attributable to the direct, VMS-independent pathway was 54.3% (95% CI, 45.8%-62.8%), with the remaining 45.7% mediated through nighttime VMS reduction.

Conclusions and clinical implications

The authors concluded that elinzanetant improves sleep disturbance in postmenopausal women through both VMS-mediated and direct mechanisms, with the majority of the sleep benefit occurring through a pathway independent of VMS reduction. These findings support the hypothesis that menopausal sleep disturbance is not solely caused by VMS, and that elinzanetant may engage distinct sleep-related central pathways—consistent with the known role of NK1 and NK3 receptor signaling in the hypothalamus.

The investigators noted a clinically meaningful implication: If elinzanetant improves sleep through direct mechanisms, it may represent an appropriate treatment option for postmenopausal women who present with sleep complaints but less severe VMS, potentially broadening the clinical utility of the drug beyond those with predominantly VMS-driven symptom burden.

Limitations of the analysis included reliance on self-reported sleep outcomes and the possibility that results may not generalize to women outside the age ranges and inclusion criteria of the contributing trials or to those with more complex comorbidities.

REFERENCES

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8. Joffe H, Soares C, Maki P, et al. Evaluating patient-reported sleep outcomes in the NIRVANA study of elinzanetant. Presented at: The Menopause Society's 2025 Annual Meeting; October 21-25, 2025; Orlando, Florida. Abstract P-81.

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