Elinzanetant Improves Sleep Independent of Hot Flash Reduction in Menopause

A post-hoc mediation analysis presented at SLEEP 2026 found elinzanetant (Veozah) improves sleep disturbances in postmenopausal women through mechanisms beyond nighttime vasomotor symptom (VMS) reduction, with more than half of its total sleep benefit occurring independently of hot flash suppression.¹

Pauline Maki, PhD, a professor of psychiatry, psychology and OB/GYN at University of Illinois at Chicago, who presented the research, noted the clinical motivation behind the analysis: elinzanetant's NK1 receptor antagonism was already understood to play a role in sleep, but the relative contribution of direct sleep effects versus hot flash reduction had not been formally quantified across trials.

"We want to tailor our recommendations for the individual woman," Maki said, "so that was the motivation for the study."¹

Elinzanetant received US Food and Drug Administration (FDA) approval in 2023 as the first non-hormonal neurokinin-1,3 (NK1,3) receptor antagonist indicated for moderate-to-severe VMS associated with menopause. Prior randomized trials consistently showed improvements in both VMS and sleep, but whether those sleep gains were driven by VMS suppression or a direct neural mechanism remained unresolved.

Elinzanetant Efficacy on Sleep Disturbance Across OASIS-1, -2, -3 and NIRVANA Trials

Pooled data from the phase 3 OASIS-1, OASIS-2, and OASIS-3 trials and the phase 2 NIRVANA trial were used to conduct a longitudinal causal mediation analysis comparing elinzanetant 120 mg with placebo across 1345 postmenopausal women (elinzanetant, n = 668; placebo, n = 677). The 12-week OASIS studies enrolled women with moderate-to-severe VMS without a minimum threshold for sleep disturbance, while NIRVANA required both moderate-to-severe VMS and documented sleep disturbance at enrollment.

Sleep outcomes were measured using the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b total T-score at weeks 1 through 12. Nighttime VMS frequency, documented via morning diary, served as the mediator variable.

At baseline, mean nighttime moderate-to-severe VMS frequency was 4.83 and mean PROMIS SD SF 8b T-score was 59.58. The total treatment effect of elinzanetant on sleep was -4.92 (95% CI, -5.73 to -4.12).¹ Of this, the natural direct effect (NDE), representing sleep improvement independent of nighttime VMS reduction, accounted for -2.67 (95% CI, -3.28 to -2.07), while the natural indirect effect mediated through VMS reduction contributed -2.25 (95% CI, -2.81 to -1.69). The NDE represented 54.3% of the total treatment effect (95% CI, 45.8% to 62.8%), indicating elinzanetant's sleep benefit is not fully explained by hot flash suppression alone.

Clinical Implications for Sleep Disturbance Management in Menopause

These findings carry direct relevance for physicians managing perimenopausal and postmenopausal patients with prominent sleep complaints. Menopausal sleep disturbance is common and often undertreated, in part because traditional pharmacologic options carry significant safety concerns. The "Z drug" class of hypnotics is generally discouraged for long-term use given risks of dependence, cognitive effects, and falls.

Because many menopausal women experience sleep disturbance and VMS concurrently, a single agent addressing both pathways represents a meaningful clinical option. The mediation analysis suggests elinzanetant's NK1 receptor antagonism may directly influence sleep circuitry, separate from its thermoregulatory effects in the hypothalamus.

"My menopause is not your menopause," Maki said. "Because hot flashes are accompanied by sleep disturbance, oftentimes if there's a medication affecting both, then many will choose to provide it to their patients, and elinzanetant seems to do that."¹

Looking ahead, Maki identified several critical research questions prompted by these findings. Whether elinzanetant improves sleep in postmenopausal women without significant VMS remains unknown, as does its potential utility in men experiencing sleep disruption, including those undergoing androgen deprivation therapy for prostate cancer. If sleep benefits persist in populations with minimal to no hot flashes, Maki noted, the findings would implicate disrupted NK1 signaling as a broader contributor to sleep dysregulation at midlife.²

Editors’ note: Maki reports relevant disclosures with Astellas and Bayer.

References

1. Maki P. Elinzanetant improves sleep disturbances partly independent of nighttime vasomotor symptoms: post-hoc mediation analysis from four trials. Presented at: SLEEP 2026; June 2026.

2. US Food and Drug Administration. FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause. May 12, 2023. Accessed June 15, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause