NIRVANA: Elinzanetant cuts objective wakefulness in menopausal women

Findings from the exploratory phase 2 NIRVANA trial (NCT06112756) showed that elinzanetant (Lynkuet) produced a numerically greater reduction in polysomnography (PSG)-measured wakefulness after sleep onset (WASO) compared with placebo in postmenopausal women with vasomotor symptoms (VMS) and objectively confirmed sleep disturbance, with the effect most pronounced at week 4.¹

The results were presented as a poster at the SLEEP 2026 Annual Meeting in Baltimore, Maryland, by investigators led by Hadine Joffe, MD, MSc, a professor of psychiatry at Beth Israel Deaconess Medical Center and head of the Department of Psychiatry at Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Background

Sleep disturbance is frequently reported among menopausal women and can significantly impact quality of life, yet effective therapies with benefit confirmed by objective PSG measurement have been lacking in this population. Elinzanetant is a selective dual neurokinin-1 (NK1) and NK3 receptor antagonist that previously demonstrated significant improvements in patient-reported sleep outcomes in the pivotal OASIS studies.² NIRVANA was designed to extend this evidence by evaluating elinzanetant's effect on objective PSG sleep parameters in addition to patient-reported outcomes (PROs), and was the first study to assess elinzanetant using PSG-confirmed sleep disturbance as an entry criterion.

Methods

NIRVANA enrolled 110 postmenopausal women aged 40 to 65 years (mean age, 54.8 years [standard deviation, 4.6]) with PSG-confirmed sleep disturbance (WASO of at least 30 minutes) and at least 20 moderate-to-severe VMS per week. Participants were randomly assigned to elinzanetant 120 mg (n=55) or placebo (n=55) once daily for 12 weeks. In-lab PSG assessments were conducted at baseline, week 4, and week 12 over 2 consecutive nights per time point; for each participant, mean values of the 2 consecutive nights at each visit were used in the analysis. No statistical hypothesis testing was planned; the primary objective was to estimate the treatment effect.

The primary and secondary end points were changes from baseline in WASO at weeks 4 and 12, respectively. Given skewed data distribution, a prespecified analysis with log transformation was applied, and least-squares geometric mean ratios (LSGMR) to baseline are reported. A post-hoc random coefficient model was additionally applied to all individual in-lab PSG night data across the 12-week treatment period to assess overall treatment effect while accounting for night-to-night variability.

Results

At baseline, median WASO was 72.0 minutes (quartile [Q]1, Q3: 48.0, 90.3) in the elinzanetant arm and 76.8 minutes (Q1, Q3: 54.0, 102.5) in the placebo arm. Median WASO decreased numerically from baseline in both arms at weeks 4 and 12. At week 4, median WASO was 52.5 minutes with elinzanetant vs 68.8 minutes with placebo. At week 12, median WASO was 47.3 minutes with elinzanetant vs 64.0 minutes with placebo.

For the primary end point, the LSGMR to baseline at week 4 was 0.68 (unadjusted 90% CI, 0.59-0.77) for elinzanetant and 0.94 (unadjusted 90% CI, 0.82-1.08) for placebo, representing a 28% (unadjusted 90% CI, 13%-41%) greater reduction in WASO with elinzanetant vs placebo. At week 12, the LSGMR was 0.67 (unadjusted 90% CI, 0.57-0.79) for elinzanetant and 0.76 (unadjusted 90% CI, 0.65-0.90) for placebo, representing a 12% (unadjusted 90% CI, -11% to 30%) greater reduction with elinzanetant.

Notable night-to-night variability in WASO was observed, with values differing by more than 60 minutes between consecutive nights in 15% of cases. The post-hoc random coefficient model, which accounted for this variability across all individual PSG nights, showed an 18% (unadjusted 95% CI, 5%-30%) greater WASO reduction with elinzanetant vs placebo across the full 12-week treatment period, equating to an absolute reduction of approximately 13 minutes per night, assuming a baseline WASO of 75 minutes.

Conclusions

Elinzanetant produced a numerically greater reduction in PSG-measured WASO vs placebo across the 12-week NIRVANA trial, with the effect more pronounced at week 4 than week 12. The investigators noted that while the magnitude of improvement was modest, the findings are meaningful given the prevalence of menopausal sleep disturbance and the absence of therapies with PSG-confirmed benefit in this population. The results add objective evidence in support of elinzanetant's effect on menopause-related sleep disturbance, consistent with PRO-based findings from the OASIS trials.²

REFERENCES

1. Soares CN, Joffe H, Maki PM, et al. Effect of elinzanetant in reducing polysomnographic wakefulness after sleep onset in postmenopausal women: results from the exploratory Phase II NIRVANA study. Sleep. 2026;49(Suppl 1):A372

2. Pinkerton JV, Simon JA, Joffe H, et al. Elinzanetant for the treatment of vasomotor symptoms associated with menopause: OASIS 1 and 2 randomized clinical trials. JAMA. 2024;332(16):1343-1354. doi:10.1001/jama.2024.14618