0840 Elinzanetant Improves Sleep Disturbances Party Independent of Nighttime Vasomotor Symptoms: Post-Hoc Mediation Analysis from Four Trials

Abstract Introduction Elinzanetant has demonstrated efficacy in reducing vasomotor symptoms (VMS) and sleep disturbances in postmenopausal women. This post hoc analysis assessed whether elinzanetant improves sleep disturbances independently of nighttime VMS reduction via mediation analysis. Methods Pooled data from the elinzanetant 120 mg and placebo arms of the Phase III OASIS-1, -2, -3 trials and the Phase II NIRVANA trial were analyzed. The 12-week OASIS studies enrolled postmenopausal women with moderate-to-severe VMS (≥50/week for OASIS-1, -2; no minimum for OASIS-3) but no requirements for sleep disturbances. NIRVANA included postmenopausal women with moderate-to-severe VMS (≥20/week) and sleep disturbances. VMS frequency was documented twice daily via a morning diary (recalling nighttime VMS) and evening diary (recalling daytime VMS). Sleep disturbances were assessed using Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b total T-scores at weeks 1, 2, 3, 4, 8, and 12. Nighttime VMS frequency served as a mediator in a longitudinal causal mediation analysis that partitioned total treatment effect (elinzanetant versus placebo) into natural direct effect (NDE; sleep improvement independent of nighttime VMS reduction) and natural indirect effect (NIE; improvements on sleep mediated by nighttime VMS reduction), adjusted for baseline values and confounders. Results Among 1,345 women (elinzanetant: n=668; placebo: n=677), baseline mean (standard deviation [SD]) nighttime moderate-to-severe VMS frequency was 4.83 (4.84), while mean (SD) PROMIS SD SF 8b total T-score was 59.58 (7.26). The total treatment effect of elinzanetant on sleep was -4.92 (95% confidence interval [CI] -5.73, -4.12). Of this effect, the NDE accounted for -2.67 (95% CI -3.28, -2.07), while the NIE contributed to -2.25 (95% CI -2.81, -1.69). The proportion of the total effect attributable to the NDE was 54.3% (95% CI 45.8%, 62.8%). Conclusion Elinzanetant improved sleep disturbances both directly and indirectly via reduction of nighttime VMS, indicating that over half of its benefit on sleep occurs independently of VMS improvement. These findings suggest that menopausal sleep disturbances are partly independent of VMS and that elinzanetant may target distinct sleep-related pathways. Support (if any) Sponsored by Bayer. Medical writing assistance (Highfield, Oxford, UK) funded by Bayer.