Does fezolinetant have an effect on sleep?

• Sleep disturbances are associated with vasomotor symptoms (VMS) and frequent awakenings during the night due to night sweats.^4,5 Disturbed sleep increases with increasing VMS frequency and severity.⁶  Reducing VMS may also mitigate downstream effects, including sleep disturbances.
• The complex relationship between VMS and sleep disturbances during menopause has been an area of active research.⁷ 
• Fezolinetant is a selective neurokinin-3 receptor antagonist.^1,8,9 Fezolinetant has been found to improve sleep disturbances by addressing the underlying cause of VMS and night sweats, without inducing sleep.
• Patient-reported outcome measures of sleep disturbance / impairment measured in trials of fezolinetant included:
  • Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b): assesses sleep disturbance over the previous seven days and includes perceptions of restless sleep, satisfaction with sleep, refreshing sleep, difficulties sleeping, getting to sleep or staying asleep, amount of sleep, and sleep quality.⁵
  • PROMIS Sleep-Related Impairment - Short Form 8a (PROMIS SRI SF 8a): assesses the impact of sleep impairments over the previous seven days.¹
  • Patient Global Impression of Change - Sleep Disturbance (PGI-C SD): assesses how well participants were sleeping at that time compared with the start of the study.^8,9
  • Patient Global Impression of Severity - Sleep Disturbance (PGI-S SD): assesses the severity of any current problems while sleeping at night.^8,9
• Higher scores on each measure indicate more sleep disturbance / impairment.
• Disturbed sleep was not a prerequisite for study inclusion.^2,8,9

SKYLIGHT 1 and 2 individual trial results

• In SKYLIGHT 1, improvements in patient-reported sleep disturbance in fezolinetant-treated participants were observed but generally did not reach statistical significance.⁸ 
• In SKYLIGHT 2, fezolinetant 45 mg significantly reduced PROMIS SD SF 8b total score from Baseline to Weeks 4 and 12 compared with placebo (p ≤ 0.01).⁹ 

Figure 1. Change in PROMIS SD SF 8b total score from Baseline to Weeks 4 and 12 in SKYLIGHT 1 and SKYLIGHT 2^8,9

SKYLIGHT 1 and 2 trial pooled analysis results

• The analyses for SKYLIGHT pooled data do not control for the type I error rate (i.e., without multiplicity adjustment). The p-values should be considered indicative, and not confirmatory, and have been used for the purposes of hypothesis generation.

Figure 2. Change in PROMIS SD SF 8b total score from Baseline to Weeks 4 and 12¹

Figure 3. Change in PROMIS SRI SF 8a total score from Baseline to Weeks 4 and 12¹

Figure 4. Distribution of the PGI-C SD at Weeks 4 and 12¹

Figure 5. Distribution of the PGI-S SD at Baseline, Week 4, and Week 12¹

DAYLIGHT trial results

• The analyses below do not control for the type I error rate (i.e., without multiplicity adjustment). The p-values should be considered indicative, and not confirmatory, and have been used for the purposes of hypothesis generation.

Figure 6. Change in PROMIS SD SF 8b total score from baseline to Week 24^2,10

Figure 7. Distribution of PGI-C SD at Week 24²

Figure 8. Distribution of PGI-S SD at Baseline and Week 24³

1. Shapiro M, Cano A, Nappi RE, et al. Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause. Maturitas. 2024; Available at: https://doi.org/10.1016/j.maturitas.2024.107999.

2. Schaudig K, Wang X, Bouchard C, et al. Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomized controlled trial. BMJ. 2024;(387):e079525. Available at: https://doi.org/10.1136/bmj-2024-079525.

3. Shapiro M, Wu X, Wang X, et al. Effect of fezolinetant on patient-reported quality-of-life outcomes: Data from a phase 3b study (DAYLIGHT) of the treatment of moderate to severe vasomotor symptoms associated with menopause in women considered unsuitable for hormone therapy. Maturitas. 2024; Available at: https://doi.org/10.1016/j.maturitas.2024.108159.

4. Thurston R, Chang Y, Buysse D, et al. Hot flashes and Awakenings Among Midlife Women. Sleep. 2019;(0161-8105) Available at: https://doi.org/10.1093/sleep/zsz131.

5. English M, Stoykova B, Slota C, et al. Qualitative study: burden of menopause-associated vasomotor symptoms (VMS) and validation of PROMIS Sleep Disturbance and Sleep-Related Impairment measures for assessment of VMS impact on sleep. J. Patient-Rep. Outcomes. 2021;5(1):37. Available at: https://doi.org/10.1186/s41687-021-00289-y.

6. DePree B, Shiozawa A, King D, et al. Association of menopausal vasomotor symptom severity with sleep and work impairments: A US survey. Menopause. 2023;30(9):887-897. Available at: https://doi.org/10.1097/gme.0000000000002237.

7. Maki PM, Panay N, Simon JA. Sleep disturbance associated with the menopause. Menopause. 2024;31(8):724-733. Available at: https://doi.org/10.1097/gme.0000000000002386.

8. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401(10382):1091-1102. Available at: https://doi.org/10.1016/s0140-6736(23)00085-5.

9. Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocr Metab. 2023;108(8):1981-1997. Available at: https://doi.org/10.1210/clinem/dgad058.

10. Data on file.