ORF38-03 - Central Nervous System Safety of Fezolinetant from Pooled Analysis of 52-Week, Phase 3 Studies (SKYLIGHT 1, 2, and 4)

Introduction
Fezolinetant, a non-hormonal treatment, is globally-approved for moderate to severe vasomotor symptoms (VMS) due to menopause at a dose of 45 mg once daily. As fezolinetant acts centrally by selectively targeting neurokinin 3 receptors on hypothalamic neurons, a review of central nervous system (CNS) effects was performed through collection of treatment-emergent adverse events (TEAEs); prespecified adverse events of special interest (AESIs); and the Columbia Suicide Severity Rating Scale (C-SSRS).

Objective
To present pooled CNS safety data from three 52-week phase 3 fezolinetant studies (SKYLIGHT 1, 2 and 4; NCT04003155, NCT04003142, NCT04003389, respectively) in women with VMS due to menopause.
Methods
SKYLIGHT 1 and 2 were identical, double-blind, placebo-controlled 52-week efficacy and safety studies. Women aged ≥40-≤65 years with moderate to severe VMS were randomized to once-daily placebo, fezolinetant 30 mg or 45 mg (1:1:1) for 12 weeks. Those on fezolinetant continued their dose; those on placebo were re-randomized to fezolinetant 30 or 45 mg for 40 weeks. SKYLIGHT 4 was a placebo-controlled, double-blind, 52-week long-term safety study.
Results
952 participants receiving placebo, 1103 receiving fezolinetant 30 mg and 1100 receiving fezolinetant 45 mg took ≥1 dose of study medication. The most common CNS TEAE (≥2% of fezolinetant total groups) was headache (7.7% for placebo, 6.8% and 8.2% for fezolinetant 30 mg and 45 mg total). Dizziness was reported in 1.1%, 1.5% and 1.7%, and fatigue in 2.2%, 1.7% and 2.4%, respectively. The majority of events were not drug related.

CNS AESIs were low and similar across groups for potential abuse liability (0.1% for placebo, 0.3% and 0.1% for fezolinetant 30 mg and 45 mg groups); depression (2.0%, 2.4%, 1.9%); somnolence (0.6%, 1.0%, 0.6%); effect on memory (0.1%, 0.2%, 0.2%). Preferred terms included mood altered/swings, feeling abnormal, impaired memory, and poor-quality sleep. There was no difference in CNS AESIs between fezolinetant and placebo in SKYLIGHT 4, based on analysis using the Santner-Snell approach.

CNS TEAE incidence leading to treatment withdrawal was low/similar among treatment groups: fatigue in 0%, 0.4%, 0.3%; dizziness in 0.2%, 0.4%, 0.2%; somnolence in 0%, 0.1%, 0%; headache in 0.6%, 0.2%, 0.5%; depression in 0%, 0%, 0.1%.

C-SSRS showed no fezolinetant effect on suicidal ideation or behavior. Incidence rates were low, consistent with baseline, similar to placebo, and there was no apparent dose-relationship in the fezolinetant groups.

Conclusions
CNS-related AE incidence was similar between fezolinetant and placebo groups. There is no evidence to support risk for depression, somnolence, memory loss, or abuse liability with fezolinetant. This analysis supports the CNS safety of fezolinetant for treatment of moderate to severe VMS.