Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies

Introduction: This study evaluated the safety and tolerability of fezolinetant in women with vasomotor symptoms (VMS) due to menopause in a pooled analysis of data from three 52-week phase 3 studies (SKYLIGHT 1, 2, and 4).

Methods: SKYLIGHT 1 and 2 were double-blind, placebo-controlled studies where women (≥ 40 to ≤ 65 years), with moderate to severe VMS (minimum average ≥ 7 hot flashes/day) were randomized to once-daily placebo, fezolinetant 30 mg or 45 mg. After 12 weeks, those on placebo were re-randomized to fezolinetant 30 mg or 45 mg, while those on fezolinetant continued on their assigned dose for 40 weeks. SKYLIGHT 4 was a placebo-controlled, double-blind, 52-week safety study. Safety was assessed by frequency of treatment-emergent adverse events (TEAEs) and endometrial events. TEAEs of special interest included liver test elevations and endometrial hyperplasia or cancer or disordered proliferative endometrium.

Results: Totals of 952 participants receiving placebo, 1100 receiving fezolinetant 45 mg, and 1103 receiving fezolinetant 30 mg took ≥ 1 dose of study medication. TEAEs occurred in 55.3%, 62.9%, and 65.4%, respectively; exposure-adjusted results were consistent with these results. Most frequent TEAEs in fezolinetant-treated participants included upper respiratory tract infection (7.7-8.3%), headache (6.8-8.2%), coronavirus disease 2019 (5.8-6.1%), back pain (3.1-3.7%), arthralgia (2.9-3.2%), diarrhea (2.3-3.2%), urinary tract infection (2.9-3.4%), and insomnia (2.0-3.0%). The incidence of drug-related serious TEAEs and associated treatment withdrawals was low. Elevations in liver transaminases occurred in 1.5-2.3% of fezolinetant-treated participants, were typically asymptomatic and transient, resolved on treatment or discontinuation, with no evidence of severe drug-induced liver injury (Hy's law). Endometrial safety results were well within US Food and Drug Administration criteria. Analysis of benign and non-benign neoplasm controlled for exposure demonstrated no increased risk versus placebo.

Conclusion: Pooled data confirm the safety and tolerability of fezolinetant over 52 weeks.

Trial registration: ClinicalTrials.gov identifiers, NCT04003155, NCT04003142, and NCT04003389. Graphical abstract available for this article.