This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.
Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms
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 Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
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;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.
A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.
The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.3-5
Key study findings
Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.8 Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.6-9
The published phase 2 trials9 and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.6,7
Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.10 Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.6 A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.6
Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.6 Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.6
Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.6
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Fezolinetant offers a much-needed effective and safe selective nonhormone NK3 receptor antagonist therapy that reduces the frequency and severity of menopausal VMS and has been shown to be safe through 52 weeks of treatment.
Fezolinetant offers a much-needed effective and safe selective nonhormone NK3 receptor antagonist therapy that reduces the frequency and severity of menopausal VMS and has been shown to be safe through 52 weeks of treatment.
For more information
To read more about how fezolinetant specifically targets the hormone receptor that triggers hot flashes as well as on prescribing hormone therapy for women with menopausal symptoms, see “Focus on menopause: Q&A with Jan Shifren, MD, and Genevieve NealPerry, MD, PhD,” in the December 2022 issue of OBG Management at https://www.mdedge.com/obgyn/article/260380/menopause
To read more about how fezolinetant specifically targets the hormone receptor that triggers hot flashes as well as on prescribing hormone therapy for women with menopausal symptoms, see “Focus on menopause: Q&A with Jan Shifren, MD, and Genevieve NealPerry, MD, PhD,” in the December 2022 issue of OBG Management at https://www.mdedge.com/obgyn/article/260380/menopause
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