Endometrial and bone safety
Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.8
Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).8 For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.8
In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.8
Liver safety
Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.8
The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.11,12
Unmet need for nonhormone treatment of VMS
Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.2 Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.13-15
Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).16 Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.17 Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.15
Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.19,21
Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.19,21
Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.2 In addition, many symptomatic menopausal women without health contraindications choose not to take HT.2 Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.
Bottom line
A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.
One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.
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