Neurokinin Receptor Antagonist, Fezolinetant, for Treatment of Menopausal Vasomotor Symptoms

Breakthroughs in women's health are uncommon; accordingly, it is exciting to read results from a phase 3 trial of fezolinetant (1), a selective neurokinin-3 receptor (NK3R) antagonist, confirming its efficacy and safety in treating menopausal vasomotor symptoms (VMS).

VMS affect up to 80% of women, approximately 25% bothersome enough to need treatment, persistent for a median of 7 years, with duration and severity varying by race and ethnicity.

Although hot flashes, night sweats, and associated sleep disturbances are often considered just a nuisance, they impact many aspects of women's lives. Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) report interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%). The more severe the VMS, the more daily activities are impacted, leading women to seek treatment to improve quality of life (2).

To date, menopausal hormone therapy (HT) has been the primary and most effective treatment for VMS. In placebo-controlled randomized control trials, HT has been shown to reduce the frequency and severity of hot flashes and benefit sleep, mood, fatigue, skeletal health, vaginal health, and, potentially, cardiovascular health. For women with early menopause, observational studies suggest HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction (3). Furthermore, HT can be individualized through a variety of routes of administration (oral, transdermal, vaginal), doses, and formulations. Notwithstanding the fear caused by the initial 2002 publication of Women's Health Initiative findings, guidelines from major medical societies agree that, for healthy women under age 60 or within 10 years of menopause, HT is safe and effective, not only to treat bothersome VMS but to prevent osteoporosis and genitourinary changes.

For some women, eg, breast cancer survivors, using HT is contraindicated. Other women prefer not to use HT. The only Food and Drug Administration-approved nonhormonal treatment for VMS is low dose 7.5 mg paroxetine salt, which, unfortunately, along with off-label use of other antidepressants, gabapentinoids, and clonidine, is substantially less effective than HT in treating VMS.

Enter the new neurokinin receptor antagonists. These agents offer a targeted approach to VMS by modulating brain circuits triggered by decreasing estrogen levels at menopause, which leads to reduced frequency and severity of VMS comparable to HT, with rapid onset of action within 1 week.

Fezolinetant represents an investigational oral selective neurokinin 3 receptor antagonist for treating moderate to severe menopausal VMS. The pathophysiology of VMS is not yet entirely understood. However, it involves neurons that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy neurons), which respond to estradiol negative feedback and innervate the thermoregulatory center in the hypothalamus (4). Though the exact mechanism remains unclear, the decline in estrogen at menopause results in an increase in neurokinin B signaling at the KNDy neurons in the thermoregulatory zone with resultant increases in hot flashes (4). By antagonizing neurokinin B binding on the KNDy neurons in the hypothalamus, fezolinetant dampens neuronal signaling, leading to reduced hot flashes (1).

Earlier data found significant reductions in VMS with fezolinetant compared to placebo (5). Investigators have published findings from 2 year-long international phase 3 trials assessing the safety and efficacy of 2 doses of oral fezolinetant (30 and 45 mg) in the treatment of VMS (1, 6). In both trials, fezolinetant significantly reduced VMS frequency and severity. In Skylight 2, Johnson and colleagues (1) report results from their double-blind controlled 12-week trial of fezolinetant (30 and 45 mg) followed by an additional 40-week active treatment extension. At weeks 4 and 12, both doses achieved statistical significance in reducing VMS frequency and severity, with sustained reduction to 52 weeks.

Mean percentage changes were reported. The 45 mg dose of fezolinetant reduced the mean (SD) daily moderate to severe hot flashes from 11.79 hot flashes per day (8.26) at baseline to 5.67 (7.29) at week 4 (−55.16%) and 4.49 (5.39) at week 12 (−64.27%). In the placebo group, reductions from 11.59 (5.02) to 8.08 (6.50) at week 4 (−33.60%) and 6.73 (7.58) (−45.35) at week 12 were observed. In a dose-finding study, Fezolinetant produced higher responder rates than placebo and larger improvements in quality of life (7).

Serious treatment-emergent adverse events in Skylight 2 (1) were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. As prior trials of neurokinin receptor antagonists suggested potential hepatotoxicity, investigators paid close attention to liver function tests. Increases in alanine aminotransferase or aspartate aminotransferase were described as asymptomatic, isolated, intermittent, or transient and returned to baseline while on treatment (2 participants), treatment interruption (2 participants), and after treatment discontinuation (1 participant). No new safety signals were observed in the 40-week extension. Adverse effects on the endometrium were not seen or expected with this centrally acting class of medications.

VMS may impair daily function, quality of life, and productivity and result in absenteeism. Accordingly, for women who cannot or choose not to take menopausal HT, there remains a substantial unmet need for targeted therapy of VMS (2). The list of medical conditions that may make HT inappropriate use is long. It includes current or past breast and other estrogen-sensitive cancers, use of tamoxifen and aromatase inhibitors, those at high risk of breast cancer (hereditary predispositions), cardiovascular disease, stroke, or venous thrombosis, endometriosis prior to surgical menopause, enlarging fibroids, and migraine headaches with aura. Women with these concerns need more effective relief from moderate to severe VMS than provided by existing nonhormonal options. Although an Institute for Clinical and Economic Review (8) comparing fezolinetant to hormone therapy raised the need for longer term safety and efficacy data (a 52-week long-term placebo-controlled safety and tolerability clinical trial is underway) and equity in drug pricing, the development of neurokinin receptor antagonists represents a major breakthrough in the care of menopausal women. Fezolinetant, and potentially other neurokinin antagonists in development, offer much-needed effective, safe, nonhormonal therapy to reduce the frequency and severity of VMS associated with menopause, particularly for women who cannot or will not take hormone therapy.

Disclosures

A.M.K. has served on the advisory board for Merck, Mithra Pharmaceuticals, and Pfizer. The University of Florida College of Medicine receives research funding from Merck and Bayer for ongoing clinical trials; J.V.P. Bayer Pharmaceuticals Multicenter Research Trial; fees to the University of Virginia; D.L.R. has nothing to disclose; L.N.H. has nothing to disclose.