Neurokinin 3 receptor antagonists for menopausal vasomotor symptoms, an appraisal

Abstract

Fezolinetant is a neurokinin 3 receptor antagonist under investigation for treatment of menopausal symptoms. In a recent study, Lederman and colleagues¹ reported the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.

Fezolinetant is a neurokinin 3 receptor antagonist under investigation for treatment of menopausal symptoms. In a recent study, Lederman and colleagues¹ reported the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause.

Main text

The neurokinin 3 receptor (NK3R) antagonists belong to a new class of drugs initially developed in the 80s for the treatment of schizophrenia, an indication that was subsequently abandoned. They were approved by the United States Food and Drug Administration on May 12, 2023 and are now under regulatory review in the Europe, and Australia for the primary indication of treatment of vasomotor symptoms (VMS) of menopause.²

During the menopause transition and in the years following menopause, VMS (hot flushes) affect about 80% of women, and for some, they can be extremely bothersome, of long duration, and can negatively impact quality of life. These symptoms are attributed to a narrowing of the hypothalamic thermoneutral zone triggered by altered control mechanisms in the setting of declining estrogen levels. This results in activation of VMS by smaller elevations in core body temperature than premenopausally. A central nervous system network of kisspeptin, neurokinin B, and dynorphin (KNDy) neurons, shown by Rance et al. to be located within the hypothalamic preoptic nucleus, activates the NK3R.³ They also demonstrated that KNDy neurons were involved in regulating body temperature. In postmortem studies of postmenopausal women, with marked reduction of endogenous estradiol, hypertrophy of KNDy neurons, and a dramatic increase in neurokinin B gene expression were observed.³ Of the NK3R antagonists that were initially evaluated to alleviate VMS in postmenopausal women, few remain in clinical development because of side effects. Of those compounds currently being evaluated in ongoing clinical trials, fezolinetant is the first to be considered for approval by the US Food and Drug Administration.⁴

Published March 13, 2023 in the Lancet online, a 12-week, phase 3 randomized double-blind, placebo-controlled trial called SKYLIGHT 1, with a 40-week active treatment safety extension, provides additional evidence regarding the efficacy and safety of fezolinetant for treatment of VMS.¹ Fezolinetant was administered at doses of 30 mg/day and 45 mg/day. Following 12 weeks, women initially randomized to placebo (n = 175) were re-randomized equally to 30 or 45 mg for the next 40 weeks. The primary outcome was frequency and severity of hot flushes. Quality of sleep, evaluated by Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b, was a second end point. Fezolinetant 30 mg decreased hot flush frequency from 10.7 events/24 h (SD 4 · 7) at baseline to 4.5 events/24 h (3 · 7) at week 12 with a −56% [35.9] mean reduction from baseline; 45 mg reduced VMS frequency from 10.4 events/24 h (3 · 9) at baseline to 4.1 events per 24 h (3.9) at week 12, a −61% [32.7] mean change from baseline. For the placebo group, at week 12, the reduction was −35% [39.7]. Hot flush severity was also reduced. Improvement in VMS was sustained up to the end of the 52-week trial. For sleep disorders, at week 12 the observed improvements for either dose of fezolinetant versus placebo were not statistically significant. Similar results for efficacy and safety were obtained in other SKYLIGHT trials.^5,6

Menopausal hormone therapy (MHT) is now used by fewer than 10% of postmenopausal women globally. This reduction arose following publicity around the 2002 outcomes of the Women Health Initiative trials, primarily because of fear of breast cancer and cardiovascular disease, and is exacerbated by the contemporary lack of clinician education regarding menopause management. Nevertheless, estrogen treatment, alone or combined with a progestogen to provide endometrial safety, remains the most effective treatment of VMS with 75% to 90% efficacy.⁷ Additionally, MHT improves mood, alleviates urogenital symptoms and uncomfortable sex, prevents bone loss and osteoporotic fractures, and improves sleep. In a meta-analysis, which has included only randomized studies, decreased mortality was observed in women using MHT (pooled results from estrogen+ combined MHT) below the age of 60 years or if used in the ten years following menopause.⁸ However, its use is contraindicated or severely limited in women with a history of breast cancer or a high breast cancer risk or in women with a history of or high risk for cardiovascular disease. Available alternatives to MHT include serotonin or norepinephrine reuptake inhibitors (SSRI/SNRI), gabapentin, and clonidine. These products are less efficacious than MHT.⁹ A recent analysis comparing the efficacy of SSRI/SNRI and NK3R antagonists reported that SSRI/SNRI efficacy varies from 48% to 67% from baseline at weeks 8 or 12,¹⁰ similar to reports with NK3R antagonists. This efficacy might be inadequate for some women with breast cancer using aromatase inhibitors or tamoxifen. Adverse effects of SSRI/SNRI include nausea, dry mouth, insomnia, dizziness, and constipation, which limit clinical tolerance. With the initial high doses of NK3R antagonists (90 mg), a relatively high prevalence of gastrointestinal symptoms was observed. In recent trials, with fezolinetant doses ⅓ to ½ strength of those used earlier, headache was the most common side effect, but an increase in hepatic transaminases occurred in 1%–6% of participants. In most cases, elevations were transient or reversed with treatment interruption.¹ This signal previously occurred with NK3R antagonists no longer under consideration.

In addition to healthy postmenopausal women, a target population for NK3R antagonists includes those with contraindications to MHT, namely a history of breast cancer or cardiovascular disease. These women are likely also be treated with drugs that could possibly interact with the NK3R antagonist. Clinical trials in these women are lacking. Trials to date in healthy women have not been powered to provide data on the impact of NK3R antagonists on clinical endpoints regarding bone fractures, cardiovascular events, or breast cancer. Neither have head-to-head trials with MHT been conducted to directly compare efficacy. Furthermore, the efficacy of the drug could depend on population genetic characteristics since it was not as effective in Asian women participating in the MOONLIGHT 1 trial.²

A new option to treat bothersome menopausal symptoms definitely represents a step forward. Although there will be a clinical role for NK3R antagonists, gaps remain in ascertaining the precise balance of benefit/risk, especially in women with contraindications or at high risk for MHT who could benefit most from this new addition.