Astellas Advances Fezolinetant into Phase III for Menopausal Vasomotor Symptoms Following Phase IIa Data Showing 93% Reduction in Hot Flashes

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Japanese pharmaceutical company Astellas recently announced,The pivotal Phase III clinical study SKYLIGHT 1, evaluating fezolinetant for the treatment of moderate to severe vasomotor symptoms (VMS, such as menopause-related hot flashes and night sweats) in postmenopausal women, has initiated dosing of the first patient.。

Vasomotor symptoms are caused by a loss of thermoregulatory control. The thermoregulatory center in the brain is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. The activity of KNDy neurons is stimulated by activation of neurokinin 3 receptors (NK3R) and inhibited by negative feedback from estrogen. The decline in estrogen levels during menopause disrupts this balance, leading to VMS.

Fezolinetant is a selective neurokinin-3 receptor (NK3R) antagonist currently being developed as an oral, non-hormonal therapy for the treatment of menopause-associated vasomotor symptoms. Its mechanism of action involves blocking neurokinin B (NKB) signaling to normalize KNDy neuron activity, thereby modulating the thermoregulatory center and reducing the frequency and severity of hot flashes.

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Fezolinetant was developed by the Belgian biotechnology company Ogeda, which Astellas acquired in May 2017 for €800 million. This transaction was driven by the results of a Phase IIa clinical study, in whichAfter 12 weeks of treatment, fezolinetant significantly reduced the most common symptom of menopause-related vasomotor symptoms—hot flashes—by 93%., with a 54% reduction in the placebo group. Furthermore, at the same time point, fezolinetant reduced hot flash severity by 70%, compared to a 23% reduction in the placebo group.

In March this year, Astellas further presented data from the Phase IIb study of fezolinetant at the Annual Meeting of the Endocrine Society. This was a randomized, double-blind, placebo-controlled, dose-ranging study. The enrolled patients were postmenopausal women aged 40–65 years who experienced at least 50 moderate-to-severe hot flashes per week. In the study, a total of 356 patients were randomly assigned to one of the following treatment groups: placebo; fezolinetant 15 mg, 30 mg, 60 mg, or 90 mg twice daily (BID); or fezolinetant 30 mg, 60 mg, or 120 mg once daily (QD).

The results showed that most trial groups simultaneously met the four co-primary endpoints recommended by the US FDA for the mean reduction in the frequency and severity of VMS at both Week 4 and Week 12. At Weeks 4 and 12, compared with the placebo group, the mean changes in the frequency and severity of moderate-to-severe VMS in most fezolinetant treatment groups were statistically significant. This effect was maintained throughout the 12-week treatment period; however, upon discontinuation of treatment, the mean changes returned to baseline levels.

Specific data are as follows:Compared with placebo, fezolinetant significantly reduced the frequency of vasomotor symptoms (VMS). At Week 4, the mean reduction in daily VMS frequency from baseline was 1.9–3.5 episodes for the twice-daily (BID) dosage group and 2.5–3.0 episodes for the once-daily (QD) dosage group. At Week 12, the mean reduction from baseline was 1.8–2.6 episodes for the BID group and 2.1–2.6 episodes for the QD group. By Week 12, compared with baseline, the frequency of VMS was reduced by 74.3%–86.9% in the BID group, by 75.1%–77.9% in the QD group, and by 55% in the placebo group.

Furthermore, compared with placebo, fezolinetant effectively alleviated the severity of vasomotor symptoms (VMS). At Week 4, the mean daily changes in VMS severity were -0.5 to -1.0 for the twice-daily (BID) dosing group and -0.4 to -0.7 for the once-daily (QD) dosing group. At Week 12, the mean daily changes in VMS severity were -0.3 to -0.6 for the BID dosing group and -0.2 to -0.5 for the QD dosing group. Regarding safety, the overall incidence of treatment-emergent adverse events was similar across groups, mostly mild or moderate in severity, with no reports of deaths or treatment-related serious adverse events.

It is reported that globally, approximately 57% of women aged 40–64 years experience symptoms of hot flashes and night sweats. Vasomotor symptoms (VMS) significantly impair sleep and quality of life in women, leading to anxiety, irritability, reduced work productivity, and depression. Currently, the recommended treatment for VMS is hormone therapy, often combined with other therapies such as selective serotonin reuptake inhibitor (SSRI) antidepressants and over-the-counter medications. The use of these agents requires careful balancing of safety and efficacy. In particular, hormone therapy is often not considered due to its known association with a slight increase in the risk of breast cancer and endometrial cancer.

Earlier this year, Astellas estimated that the market potential for a non-hormonal drug targeting vasomotor symptoms (VMS) could reach as high as $1 billion, with further growth expected in the coming years driven by global population aging. In addition to Astellas, other companies are also developing NK3 receptor antagonists, such as KaNDy Therapeutics’ NT-814 and Millendo Therapeutics’ MLE4901. Notably, NT-814 exhibits activity at both NK1 and NK3 receptors, suggesting that it may address other menopausal symptoms, including sleep and mood disorders.

In addition to VMS, Astellas also plans to develop fezolinetant for the treatment of uterine fibroids. In this regard, AbbVie recently submitted a supplemental application to the U.S. FDA for Orilissa, an oral non-peptide small-molecule gonadotropin-releasing hormone (GnRH) receptor antagonist, for the treatment of heavy menstrual bleeding associated with uterine fibroids.

Reference Source:

1、Astellas Initiates Phase 3 Clinical Trials for Fezolinetant in Postmenopausal Women with Vasomotor Symptoms

2、Astellas Presents Fezolinetant Phase 2b Clinical Trial Results at Endocrine Society's Annual Meeting (ENDO)

3、OR33-6. The Neurokinin 3 Receptor Antagonist, Fezolinetant, Is Effective in Treatment of Menopausal Vasomotor Symptoms: A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging Study

4、Astellas pushes non-hormonal menopause drug into phase 3