Perimenopausal vasomotor symptoms (VMS) are triggered by a fall in circulating levels of estrogen and other sex steroids. It has been hypothesized that thermoregulatory centers in the hypothalamus play a crucial role in mediating the hot flash response. Recent research has focused on the hypothalamic hormone neurokinin B (NKB) as a possible mediator linking estrogen deficiency to hot flashes. NKB is a decapeptide and a member of the tachykinin family of peptides.
In animal and human studies, it has been demonstrated that stimulation of NKB-neurokinin 3 receptor (NK3R) signaling can induce hot flashes, thus researchers have focused on antagonism of this signaling pathway as a potential target for mitigating menopausal symptoms. Several preliminary studies in humans have shown that NK3R antagonists produce significant reductions in menopausal symptoms, with a reduction in the severity and frequency of moderate to severe vasomotor symptoms.
Fezolinetant is a novel, nonhormonal selective neurokinin-3 receptor (NK3R) antagonist from Astellas. The New Drug Application (NDA) is supported by the pivotal phase 3 SKYLIGHT 1 and SKYLIGHT 2 clinical trials, along with the SKYLIGHT 4 safety study. The randomized, double-blind, placebo-controlled SKYLIGHT 1 and 2 studies evaluated the efficacy and safety of once daily fezolinetant at doses of 30mg and 45mg in 1,028 women aged 40 to 65 years with moderate to severe VMS.
Both doses of fezolinetant resulted in statistically significant reductions in the frequency and severity of moderate to severe VMS at weeks 4 and 12 from baseline compared with placebo. The most common treatment emergent adverse event was headache.
These findings are exciting and herald the development of new non-hormonal approaches for the management of menopausal vasomotor symptoms. For many women, menopausal symptoms are manageable, but for a sizable subset of midlife women, these symptoms can negatively affect sleep, mood, and quality of life. While clinical guidelines suggest that menopausal vasomotor symptoms typically last from 6 months to 2 years, new research suggests that for many women, the duration of symptoms is much longer and are associated with significant morbidity.
Ruta Nonacs, MD PhD