Nonhormonal therapy reduces moderate to severe menopausal hot flashes
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An investigational nonhormonal therapy for moderate to severe hot flashes significantly reduced symptom frequency at 12 weeks compared with placebo, with improvements observed as early as 1 week after treatment, data from SKYLIGHT 2 show.
Fezolinetant (Astellas Pharma Inc.) is a selective neurokinin-3 receptor antagonist that blocks neurokinin B binding on the kisspeptin/neurokinin/dynorphin neuron in the hypothalamus to reduce the frequency and severity of vasomotor symptoms associated with menopause. As Healio previously reported, top-line data from the SKYLIGHT 1 and SKYLIGHT 2 trials showed statistically significant reductions from baseline to weeks 4 and 12 in the frequency and severity of moderate to severe vasomotor symptoms for women assigned once-daily fezolinetant 30 mg and 45 mg compared with placebo.
“This 12-week study shows that fezolinetant is the first nonhormone treatment for hot flashes that has efficacy that is similar to hormone therapy,” Nanette Santoro, MD, the Professor and E. Stewart Taylor Chair of Obstetrics and Gynecology at the University of Colorado School of Medicine, told Healio. “It also appears that it helps with sleep. This is very good news for menopausal women who cannot or do not want to take hormones to treat this common menopausal symptom.”
Santoro and colleagues analyzed data from 500 women aged 40 to 65 years with moderate to severe vasomotor symptoms associated with menopause enrolled in SKYLIGHT 2, a double-blind, placebo-controlled trial for the first 12 weeks, followed by a 40-week active treatment extension phase. Moderate to severe vasomotor symptoms were defined as a minimum average of seven hot flashes per day. Participants were randomly assigned 1:1:1 fezolinetant 30 mg (n = 166), 45 mg (n = 167) or placebo (n = 167) once daily.
For the co-primary endpoint of reduction in mean frequency of moderate to severe vasomotor symptoms compared with placebo, fezolinetant 30 mg demonstrated a –1.82 (P < .001) and –1.86 (P < .001) mean change per day at weeks 4 and 12, respectively. At the 45 mg dose, fezolinetant showed a –2.55 (P < .001) and –2.53 (P < .001) mean change per day in vasomotor symptom frequency compared with placebo at weeks 4 and 12, respectively.
For the co-primary endpoint of reduction in mean severity of moderate to severe vasomotor symptoms vs. placebo, fezolinetant 30 mg demonstrated a –0.15 (P < .021) and –0.16 (P < .049) mean change per day at weeks 4 and 12, respectively. The 45-mg dose of fezolinetant showed a –0.29 (P < .001) mean change in severity per day compared with placebo at weeks 4 and 12.
Fezolinetant 45 mg, but not fezolinetant 30 mg, significantly reduced PROMIS-assessed sleep disturbance vs. placebo at week 12. Improvement in vasomotor symptom frequency and severity was observed as early as 1 week after treatment onset and was maintained throughout the 12-week placebo-controlled period.
“The findings are not surprising in light of prior studies with fezolinetant and similar molecules that block the neurokinin-3 receptor,” Santoro told Healio. “This receptor appears to be key in the pathway that causes hot flashes. The positive effect on sleep has been reported before, but this is a more detailed report, and that is further good news for menopausal women suffering from hot flashes.”
Serious treatment-related adverse events occurred in less than 2% of trial participants, with headache as the most common adverse event.
SKYLIGHT 4, a 52-week double-blind, placebo-controlled study to investigate the long-term safety of fezolinetant in 1,833 women at 200 sites, is currently underway.
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Johnson K, et al. S-13. Presented at: North American Menopause Society Annual Meeting; Sept. 22-25, 2021 (hybrid meeting).
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