Treatment with fezolinetant, an investigational oral, nonhormonal selective neurokinin-3 (NK3) receptor antagonist being studied for the treatment of moderate to severe menopause-related vasomotor symptoms (VMS), resulted in statistically significant reductions in the frequency and severity of VMS in a pivotal phase 3 trial, according to an announcement from Astellas Pharma, Inc.
The phase 3 SKYLIGHT 1 study published March 13, 2023, in The Lancet, met the 4 coprimary endpoints, with both the 30 mg and 45 mg doses achieving statistically significant improvements from baseline in VMS at 4 weeks and 12 weeks vs placebo. Investigators observed these improvements as early as study week 1 and report they were maintained over the 52 weeks of treatment. In addition, the reduced frequency and severity of VMS over a prolonged period translated into clinically meaningful improvement in quality of life at weeks 4 and 12 as measured by the Menopause-Specific Quality of Life questionnaire, according to SKYLIGHT 1 authors writing in The Lancet.
Menopausal hormone therapy with combined estrogen and progestogen, or estrogen alone, is effective for symptom management. Many women, however, cannot or choose not to take the medications to ameliorate menopause-related VMS and for some the products are contraindicated. SKYLIGHT 1 study authors underscore the need for a targeted nonhormonal option.
"The SKYLIGHT 1 study showed that women receiving fezolinetant experienced a reduction in the frequency and severity of VMS and improvements in quality of life over the one-year treatment period," said Genevieve Neal-Perry, MD, PhD, chair of the UNC School of Medicine Department of Obstetrics and Gynecology, in the Astellas statement. "As a healthcare provider, I truly understand the burden of VMS due to menopause on my own patients, and I'm really excited about this potential new nonhormonal treatment option to help women experiencing moderate to severe VMS."
SKYLIGHT 1 is a randomized, double-blind placebo-controlled trial with a 40-week active treatment extension performed at 97 facilities across the US, Canada, eastern Europe, and the UK. Participants were aged 40 to 60 years and had an average of ≥7 moderate-to-severe hot flashes per day. Random assignment (1:1:1) was made to once-daily exact-matched placebo, fezolinetant 30 or fezolinetant 45 mg. Comparisons with placebo at weeks 4 and 12 demonstrated significantly significant reductions in symptom frequency and severity.
The secondary endpoint of the study was a mean change sleep disturbance as measure by a sleep disturbance-specific tool from baseline to week 12. Improvements in sleep disturbance were observed, however, differences were not statistically significant for either fezolinetant 30 mg or 45 mg. Further analyses of sleep with 2 additional sleep quality found a higher proportion of patients in the fezolinetant groups who reported improvements at 4 weeks and 12 weeks vs placebo.
Treatment-emergent adverse events (TEAEs) observed during the study occurred in 37% of fezolinetant 30 mg, 43% of 45 mg, and 45% of placebo participants. The safety profile during the 40-week extension period was also consistent with the safety profile of the 12-week study period, with the more commonly reported TEAEs being COVID-19 and headache.
"This manuscript, which provides further insights into the safety and effectiveness of fezolinetant, reinforces Astellas' commitment to turning innovative science into value for patients," said Ahsan Arozullah, MD, MPH, senior vice president and head of development therapeutic areas at Astellas.
Currently, the New Drug Application for fezolinetant is under FDA review, with a target action date of May 22, 2023.
Reference: Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. The Lancet. Published online March 13, 2023. doi:/10.1016/S0140-6736(23)00085-5