SKYLIGHT data: Fezolinetant for vasomotor symptoms appears safe, well tolerated

Key takeaways :

• All three phase 3 SKYLIGHT studies showed fezolinetant to be an acceptable treatment option for postmenopausal vasomotor symptoms.
• The FDA decision on fezolinetant is expected in May.

Three SKYLIGHT phase 3 trials demonstrated that treatment with nonhormonal fezolinetant was associated with alleviation moderate to severe vasomotor symptoms during menopause with acceptable safety and tolerability.

The most recently published trial, SKYLIGHT 1, was published in The Lancet following published results of both SKYLIGHT 2 and SKYLIGHT 4. All three phase 3 studies analyzed the nonhormonal selective neurokinin-3 receptor antagonist fezolinetant (Astellas Pharma) in both 30 mg and 45 mg doses for postmenopausal women with a minimum average of seven moderate to severe menopausal vasomotor symptoms per day.

“This publication of the SKYLIGHT 1 study is another important report of a phase 3 randomized trial assessing the utility of an investigational nonhormonal agent, fezolinetant, that targets the neurokinin-3 receptor to reduce the frequency and severity of moderate to severe [vasomotor symptoms] due to menopause, and we are honored to see it published in The Lancet,” Ahsan Arozullah, MD, MPH, senior vice president and head of development therapeutic areas at Astellas, said in a related press release. “This manuscript, which provides further insights into the safety and effectiveness of fezolinetant, reinforces Astellas’ commitment to turning innovative science into value for patients.”

Evaluating SKYLIGHT

“Vasomotor symptoms can start before menopause, continue for more than 10 years and have been associated with a decline in physical health,” Samuel Lederman, MD, regional medical director at Altus Research in Lake Worth, Florida, and colleagues wrote. “Available treatments, such as menopausal hormone therapy and selective serotonin receptor antagonists, are not appropriate for all women. Therefore, an unmet need exists for effective treatment alternatives for vasomotor symptoms in menopausal women.”

In SKYLIGHT 1, a randomized, double-blind, placebo-controlled, 12-week, phase 3 trial, 527 women were recruited between July 2019 and August 2021 from 97 facilities across the U.S., Canada, Czech Republic, Hungary, Poland, Spain and the U.K. Women were randomly assigned to fezolinetant 30 mg (n = 176), fezolinetant 45 mg (n = 176) or once-daily exact-matched placebo (n = 175).

The primary outcomes were mean change in frequency and severity of vasomotor symptoms from baseline to 4 and 12 weeks.

Overall, 31 women in the fezolinetant 30 mg group, 13 in the fezolinetant 45 mg group and 23 in the placebo group discontinued treatment prior to 12 weeks, mostly due to adverse events or participant choice.

Results demonstrated that fezolinetant 30 mg and 45 mg were significantly associated with reduced vasomotor symptom frequency at 4 weeks (–1.87 and –2.07, respectively) and 12 weeks (–2.39 and –2.55, respectively) compared with placebo. In addition, fezolinetant 30 mg and 45 mg were also significantly associated with reduced vasomotor symptom severity at 4 weeks (–0.15 and –0.19, respectively) and 12 weeks (–0.24 and –0.2, respectively) compared with placebo.

Researchers observed improvements in both vasomotor symptom frequency and severity at 1 week of fezolinetant treatment at either dose. This improvement was maintained over 52 weeks. During the first 12 weeks, 37% of women who received fezolinetant 30 mg, 43% who received fezolinetant 45 mg and 45% who received placebo experienced treatment-emergent adverse events.

Healio previously reported results of SKYLIGHT 2, published in The Journal of Clinical Endocrinology & Metabolism. This trial included 500 women aged 40 to 65 years meeting study criteria for daily moderate to severe menopausal vasomotor symptoms. These women were randomly assigned to 12 weeks of placebo (n = 167), fezolinetant 30 mg (n = 166) or fezolinetant 45 mg (n = 167) and then randomly assigned once more to 30 mg or 45 mg fezolinetant for an additional 40 weeks.

Results demonstrated that both doses of fezolinetant significantly reduced the frequency and severity of vasomotor symptoms at 4 and 12 weeks. Reductions in frequency ranged from –1.82 to –1.86 at 4 and 12 weeks, respectively, for fezolinetant 30 mg and from –2.55 to –2.53, respectively, for fezolinetant 45 mg. At 4 and 12 weeks, reductions in severity ranged from –0.15 to –0.16, respectively, for fezolinetant 30 mg and from –0.29 to –0.29, respectively, for fezolinetant 45 mg.

Finally, in SKYLIGHT 4, a randomized, double-blind, phase 3, 52-week safety study, researchers randomly assigned 1,830 participants to fezolinetant 30 mg (n = 611), fezolinetant 45 mg (n = 609) or placebo (n = 611) between July 2019 and January 2022.

The primary outcomes were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia and percentage of participants with endometrial malignancy.

“Demonstrating endometrial safety is required for any treatment used to alleviate menopause symptoms according to the FDA draft guidance,” Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina School of Medicine, Chapel Hill, and colleagues wrote. “The risk for endometrial hyperplasia or malignancy in individuals with a uterus is increased by unopposed estrogen exposure; hence, with hormonal therapy, progestogen is frequently used in combination for endometrial protection.”

In total, 67.9% of women who received fezolinetant 30 mg, 63.9% who received fezolinetant 45 mg and 64.1% who received placebo experienced treatment-emergent adverse events. Treatment-emergent adverse events that led to discontinuation occurred among 5.6% of those in the fezolinetant 30 mg group, 4.6% of those in the fezolinetant 45 mg and 4.3% of those in the placebo group.

Endometrial hyperplasia was observed for one participant in the fezolinetant 45 mg group and endometrial malignancy was observed for one participant in the fezolinetant 30 mg group. Liver enzyme elevations more than three times the upper limit of normal were observed among five participants in the fezolinetant 30 mg group, 12 participants in the fezolinetant 45 mg group and six participants in the placebo group.

Future research

Currently, fezolinetant has regulatory applications under review in the U.S., European Union, Switzerland and Australia. If fezolinetant is approved, then it would be a first-in-class, nonhormonal treatment option to reduce both the frequency and severity of vasomotor symptoms for women with moderate to severe symptoms due to menopause.

“Phase 3 data obtained from SKYLIGHT 1 and 2 demonstrated the efficacy of fezolinetant in reducing the frequency and severity of vasomotor symptoms and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks,” the researchers wrote. “Results from SKYLIGHT 4 provide additional evidence confirming the longer-term safety during a 52-week treatment period, and the data support the continued development of fezolinetant as a novel nonhormonal treatment option for moderate to severe vasomotor symptoms associated with menopause.”

References:

• Johnson KA, et al. J Clin Endocrinol Metab. 2023;doi:10.1210/clinem/dgad058.
• Lederman S, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)00085-5.
• Results from Astellas’ pivotal phase 3 SKYLIGHT 1 study of fezolinetant for vasomotor symptoms due to menopause published in The Lancet. newsroom.astellas.us/2023-03-13-Results-from-Astellas-Pivotal-Phase-3-SKYLIGHT-1-TM-Study-of-Fezolinetant-for-Vasomotor-Symptoms-Due-to-Menopause-Published-in-The-Lancet. Published March 13, 2023. Accessed March 14, 2023.