Fezolinetant for moderate to severe vasomotor symptoms associated with menopause

Approved indication: moderate to severe vasomotor symptoms associated with menopause
Veoza (Astellas)
45 mg film-coated tablets

Around the time of menopause many women experience symptoms such as hot flushes and night sweats. These vasomotor symptoms can recur for years, disturb sleep and diminish quality of life. For women who require treatment, menopausal hormone therapy is effective, but can have significant adverse effects. It is also contraindicated for women with a history of conditions such as breast cancer or thromboembolism. Alternative nonhormonal drug therapies, such as clonidine, also have limitations.¹

Vasomotor symptoms have been linked to the disruption in the balance of neurotransmitters in the thermoregulatory area of the hypothalamus. Before menopause, the activity of neurokinin B in the thermoregulatory area of the hypothalamus is opposed by estrogen. Declining estrogen secretion after menopause is therefore associated with an increase in neurokinin B activity. Fezolinetant is a selective neurokinin 3 receptor antagonist, which aims to reduce menopausal vasomotor symptoms by blocking the action of neurokinin B.²

The main efficacy trials of fezolinetant (Skylight 1³ and 2⁴) were double-blind studies of postmenopausal women experiencing moderate to severe vasomotor symptoms at a mean event rate of at least 7 times a day. They were given fezolinetant or a placebo for 12 weeks to see if the frequency and severity of symptoms were reduced. The women in the placebo group were then switched to fezolinetant and all participants continued treatment for a further 40 weeks.

Across the 2 trials conducted at sites in Europe and North America, a total of 339 women were randomised to take fezolinetant 30 mg daily, 341 to take fezolinetant 45 mg daily and 342 to take a placebo. In both trials, fezolinetant rapidly reduced the average daily frequency of vasomotor symptoms. After 12 weeks, pooled data from the 2 trials showed fezolinetant 30 mg had reduced symptom frequency from 10.94 to 4.63 events per day while fezolinetant 45 mg reduced symptom frequency from 11.10 to 4.27 events per day. In the placebo group, daily events fell from 11.04 to 6.79.² There was also a reduction in the severity of symptoms compared with placebo, with the greatest reduction observed with fezolinetant 45 mg.² During the extension period of both trials, symptoms improved for the women in the placebo group who switched to either fezolinetant 30 mg or fezolinetant 45 mg, and improvement in symptoms was maintained in all patients.^3,4

While both the 30 mg and 45 mg doses of fezolinetant were statistically superior to placebo for these outcomes in the Skylight 1 and 2 trials, another trial (Moonlight) of fezolinetant 30 mg in East Asia found no statistical difference compared with placebo.⁵

In addition to the extended data from the Skylight 1 and 2 trials, there was also a 52-week safety study (Skylight 4). This involved 1831 women randomised to receive fezolinetant 30 mg (n=611), 45 mg (n=609) or placebo (n=611).⁶ Across all 3 Skylight trials the adverse events of fezolinetant were similar to placebo. The most frequent adverse events included headache, fatigue, insomnia, nausea and diarrhoea.⁷ In the safety study, adverse events led to treatment being stopped in 4.3% of the placebo group and 5.1% of the fezolinetant groups. Liver enzymes increased in 5.5% of the patients taking fezolinetant, compared with 4.9% of the placebo group.⁶

In Australia, only the 45 mg dose of fezolinetant is approved. It is taken orally once a day with or without food. Most of the dose is metabolised in the liver and then excreted mainly in the urine. Metabolism involves cytochrome P450 1A2 so moderate or strong inhibitors of this enzyme, such as fluvoxamine, are contraindicated. Other contraindications to fezolinetant include moderate or severe hepatic impairment and severe renal impairment. In patients taking fezolinetant, liver function should be assessed at baseline and monitored during treatment (at least once in the first 3 months).⁷

A reduction of at least 50% in the frequency of vasomotor symptoms is considered clinically significant.⁸ Based on the Skylight trials, most women taking fezolinetant 45 mg for 12 weeks can expect an average reduction of approximately 63% in the daily frequency of moderate to severe vasomotor symptoms (compared with a placebo response of 40%).⁷ The trials did not specifically investigate postmenopausal women with contraindications to menopausal hormone therapy.

This new drug comment was finalised on 9 September 2024.

🅃 🅃 manufacturer provided additional useful information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

References

1. Magraith K, Jang C. Management of menopause. Aust Prescr 2023;46:48-53.
2. Therapeutic Goods Administration. Australian Public Assessment Report for Veoza. Department of Health and Aged Care; 2024. [cited 2024 Aug 26]
3. Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023;401:1091-102.
4. Johnson KA, Martin N, Nappi RE, Neal-Perry G, Shapiro M, Stute P, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab 2023;108:1981-97.
5. Ruan X, Bai W, Ren M, Kim T, Lee JY, Chuang FC, et al. Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I). J Int Med Res 2024;52:3000605241247684.
6. Neal-Perry G, Cano A, Lederman S, Nappi RE, Santoro N, Wolfman W, et al. Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial. Obstet Gynecol 2023;141:737-47.
7. Therapeutic Goods Administration. Australian Product Information - VEOZA fezolinetant 45 mg film coated tablet blister pack. Department of Health and Aged Care; 2024. [cited 2024 Aug 26]
8. Newton KM, Carpenter JS, Guthrie KA, Anderson GL, Caan B, Cohen LS, et al. Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network. Menopause 2014;21:45-58.

 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.