fezolinetant
What is fezolinetant used for?
Why is fezolinetant important for menopausal women?
How does menopause cause hot flashes?
What is the mechanism of action of fezolinetant?
What are the side effects of fezolinetant?
fezolinetant, nonhormonal drug used to treat vasomotor symptomsânamely, hot flashes and night sweatsâassociated with menopause. The drug is known by the trade names Veozah in the United States and Veoza in Europe.
Fezolinetant fills a critical gap for women seeking effective relief from menopause symptoms without the risks associated with hormone therapy. Menopausal hormone therapy, which uses estrogen alone or in combination with a progestin (a synthetic form of progesterone), is a reliable way to relieve hot flashes for most women. However, for older women or women with conditions such as hormone-responsive cancers or cardiovascular disease, the side effects of hormone therapy outweigh its benefits. These restrictions leave a substantial number of women without suitable treatment options, creating a need for nonhormonal therapies such as fezolinetant.
Hot flashes occur during menopause because changing estrogen levels interfere with the brainâs ability to regulate body temperature. As estrogen levels decline, the hypothalamusâthe brainâs temperature control centerâbecomes overly sensitive to even minor factors that influence body temperature. This can cause the brain to mistakenly signal that the body is too warm, setting off rapid cooling reactions. Blood vessels widen, the heart rate may increase, and sweating begins, often followed by chills as the body overshoots its cooling response. These sudden shifts can feel intense and uncomfortable, even though actual body temperature changes are often modest.
Mechanism of action
The term vasomotor refers to mechanisms that influence the diameter of blood vessels, causing them to constrict or dilate. Core body temperature is regulated by the hypothalamus, a region of the brain that continuously monitors internal temperature and activates responses such as vasodilation and sweating or vasoconstriction and shivering to maintain balance. Under normal conditions, estrogen influences this regulatory process by suppressing the activity of neurokinin B (NKB), a signaling molecule produced by specialized hypothalamic neurons known as KNDy neurons. During menopause, when estrogen levels fall, this inhibitory effect is lost, allowing NKB signaling through neurokinin 3 (NK3) receptors to become overactive. The resulting surges in activity overstimulate vasodilation and heat-dissipation pathways, triggering hot flashes and other vasomotor symptoms. Fezolinetant helps stabilize the bodyâs temperature control system by blocking the NK3 receptor, which dampens NKB signaling.
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History and development
Fezolinetant emerged from drug discovery programs aimed at blocking the NK3 receptor, which was discovered to be linked to reproductive hormone signaling in 2009. The compound initially was developed by the Belgian company Ogeda SA (formerly Euroscreen). In 2017 Tokyo-based Astellas Pharma acquired Ogeda, bringing fezolinetant into its womenâs health pipeline and supporting larger clinical trials.
Clinical development of fezolinetant progressed rapidly through mid-stage trials and into pivotal phase 3 studies. Results from the SKYLIGHT phase 3 trial, carried out from 2019 to 2021, helped establish the drugâs efficacy in reducing hot flash frequency and severity and provided longer-term safety information. The U.S. Food and Drug Administration (FDA) approved fezolinetant in May 2023 for moderate to severe menopausal vasomotor symptoms, identifying it as the first NK3 receptor antagonist approved in the United States for this purpose. In late 2023 the European Medicines Agencyâs review supported authorization of Veoza for the same indication, permitting its use in the European Union.
Side effects and safety
The most commonly reported adverse reactions to fezolinetant include abdominal pain, back pain, diarrhea, hot flashes, and insomnia. Fezolinetant carries a rare but significant risk of hepatotoxicity (liver injury). Patients undergo baseline liver testing prior to starting therapy, followed by scheduled monitoring (monthly for the first three months and again at six and nine months) to detect elevations in liver enzymes known as alanine transaminase (ALT) and aspartate transaminase (AST), which are released into the bloodstream when liver cells are damaged. Symptoms suggestive of liver injury include dark urine, decreased appetite, fatigue, itching, jaundice (yellowing of the eyes and skin), and nausea.
Fezolinetant is processed in the liver mainly by the enzyme CYP1A2, which plays a role in breaking down many medications. Drugs that inhibit this enzymeâsuch as the antidepressant fluvoxamine and the acid reflux medication cimetidineâcan interfere with fezolinetantâs metabolism and are therefore contraindicated. For similar reasons, fezolinetant is generally not prescribed for individuals with certain liver diseases, such as cirrhosis, or with severe kidney impairment or end-stage renal disease.
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