For decades, hormone replacement therapy (HRT) has been the standard for treating menopausal symptoms, especially vasomotor symptoms (VMS) like hot flashes and night sweats, which affect nearly 80% of women during menopause.[1] However, HRT isn’t suitable for everyone. Women with a history of breast cancer and blood clots are not typically prescribed hormonal therapies since they can increase the risk of recurrence.

Until recently, there were only a few non-hormonal treatment options available for treating the disruptive symptoms of menopause, and they are mostly naturopathic treatments. However, that is changing with the development of new non-hormonal pharmaceutical drugs like fezolinetant (available under the commercial name VEOZAH™) and elinzanetant–the latest therapies and the first significant advances in more than two generations for managing vasomotor symptoms (VMS) associated with perimenopause and menopause.

What Is Fezolinetant And Elinzanetant?

​Fezolinetant (developed by Astellas Pharma) and elinzanetant (developed by Bayer) are both non-hormonal oral medications that are indicated to specifically treat the VMS associated with menopause. In May 2023, fezolinetant made history as the first of its kind to be approved by the US Food and Drug Administration (FDA) for treating severe VMS.[2] Although Bayer’s elinzanetant hasn’t been commercialized yet, it was recently submitted for FDA approval in August 2024.[3]

How Do These Drugs Work?

Fezolinetant and elizanetant are not synthetic hormone drugs like conventional HRT drugs. Instead, these are a new class of drugs that act on the neural activity that causes flushing and sweating spells in women who are experiencing the perimenopause transition.

Recently, researchers identified a new pathway in the brain that could potentially be responsible for the VMS experienced by menopausal women. This pathway involves the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which contain neurokinin 3 (NK3) receptors on their surface. When estrogen binds to the NK3 receptors, it inhibits the KNDy neurons that cause VMS. On the other hand, neurokinin B (NKB) stimulates the receptors and signals the induction of hot flashes.[4]

Before menopause, a balance exists between estrogen and NKB in the body. This balance helps women regulate their body temperature based on their surroundings. However, during menopause, when estrogen levels drop significantly, the balance gets disrupted. More NKB binds to the NK3 receptors, causing increased KNDy neuronal activity, which in the long term leads to the hypertrophy (or enlargement) of KNDy neurons. This affects the woman’s ability to regulate core body temperature and triggers hot flashes. [4]

Fezolinetant is a selective NK3 receptor antagonist. It binds to NK3 receptors, making them unavailable for NKB to bind to, which in turn blocks neuronal activity and supports thermoregulation, thereby reducing the frequency and severity of menopausal VSM. [5]

Elizanetant works similar to fezolinetant. However, it is a dual receptor antagonist drug that targets two receptors in the brain: NK3, which regulates body temperature, and NK1, which affects mood and sleep. [6]

"Oftentimes, the focus on a lot of these drugs is hot flashes, hot flashes, hot flashes, but we know hot flashes do not occur in isolation,” said Chrisandra Shufelt, MD, professor and chair of general internal medicine and associate director of the Women's Health Research Center at Mayo Clinic. “Elinzanetant is an interesting compound because it actually works on sleep, and that was critical because sleep disturbance precedes many other menopausal symptoms,” she shared with Medscape Medical News

Who Should Consider Taking Non-Hormonal Therapies?​

During the perimenopause transition phase, as a woman’s estrogen and progesterone levels start to drop significantly, menopausal hormone therapy (MHT) is considered one of the fastest and most effective ways to treat the bothersome VSM that can occur since MHT works to replenish the body’s estrogen and progesterone levels.

Some women should not be administered MHT even if they are requesting it to be prescribed by their doctors. Menopausal women with a history of breast or endometrial cancer, especially hormone receptor-positive (HR+) cancers, should not take MHT because these types of cancer cells have receptors for estrogen, progesterone, or both, which can significantly increase the risk that these tumors can grow, metastasize and cause more serious complications. For this reason, women who have had breast or endometrial cancer, any family members who had these cancers, or those women who are considered high risk for developing these cancers should not be prescribed MHT. [7]

In addition, women with a history of venous thromboembolic events or stroke, gallbladder problems, and coronary heart diseases should avoid MHT. However, they can instead consider non-hormonal treatments like fezolinetant or elinzanetant.

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How Effective Are Non-Hormonal Therapies For Treating VMS?​

SKYLIGHT 1

SKYLIGHT 1, a Phase III randomized controlled clinical study, was performed to assess the effectiveness of fezolinetant in treating moderate-to-severe vasomotor symptoms associated with menopause. The clinical study included over 500 women between 40 and 65 years of age, who were selected from around the world and who had experienced at least seven hot flashes a day. [8]

The study participants were split into three groups, one receiving a placebo intervention and the other two receiving 35 mg and 45 mg of fezolinetant, respectively. After 4 weeks, the women who were administered fezolinetant reported a reduction in the frequency and severity of hot flashes. After 12 weeks, 45% of women taking 30 mg of fezolinetant, 57% of women taking 45 mg of fezolinetant, and 30% of the placebo group reported a reduction in the frequency of hot flashes. [8]

The study's authors also wrote that the participants reported better quality of life and fewer night-time awakenings. [8]

OASIS 1 and 2

Bayer conducted three Phase III clinical studies–OASIS 1, 2, and 3–to analyze the effectiveness of elinzanetant. OASIS 1 and 2 were specifically conducted to analyze the impact of elinzanetant on moderate to severe VMS, its effects on sleep disturbances, and overall menopause-related quality of life. These trials followed a double-blind, placebo-controlled design to ensure accurate results.

Both OASIS 1 and 2 studies met all primary endpoints. Compared to the placebo, there was a 50% reduction in the frequency and severity of hot flashes in 80% of participants taking elinzanetant by the fourth and twelfth weeks. In addition, the participants also said they slept better while taking elinzanetant. Improvement in these areas was seen as early as week one, indicating a rapid onset of action. The drug’s safety was consistent with prior studies, with no unexpected adverse effects.

According to Dr. Michelle Jacobson, a Canadian OB/GYN physician and certified menopause specialist based in Toronto, Canada, these findings mark a significant milestone for managing menopausal symptoms. She said, “As a menopause specialist, I am truly excited to see the results of the Phase III trials on elinzanetant. For so long, we have been treating those suffering from menopausal symptoms with second-line, non-indicated therapies. Now, we are one step closer to having effective, indicated, and safe treatments for our patients. I look forward to being able to offer women a novel treatment that has such positive outcomes once it is approved by Health Canada. The more options we have, the better we can individualize therapies for our patients to help them live their best and healthiest lives possible."

Claudio N Soares, MD, PhD, who is a Professor of Psychiatry at Queen’s University in Canada, an experienced clinical researcher in menopause and women’s mental health, and President-elect of The Menopause Society, also expressed similar views.

​“These results are really encouraging. For too long, we have underestimated, sometimes even overlooked, the negative impact that menopausal symptoms–hot flashes, sleep disturbances, mood changes–may have on a woman’s health and quality of life. It is reassuring to see that this is no longer the case and that women may soon have access to novel, non-hormonal options to alleviate these symptoms and improve their quality of life”.

​While the findings of OASIS 3 have not yet been published, the study was performed with a large sample size of participants to confirm the findings of OASIS 1 and 2. [9][10]

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Are There Any Side Effects?

​In the SKYLIGHT 1 study, a significant number of participants had experienced side effects or adverse reactions (listed below), which were 37% of women taking 30 mg and 43% of women taking 45 mg Fezolinetant. Interestingly, 45% of women in the placebo group (who were not taking any drug) also reported similar side effects. So, the difference in side effects between the drug medication group and placebo groups was minimal. [8]

The most commonly reported side effects included:

• Headache

• Abdominal pain

• Diarrhea

• Insomnia

• Back pain

• Elevated  hepatic transaminase levels (potential risk of liver damage)

The study also included a warning for potential liver damage or elevated hepatic transaminase levels. Therefore, women considering Fezolinetant are advised to have their baseline bloodwork done to evaluate liver function and injury before starting the medication. While on the drug, follow-up blood tests should be performed every three months for the first nine months of treatment to monitor liver health.

Additionally, patients should watch for symptoms and signs of liver damage, such as nausea, vomiting, or jaundice (yellowing of the skin and eyes), and contact their physician if these signs appear.

With elinzanetant, no participant showed signs of hepatotoxicity or possible drug-induced liver injury. Safety assessments were performed to look for adverse effects in participants and included endometrial biopsies, bone mineral density, weight, and blood tests. It was found that 30.4% of participants taking elinzanetant and 14.6% of participants taking the placebo pill reported adverse effects, which were, most commonly, headache, fatigue, and sleepiness. [9]

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Conclusions

​Over 75% of menopausal women experience VMS, with 25% describing their symptoms as severe. In one-third of women, these symptoms can persist for seven years or more.[11] A pooled analysis of individual-level data revealed that women experiencing both persistent and severe hot flashes and night sweats had a significantly higher risk of cardiovascular disease (CVD). [12] In such cases, having access to medications like fezolinetant and elinzanetant will not only expand treatment options for women but also prove to be an effective alternative for women who should not take HRT.

​It should be noted that both fezolinentant and elinzanetant are very new classes of drugs that do not have a long clinical history, and as such, the clinical practice guidelines on how to incorporate them into the treatment regimen are currently unclear. While both these drugs will prove to be exciting options for women, whether they can be used in combination with other treatments for menopausal symptoms still needs further study.