2024 Brings Change, New Hope for Nonhormonal Management of Menopause

While vasomotor symptoms (VMS) have significant adverse impacts on the quality of life in menopausal women, elinzanetant and fezolinetant have emerged as promising non-hormonal treatments to alleviate symptoms, marking significant advances in menopausal health in 2024.

Approximately 80% of menopausal women are impacted by VMS, often leading to health complications such as cardiovascular and cognitive changes, bone loss, and mood disturbances.1 

Elinzanetant is a dual neurokinin receptor antagonist that has shown promise toward reducing these adverse health outcomes. During the OASIS 1 and 2 trials, the safety and efficacy of this drug was investigated for managing VMS.

In clinical trials, VMS frequency and severity were both significantly reduced over 12 weeks when compared to placebo. Additionally, these effects were maintained at 26 weeks among women with moderate-to-severe VMS regardless of whether they continued elinzanetant use for the full trial or were switched from placebo at week 12.

Symptom frequency was reduced in participants taking elinzanetant as early as week 1 of the trials, and sleep disturbances were reduced by at least 50% in over 80% of participants by week 26. During the 52-week OASIS 3 trial, similar results were reported, confirming elinzanetant’s safety and efficacy.

Following submission of this data, the FDA accepted a New Drug Application (NDA) for elinzanetant in October 2024—marking a significant step forward in advancing menopausal care among US women.

An approval for elinzanetant will mark the third nonhormonal treatment optionfor moderate-to-severe VMS associated with menopause. Tolerability, efficacy, and access to hormonal options remain significant barriers to VMS treatment in many menopausal women, highlighting the importance of expanding options.

Nanette Santoro, MD, professor and E Stewart Taylor Chair of Obstetrics and Gynecology at the University of Colorado School of Medicine, provided additional information about the impact of elinzanetant for VMS in the presentation “Vasomotor Symptoms 101” at the 2024 Annual Meeting of The Menopause Society.2

According to Santoro, VMS are the most common symptom of menopause, with a majority of women struggling with these symptoms and some being severely affected. Approximately two-thirds of menopausal women visiting the doctor’s office ask questions about their hot flashes, highlighting this symptom’s significant impact.

"For most of history, we've only had hormones,” Santoro said. “Hormones work great for hot flashes. Hormones are not bad news, they're good news. There's a lot of ways to give them, and most women can safely take them."

However, certain women may be unable or unwilling to take hormones. These women can use selective serotonin reuptake inhibitors (SSRIs) for hot flash treatment.

Previously, SSRIs were used off-label, but now neurokinin-3 (NK3) receptor antagonists, such as elinzanetant, offer an approved treatment option. By acting on neurokinin receptors, NK3 receptor antagonists may have similar efficacy to estrogen without the increased risks or side effects of hormonal treatment.

In an interview with Contemporary OB/GYN, Santoro highlighted the benefits of fezolinetant, another NK3 receptor antagonist developed for the treatment of moderate-to-severe hot flashes in menopausal women.3 Fezolinetant is the first in class of these antagonists, providing an ideal option for patients who cannot take hormones.

These therapies target the brain’s KNDy neurons, responsible for regulating the body’s temperature. By blocking these signals, fezolinetant significantly reduces the incidence of moderate-to-severe hot flashes.

The FDA approved fezolinetant for the treatment of hot flashes associated with menopause in Spring 2023.4 The drug may be taken orally at 45 mg per day. According to the FDA, the pill should be taken at the same time each day and taken as soon as possible if a patient misses their usual time.

Data has indicated a reduction in the frequency of hot flashes of 75% to 80% in patients receiving fezolinetant.3 Alongside the frequency, the severity of hot flashes is often reduced by the drug, with patients experiencing less moderate to severe hot flashes that significantly impact their quality of life.

Santoro described fezolinetant as a “breakthrough” in the menopause field in regard to side effects. Prior nonhormonal options involved antidepressants, which were discovered when used to treat depression in menopausal patients and led to a reduction in hot flashes.

The use of antidepressants for the treatment of VMS, alongside medications such as gabapentin, have off-target effects because of their primary use being for other conditions. For example, the use of antidepressants against hot flashes may lead to stomach, sexual, and mood side effects.

Gabapentin may also lead to dizziness and drowsiness. By focusing on the neurokinin receptor in the brain, fezolinetant avoids these adverse events. Current side effects linked to fezolinetant include headaches and nausea, with a rate of only 2% to 3%.

An increase in liver enzymes remains the most significant side effect associated with fezolinetant, with the FDA recommending liver function bemonitored up to 9 months in patients receiving the drug.5 However, this side effect has also only been reported in 2% to 3% of patients.

The FDA reported these risks after reviewing a postmarketing report detailing signs of liver injury in a patient after taking fezolinetant for approximately 40 days, recommending patients stop medication administration when symptoms of liver injury are present to avoid worsening the condition. This may allow liver function to return to normal.

According to the FDA, liver blood testing should be performed in patients every month for the first 2 months after starting fezolinetant, then at months 3, 6, and 9. Signs of liver problems include nausea, vomiting, unusual itching, light-colored stools, dark urine, jaundice, abdomen swelling, and right upper abdomen pain.

The FDA recommends health care professionals perform hepatic laboratory testing before prescribing fezolinetant to their patients. Additionally, patients should be warned about the risk of higher liver blood test values when they are prescribed fezolinetant.

Side effects are present in all medications when used correctly, as noted by the FDA. Individual risk will depend on patient health, diseases, other medications, and additional factors. Healthcare professionals may need to determine the individual risk of liver injury in their patients receiving fezolinetant.

This data highlights the potential of fezolinetant and other NK3 receptor antagonists in patients with breast cancer or blood clots, who are unable to receive hormonal therapy.3 Fezolinetant is best for patients who report hot flashes as their sole symptom of concern, while hormones may be the preferred option in patients with additional symptoms such as vaginal dryness.

In the future, additional compounds will be released that target the neurokinin receptor in the brain, increasing options for patients with medications that are contraindicated by fezolinetant. This highlights significant progress in non-hormonal menopause management.

“Many women still really face significant symptom burden, because there’s limitations in treatment tolerability, efficacy, and access,” said JoAnn Pinkerton, MD, a professor of obstetrics and gynecology at the University of Virginia.1 “And as such there remains a pressing need for more effective and safe treatment options for menopausal vasomotor symptom management."

References:

1. Krewson C. JoAnn Pinkerton discusses elinzanetant's crucial role in VMS therapy. Contemporary OB/GYN. October 11, 2024. Accessed December 5, 2024.https://www.contemporaryobgyn.net/view/joann-pinkerton-discusses-elinzanetant-s-crucial-role-in-vms-therapy
2. Fitch J. Nanette Santoro, MD: Vasomotor symptoms, treatment, and potential of elinzanetant. Contemporary OB/GYN. September 12, 2024. Accessed December 9, 2024.https://www.contemporaryobgyn.net/view/nanette-santoro-md-vasomotor-symptoms-treatment-and-potential-of-elinzanetant
3. Krewson C. How fezolinetant advances non-hormonal treatment of hot flashes. Contemporary OB/GYN. December 6, 2024. Accessed December 9, 2024. https://www.contemporaryobgyn.net/view/how-fezolinetant-advances-non-hormonal-treatment-of-hot-flashes
4. FDA approves novel drug to treat moderate to severe hot flashes caused by menopause. May 12, 2023. Accessed December 17, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause
5. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. US Food and Drug Administration. September 12, 2024. Accessed December 17, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes