Elinzanetant and fezolinetant are emerging as promising non-hormonal treatments to alleviate vasomotor symptoms (VMS) in menopausal women, marking significant advances in menopausal health. 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. These new therapies offer hope for those who cannot or prefer not to use hormone replacement therapy.
Elinzanetant: A Dual Neurokinin Receptor Antagonist
Elinzanetant is a dual neurokinin receptor antagonist that has demonstrated promise in reducing adverse health outcomes associated with VMS. The safety and efficacy of elinzanetant for managing VMS were investigated in the OASIS 1 and 2 trials. Results from these trials indicated a significant reduction in both the frequency and severity of VMS over 12 weeks compared to placebo. 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. The 52-week OASIS 3 trial reported similar results, confirming elinzanetant’s safety and efficacy. Following the 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. If approved, elinzanetant will be the third nonhormonal treatment option for moderate-to-severe VMS associated with menopause.
Fezolinetant: Targeting KNDy Neurons
Fezolinetant, another NK3 receptor antagonist, was developed for the treatment of moderate-to-severe hot flashes in menopausal women. It is the first in its class, providing an ideal option for patients who cannot take hormones. These therapies target the brain’s KNDy neurons, which are 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. The drug may be taken orally at 45 mg per day, at the same time each day, and as soon as possible if a dose is missed.
Data has indicated a reduction in the frequency of hot flashes of 75% to 80% in patients receiving fezolinetant. Alongside the frequency, the severity of hot flashes is often reduced by the drug, with patients experiencing fewer moderate to severe hot flashes that significantly impact their quality of life. Nanette Santoro, MD, professor at the University of Colorado School of Medicine, described fezolinetant as a “breakthrough” in the menopause field regarding side effects, as prior nonhormonal options involved antidepressants with off-target effects.
Addressing the Limitations of Existing Treatments
Previously, selective serotonin reuptake inhibitors (SSRIs) were used off-label for hot flash treatment. However, 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, while gabapentin may 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%.
Monitoring Liver Function
An increase in liver enzymes remains the most significant side effect associated with fezolinetant, with the FDA recommending liver function be monitored for up to 9 months in patients receiving the drug. This side effect has also only been reported in 2% to 3% of patients. The FDA recommends health care professionals perform hepatic laboratory testing before prescribing fezolinetant to their patients and warn patients about the risk of higher liver blood test values. Liver blood testing should be performed 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.
Future Directions in Menopause Management
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. 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. JoAnn Pinkerton, MD, a professor of obstetrics and gynecology at the University of Virginia, noted that "many women still really face significant symptom burden, because there’s limitations in treatment tolerability, efficacy, and access. And as such there remains a pressing need for more effective and safe treatment options for menopausal vasomotor symptom management."
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, highlighting significant progress in non-hormonal menopause management.
