Genevieve Neal-Perry, MD, PhD, explains real-world performance of fezolinetant

Randomized controlled trials have long demonstrated the clinical efficacy of neurokinin receptor antagonists for treating moderate-to-severe vasomotor symptoms (VMS) due to menopause. However, confirming whether these results translate to actual clinical practice remains a pivotal milestone for clinicians. At the 2026 American College of Obstetricians & Gynecologists (ACOG) Annual Clinical & Scientific Meeting in Washington, DC, Genevieve Neal-Perry, MD, PhD, Robert A. Ross Distinguished Professor and chair of the Department of Obstetrics and Gynecology at the University of North Carolina School of Medicine, Chapel Hill, presented real-world evidence from the phase 4 OPTION-VMS study (NCT06049797) establishing the broad clinical utility of fezolinetant.

Fezolinetant’s validation across real-world populations

The phase 4 OPTION-VMS study evaluated 761 non–hormone therapy users to analyze the real-world effects of fezolinetant on menopause-specific quality-of-life vasomotor symptoms. The primary end point revealed a statistically significant reduction in VMS bother from baseline to week 12, with an overall least-squares mean (LSM) change of -2.9 (95% CIs -3.5, -2.2 [P < 0.001]). Notably, the study highlighted significant improvements among specific high-burden subgroups, including Black women (LSM change of -3.1) and women with severe obesity:

• BMI ≥25-<30 (-1.8 [-2.6, -1.0])
• BMI ≥30-<35 (-3.2 [-4.2, -2.2])
• BMI ≥35 (-3.7 [-4.9, -2.5])

Neal-Perry noted that these findings provide critical reassurance to practicing clinicians.

“What really stood out to me most is that, in actual practice, it works. And you never quite know in the clinical trials if you will see the benefit in real-world [settings], and it does work,” Neal-Perry said.

She emphasized that the treatment effectively addresses populations that carry a higher symptom burden.

“The other thing that we're seeing in real-world [data] is that there are some people who are using it who are very overweight, higher weight than what was in the actual clinical trials, and there's a benefit, and that's really important because that's a population where the burden is greater. We see that it's very effective across different age groups, across different races and ethnicities, which is what you want to see.”

Mechanistic differences and clinical differentiation

For primary care providers navigating the expanding landscape of non–hormonal therapies, understanding the underlying neuroendocrine mechanisms is essential. Both fezolinetant and the newly approved elinzanetant target the KNDy (kisspeptin, neurokinin B, and dynorphin) neurons in the hypothalamus, which serve as the central thermostat triggering hot flashes.

However, Neal-Perry outlined important structural and clinical distinctions between the 2 agents.

“The difference between the elinzanetant and the fezolinetant is that one is an NK3 receptor antagonist, and one is an NK1/3 receptor antagonist. And the NK1 receptor is expressed in areas of the brain that are important for sleep. So, one of the [adverse] effects is somnolence, but that may mean that it really will work with people who have more problems with sleep,” Neal-Perry noted.

Navigating distinct liver monitoring protocols

The dual-receptor mechanism and structural differences also dictate disparate safety monitoring guidelines in clinical practice. While fezolinetant requires scheduled laboratory follow-ups based on safety signals observed during its initial clinical trials, real-world data continue to be encouraging.

“The other difference is that with fezolinetant, you do have to monitor liver enzymes over several months and ensure that the patient hasn't had a bump in their liver enzymes, because that was a safety signal in the study. I can tell you in real-world data, they're not seeing the same level or same number of people who've had a bump in their liver enzymes, but it's super important to do that testing and follow that individual,” Neal-Perry cautioned.

Conversely, she explained that elinzanetant offers a more streamlined protocol: “With the elinzanetant, they did not have the same liver safety signals. You just have to ensure the patient has normal liver enzymes beforehand, but you do not need to follow liver enzymes once the patient has started treatment.”

Reference

Neal-Perry G. Preliminary analysis of real-world effects of fezolinetant on menopause-specific quality-of-life vasomotor symptoms (MENQOL VMS) overall and by subgroups of interest: phase IV OPTION-VMS study. Presented at: 2026 American College of Obstetricians & Gynecologists Annual Clinical & Scientific Meeting; May 1-3, 2026; Washington, DC.