Novel Drug for Menopause Symptoms Passes Phase 3 Test

Ted Bosworth

June 16, 2022

Dr Genevieve Neal-Perry

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have "caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT]," Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 Trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North America and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Neal-Perry reported they were significant.

Vasomotor Severity, Like Frequency, Is Reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, "you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study," said Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No Serious Side Effects Identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

"The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study," Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT Alternatives Limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Santen said in an interview that this option is not acceptable to others "for a variety of reasons." The problem is that the alternatives are limited.

"The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective," he said. Hot flashes "can be a major disruptor of quality of life," so he is intrigued with the positive results achieved with fezolinetant.

"A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium," he said.

Neal-Perry reports no conflicts of interest.

This article originally appeared on, part of the Medscape Professional Network.


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