Hormone-Free Hot Flash Drug Succeeds in Phase III Trial

An investigational, nonhormonal treatment succeeded at quelling hot flashes associated with menopause, according to the phase III SKYLIGHT-2 trial.

In a study of 501 women with moderate-to-severe vasomotor symptoms (VMS), once-daily fezolinetant significantly improved frequency and severity of VMS versus placebo, reported Genevieve Neal-Perry, MD, PhD, of the University of North Carolina at Chapel Hill, at ENDO 2022, the Endocrine Society annual meeting.

Significant improvements in VMS frequency were seen through the first 12 weeks of treatments in both study doses compared with placebo:

• Fezolinetant 30 mg: mean baseline-to-week 12 reduction -6.83 VMS/day
• Fezolinetant 45 mg: mean baseline-to-week 12 reduction -7.50 VMS/day

And in a 40-week extension phase, these VMS frequency reductions were maintained through week 52 of treatment for both doses and continued to improve (-8.03 for fezolinetant 30 mg and -8.48 for 45 mg).

Similarly, both study doses saw significant drops in VMS severity from baseline through week 12 of treatment:

• Fezolinetant 30 mg: mean baseline-to-week 12 reduction -0.64
• Fezolinetant 45 mg: mean baseline-to-week 12 reduction -0.77

Likewise, women felt this relief in VMS severity through 52 weeks for treatment: -0.83 for fezolinetant 30 mg and -0.95 for 45 mg.

The authors reported that fezolinetant treatment was linked with an improvement in sleep disturbances, as measured by Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b (PROMIS) Total Score. From baseline to week 12, the 30-mg and 45-mg doses were tied to a 4.1-point and 5.5-point drop in PROMIS score, respectively. However, only the 45-mg dose was significantly better than placebo (3.4-point drop) at this time point. Through week 52, the 30- and 45-mg doses saw a 6.3-point and 5.7-point improvements in sleep score from baseline.

"It is a novel, nonhormonal treatment that women who either cannot take hormones or who have, for some reason, have selected not to do so," Neal-Perry said at a press conference. "They now have an opportunity to have treatment for their bothersome symptoms."

Fezolinetant acts as a neurokinin-3 receptor antagonist that works by moderating neuronal activity in the hypothalamic thermoregulatory center to prevent and reduce the intensity of hot flashes. Other nonhormonal options on the market today include selective serotonin reuptake inhibitors (SSRIs), gabapentin, herbal remedies, and clonidine, none of which have demonstrated this extent of efficacy as seen with fezolinetant, according to the authors.

"If the drug is approved, I'm excited about it," Neal-Perry said. "There hasn't been a lot of focus...on hot flashes. It's something that women are just expected to live through." If approved, fezolinetant would be a first-in-class nonhormonal treatment option for menopause-associated VMS.

"Effective opportunities and therapies have not really been there," she noted, citing a lack of funding and an inability to understand the mechanism by which hot flashes occur. "Understanding the mechanism really provided a springboard to a drug discovery."

Neal-Perry added that "we do know that hot flashes are very disruptive," with one study showing that associated management costs could be in the billions.

She said this drug would be particularly beneficial for women with hot flashes who have conditions that contraindicate hormonal therapy options, such as hormone-responsive cancer or blood clotting disorders.

"[Fezolinetant] is a boon because we haven't had other treatment options that are highly effective without significant side effects," she said.

The double-blind trial included menopausal women, ages 40-65, suffering from moderate-to-severe VMS associated with menopause, defined as an average of 7 or more hot flashes per day. Nearly 80% of the cohort were white; 20% were Black. The average participant age was 54.3 and mean BMI was 28. About a third had undergone a hysterectomy.

The 501 women were randomized in a 1:1:1 fashion for 12 weeks. During the 40-week extension phase, which included 484 of the participants, women in the placebo group were re-randomized to either the 30-mg or 45-mg fezolinetant doses. These women also experienced the same drops in VMS frequency and severity as the other treatment groups in the study.

Fezolinetant was generally well-tolerated with the most common adverse events (AE) being headaches. There weren't any significant treatment-emergent AEs requiring participants to withdrawal from the study.

"Treatment-emergent adverse events are really important because some of the other drugs that are like this category have significant side effects that required them being pulled off the market," Neal-Perry pointed out.

Correction: An earlier version of this article misstated the total number of trial participants.

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