Therapy Alleviates Hot Flashes in Patients With Moderate to Severe Vasomotor Symptoms

Individuals with vasomotor symptoms associated with hot flashes may experience disruptions in quality of life, says Dr Genevieve Neal-Perry, affiliated with University of North Carolina Chapel Hill.

For the SKYLIGHT 2 study, Dr Neal-Perry and coinvestigators sought to understand the efficacy and safety of fezolinetant in patients with moderate to severe vasomotor symptoms. In this interview, she reviews their findings and speaks to the importance of having an efficacious nonhormonal therapy option for patients who cannot be treated with hormone replacement therapy.

What existing research led you to conduct the phase 3 SKYLIGHT 2 study?

My involvement in this study is an extension of my lifelong research: trying to understand the impact of aging and the loss of hormones on the brain, specifically the hypothalamus, where the neurons that interface and affect reproduction are located. I looked at the impact of estrogen loss on kisspeptin neurons, which is how I became involved in this area of research.

As I began to understand more about the basic biology, I also began to work in the space of hot flashes and the impact of estrogen loss on women who go through menopause biochemically or naturally. I became involved in the SKYLIGHT 2 study through my interest in identifying management options for hot flashes in women who cannot take hormones.

What was the design of the study? Did any of the findings surprise you?

As you indicated, it was a phase 3 study, so we looked at fezolinetant’s effectiveness in a large group of individuals, as well as any side effects that went unrecognized in studies with small groups. We evaluated the frequency and intensity of hot flashes at several timepoints, and we also looked at the drug’s impact on sleep.

There were 3 groups: a placebo group, and then 2 groups that received either 30 mg or 45 mg of fezolinetant, respectively. These individuals were evaluated at baseline to assess their hot flashes’ severity, and then they were evaluated again at week 4, week 12, and week 52. We found both doses of fezolinetant significantly reduced the intensity as well as frequency of hot flashes as compared to placebo.

At 12 weeks, we randomized the participants on placebo to receive either the 30-mg or 45-mg dose of fezolinetant, and then we compared them to the individuals who were on those doses through the entire study. We found the individuals who were switched from placebo to fezolinetant actually had significant improvements in their hot flashes’ frequency, just like the individuals who started the drug at baseline. That was fantastic.

Fezolinetant is a nonhormonal therapy. This is important for individuals who cannot use hormone replacement therapy as a way to manage hot flashes. Within about 1 week, we saw improvements in patients who had hot flashes; this is not the case with many other nonhormonal treatments. We also saw an improvement in sleep. Loss of sleep and loss of cognitive function secondary to sleep dysfunction and severe hot flashes are frequent complaints from individuals in menopause, so that benefit is great for patients.

We looked at a range of potential adverse events, the most common of which was headaches. Importantly, the headache frequency was not any different in the treatment group vs the placebo group. The other thing that was more common was COVID-19, but again, it was the same across all treatment groups, and COVID-19 was spreading during the time of our study. Otherwise, fezolinetant was relatively well-tolerated and really effective.

Thank you, Dr Neal-Perry. How can these findings be applied in real-world clinical practice?

Some people might be saying, "Well, why now? Why do we have this drug now?" One reason why we now are able to fine-tune the treatment for hot flashes is we have only understood the basic biology behind hot flashes within the last 5 to 10 years. The loss of estrogen allows KNDy neurons to become super activated, which can cause you to feel hot even if the temperature around you has not changed. One of the peptides from these neurons that we know is associated with hot flashes is called neurokinin, and fezolinetant blocks the effects of neurokinin. Fezolinetant is considered a neurokinin-3 selective receptor inhibitor, so it works very specifically within this area of the brain, hence the few side effects.

In terms of the practical implications of the drug, there has been a huge gap in meeting the needs of individuals affected with hot flashes. Hot flashes can be triggered by the medications individuals use to treat breast cancer. In fact, hot flashes are the most common side effect of treatments for breast cancer, but these individuals cannot use hormones to manage their hot flashes, so it can be quite debilitating. The other group who cannot use hormones is individuals with blood clotting disorders.

Additionally, one of the potential side effects of using hormone replacement therapy is bleeding from the uterus. We have not found bleeding specifically related to fezolinetant use. 

We finally have a nonhormonal option that is highly effective. When people are having severe hot flashes, it is truly disruptive. To know we can give them relief relatively quickly is great.

Do you intend to expand upon this research in the future?

We do intend to continue our work in this space. There are disparities in that women of color and women with obesity tend to have more severe, more frequent, and longer-duration hot flashes. One of our goals is to understand whether treatment with fezolinetant will help reduce some of these disparities. This is relevant because some of the nonhormonal treatments used for hot flashes do not work well in women of color, so having an alternative treatment is helpful in terms of what is available for patients.

Another area we would like to research is quality of life. We see changes in quality of life more during the menopausal transition, so we will be evaluating those indicators. We will try to better understand fezolinetant’s impact on sleep and other factors frequently impacted during menopause.

Is there anything else you would like to add?

There has not been a drug like this on the market that is so effective with so few side effects. I am really excited, particularly as I think about individuals with breast cancer and hormone-responsive cancers. The other group that sometimes goes unrecognized is men with prostate cancer who must use treatments that reduce their hormones, and sometimes they can also have hot flashes. Being able to treat these individuals and meet this unmet need is exciting.

About Dr Neal-Perry

Genevieve Neal-Perry, MD, PhD, is a distinguished professor and department chair for the department of obstetrics and gynecology at the University of North Carolina Chapel Hill. Dr Neal-Perry has been OBGYN-trained, and she has completed a fellowship in reproductive endocrinology and infertility. She holds a PhD in pharmacology.