Fezolinetant Promising for Menopausal Vasomotor Symptoms

By Marilynn Larkin

August 28, 2019

NEW YORK (Reuters Health) - Fezolinetant, a neurokinin 3 receptor (NK3R) antagonist, reduced moderate-to-severe vasomotor symptoms (VMS) in menopausal women and was well tolerated, a phase 2 study showed.

The study sponsor is currently enrolling patients in a phase 3 trial of the drug (https://clinicaltrials.gov/ct2/show/NCT04003155).

"Our development timeline will depend on multiple factors, including how quickly we can enroll our phase 3 trials," Marci English, Senior Director, Global Development Lead, Medical Specialties at Astellas Pharma in Chicago, told Reuters Health. "However, we expect to obtain top-line results of pivotal studies in late 2021."

"Our Phase 3 global program will recruit a diverse population; however, it's too early to speculate on the efficacy of fezolinetant on specific patient groups," she said by email. "The SKYLIGHT 1 and SKYLIGHT 2 pivotal trials will each enroll approximately 450 women with moderate-to-severe VMS and will be double-blinded and placebo-controlled for the first 12 weeks, followed by non-controlled 40-week extension periods."

"For each pivotal trial, women with moderate-to-severe VMS will be enrolled at approximately 200 sites within the US, Canada and Europe," she noted. A follow-up year-long trial will investigate long-term safety.

For the current study, Dr. Dirk Timmerman of KU Leuven in Belgium and colleagues investigated the safety and efficacy of fezolinetant in 80 generally healthy women (mean age 53; nearly all white) with moderate/severe VMS. Participants were randomized to 90 mg fezolinetant twice daily or placebo for 12 weeks.

As reported online August 15 in the Journal of Clinical Endocrinology and Metabolism, at week 12, fezolinetant significantly reduced the total VMS score versus placebo (−26.5 versus −12.2).

The mean weekly frequency of moderate/severe VMS was 39 episodes with placebo versus 5.7 with fezolinetant. Relative to baseline, VMS frequency was reduced by 93% with fezolinetant compared to 46% with placebo. Improvements with fezolinetant were also reported in sleep quality, overall daily interference, climacteric symptoms, and function at weeks 4, 8 and 12.

The drug was well-tolerated overall; gastrointestinal disorder was the most common drug-related adverse event, occurring in six women (14%).

Dr. Robert Steiner, Professor Emeritus, Obstetrics and Gynecology and Physiology and Biophysics at the University of Washington School of Medicine in Seattle, commented by email, "NK3R antagonists such as fezolinetant show great promise for the treatment of VMS, as well as other disorders of the neuroendocrine reproductive system, including polycystic ovarian syndrome."

"VMS plague menopausal women, but also trouble women (and men!) undergoing treatment for sex steroid-sensitive cancers," he told Reuters Health. "There are effective hormonal therapies to treat hot flashes; however, these hormonal treatments carry significant risks for medical complications, and many women just find their risks unacceptable."

"There are also 'non-hormonal' treatments for hot flashes, but unfortunately, these non-hormonal alternatives aren't terribly effective," he said.

"All medications carry some attendant risk, and NK3R antagonists are not likely to be an exception," he continued. "Earlier clinical trials with one such NK3R antagonist, pavinetant (aka ADZ4901/MLE4901), revealed some degree of liver toxicity, and trials of this compound were halted in 2017 for just this reason."

"It's also worth noting that the NK3R is widely expressed in the body - e.g., in the brain, liver, and uterus - so, it will be important to maintain hyper-vigilance over other organ systems when administering these compounds," he said.

"The clinical trials with NK3R antagonists have, to date, been relatively short-term (i.e., months). Thus, it remains to be established whether an initial blockade of VMS can be sustained over the long term (with safe doses); i.e., whether the 'hot flash generator' in the brain will try to 'escape' from the drug," he said.

"There are scientific reasons to believe that the robust network of cells in the hypothalamus that generate VMS will try hard to break free from their pharmaceutical imprisonment," but it's too soon to know for sure, Dr. Steiner concluded.

The study was sponsored by Astellas Pharma Inc (which acquired the original sponsor), including editorial support. Two coauthors are employees and two are former employees.

SOURCE: http://bit.ly/2Zg8ASE

J Clin Endocrin Metab 2019.

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