By Nicole Cirino, MD, CST, IF

Reproductive Psychiatrist, Associate Professor of Psychiatry and OB/GYN, Oregon Health & Science University, Portland

Dr. Cirino reports no financial relationships relevant to this field of study.

SYNOPSIS: A phase 2b trial using seven dosing regimens of a novel neurokinin-3 receptor antagonist, fezolinetant, shows statistically significant improvement in vasomotor symptoms vs. placebo in postmenopausal women.

SOURCE: Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause 2020;27:382-392.

Fezolinetant, a selective neurokinin-3 (NK3) receptor antagonist, is an investigational oral, nonhormonal compound being studied for the treatment of vasomotor symptoms (VMS). It is believed to work on the thermoregulatory center in the hypothalamus, which is stimulated by neurokinin-3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing VMS.¹ Selective NK3R antagonists are suggested to act similarly as gonadotropin-releasing hormone (GnRH) modulators and previously have been studied in benign prostatic hyperplasia and endometriosis.² Currently, studies are ongoing for use of this NK3 to treat polycystic ovarian syndrome, uterine leiomyoma, and weight gain.³

Previously, a randomized, double-blind, placebo-controlled, phase 2a clinical trial in 87 postmenopausal women showed that single-dose fezolinetant 90 mg twice daily effectively reduced moderate/severe VMS and was well tolerated across 12 weeks of treatment, reducing the frequency of moderate/severe VMS by about 5.0 episodes per day relative to placebo (95% confidence interval [CI], -6.8 vs. -3.3).¹

This phase 2b study, funded by Astellas Pharma Global Development, Inc., is a randomized, double-blind, placebo-controlled, dose-ranging, parallel group study conducted at 51 sites in the United States. Three hundred fifty-six women were randomized to receive either placebo or fezolinetant doses ranging from 15 mg to 90 mg twice daily or 30 mg to 120 mg once daily. Coprimary endpoints were mean change in both frequency and severity of moderate/severe VMS from baseline to week 4 and from baseline to week 12. Treatment was stopped after week 12. The trial length was 15 weeks.

Women were eligible for inclusion if they recorded ≥ 50 moderate/severe VMS over any seven consecutive days during the 35-day screening period. Mild VMS were defined as sensations of heat without sweating or noting damp sheets or clothing upon awakening. Moderate VMS were defined as sensations of heat with sweating but being able to continue activities, or waking from sleep because of feeling hot. Severe VMS were defined as feelings of intense heat with sweating that disrupts activities or, for night sweats, feelings of being so hot as to require action (e.g., removing layers of clothing, opening a window). Participants continued to record VMS frequency and severity at least twice daily in an electronic diary.

At baseline, participants had an average of nine to 11 moderate/severe VMS per day, which was similar across treatment groups. Participants ranged in age from 41 to 65 years (mean: 54.6 years), and the study population was 73% white, 25% black, 1% Asian, and 1% other races. Body mass index average was 27.3, and 58.1% of participants had undergone natural menopause. Outcomes in frequency and severity were self-reported through diaries.

Most groups showed statistically significant improvement from placebo in mean change in the frequency and severity of moderate/severe VMS at both week 4 and week 12. Results were maintained throughout the 12-week treatment period, with a return to baseline after treatment was stopped at week 15. All treatment groups exhibited a decrease in frequency of moderate/severe VMS. All fezolinetant regimens significantly reduced the frequency of moderate/severe VMS at weeks 4 and 12 compared with placebo, showing a decrease of -1.9 to -3.5 mean change per day from baseline for the twice-daily doses and between -2.3 and -3.0 mean change per day for the once-daily doses at week 4. Fezolinetant reduced moderate/severe VMS by about 62% to 81% at week 4, depending on dose, compared with about a 39% reduction with placebo. At week 12, fezolinetant demonstrated reduced VMS frequency compared to placebo, showing between -1.8 and -2.6 mean change per day for the twice-daily doses and between -2.1 and -2.6 mean change per day for the once-daily doses. Moderate/severe VMS were reduced by about 74% to 87% with fezolinetant vs. 55% with placebo.

Additionally, fezolinetant showed improvement in VMS severity compared to placebo, with a mean change per day range of -0.5 to -1.0 for the twice-daily doses and -0.4 to -0.7 for the once-daily doses at week 4. At week 12, fezolinetant demonstrated improvement in VMS severity compared to placebo, with a mean change per day range of -0.3 to -0.6 for the twice-daily doses and -0.2 to -0.5 for the once-daily doses.

Overall treatment-emergent adverse event (TEAE) rates were similar across groups and mostly mild or moderate. No deaths or treatment-related serious adverse events (SAEs) were reported. Common TEAEs (≥ 5% in any treatment arm) included headache, nausea, urinary tract infection, diarrhea, upper respiratory tract infection, fatigue, viral upper respiratory tract infection, sinusitis, and cough. There were no reports of endometrial hyperplasia. Other reported effects were: increased liver function test values (n = 1, fezolinetant 90 mg twice daily), adjustment disorder with depressed mood (n = 1, fezolinetant 30 mg once daily), cholelithiasis (n = 1, fezolinetant 60 mg once daily), drug-induced liver injury (n = 1, fezolinetant 60 mg once daily), and retinal detachment (n = 1, fezolinetant 120 mg once daily). Nine patients (less than 3%) treated with the higher doses of fezolinetant experienced brief increases in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). There were no cases of bilirubin levels greater than two times the upper limit of normal. Patients returned to baseline levels after discontinuing fezolinetant. No other clinically meaningful changes were noted in the vital signs and laboratory tests, electrocardiogram parameters, or plasma bone marker concentrations.The investigators considered the cholelithiasis and drug-induced liver injury to be treatment-related events. Changes in bone turnover markers were no different across treatment groups.

Although luteinizing hormone (LH) levels remained relatively stable in the placebo group, fezolinetant was associated with dose-dependent LH reductions three hours post-dose compared with either baseline or pre-dose levels. All groups, including placebo, showed small decreases from baseline in follicle-stimulating hormone (FSH) levels, and no treatment- or dose-related effects were observed. There were no clear trends or differences from placebo in estradiol or sex hormone binding globulin (SHBG) levels over the course of the study.

COMMENTARY

VMS affect up to 80% of U.S. women and are the most common reason for U.S. women to seek treatment during the menopausal transition.⁴ Currently, the only Food and Drug Administration-approved nonhormonal treatment for VMS is paroxetine. Other commonly used nonhormonal medications involve other selective serotonin reuptake inhibitors and gabapentin. The NK3 receptor antagonist is a novel agent believed to work more selectively on VMS by targeting thermodynamic centers implicated in VMS disruption and to work as GnRH modulators.² In animal models, NK3 receptor antagonists, such as fezolinetant, have been found to cause a dose-dependently suppression of LH secretion, but not FSH secretion. Consequently, this has resulted in a dose-dependent decrease estradiol and progesterone levels in women and testosterone levels in men.² LH levels were decreased in the treatment arm in this trial, but more data are needed to determine the mechanism in humans. This agent also is being studied in weight management, prostatic hyperplasia, endometriosis, polycystic ovarian syndrome, and uterine leiomyoma. NK3 modulators may be the next phase of management for VMS and may offer an alternative nonhormonal option.

According to Astellas, the pharmaceutical company funding this drug, phase 3 trials now are underway with two doses, fezolinetant 30 mg or 45 mg once daily. The stated goal is to recruit approximately 450 women for a double-blinded, placebo-controlled trial for moderate/severe VMS for the first 12 weeks, followed by noncontrolled 40-week extension periods. This will be followed by a 52-week double-blinded, placebo-controlled study to investigate long-term safety, with a goal of 1,150 participants with VMS.⁵ Limitations to this study are the subjective nature of using self-reported diaries to determine hot flash severity and frequency, the number of subjects in each arm, and the short length of the trial. All participants were postmenopausal, not perimenopausal, and there are no plans to study this population. More research needs to be done with longer length of treatment, perimenopausal patients, and head-to-head trials. Timing, dosing, and further study of side effects, such as endometrial hyperplasia, quality of sleep, and mood-related side effects, are important to determine which patient populations would benefit most from this agent. The placebo response rate was as high as 55% in this trial, further highlighting the effect that stress-related factors and stress reduction techniques play in the frequency, severity, and management of VMS.

REFERENCES

1. Depypere H, Timmerman D, Donders G, et al. Treatment of menopausal vasomotor symptoms with fezolinetant, a neurokinin 3 receptor antagonist: A phase 2a trial. J Clin Endocrinol Metab 2019;104:5893-5905.
2. Fraser GL, Ramael S, Hoveyda HR, et al. The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J Clin Endocrinol Metab 2016;101:417-426.
3. Springer Science and Business Media Adis Insight. Fezolinetant - Ogeda. Updated April 11, 2020. https://adisinsight.springer.com/drugs/800039455
4. Williams RE, Kalilani L, DiBenedetti DB, et al. Healthcare seeking and treatment for menopausal symptoms in the United States. Maturitas 2007;58:348-358.
5. Astellas Pharma US. Astellas initiates phase 3 clinical trials for fezolinetant in postmenopausal women with vasomotor symptoms. Aug. 6, 2019. https://newsroom.astellas.us/2019-08-06-Astellas-Initiates-Phase-3-Clinical-Trials-for-Fezolinetant-in-Postmenopausal-Women-with-Vasomotor-Symptoms