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Randomized Controlled Trial
. 2021 Aug 18;106(9):e3519-e3532.
doi: 10.1210/clinem/dgab320.

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome

Graeme L Fraser, Barbara Obermayer-Pietsch  1 , Joop Laven  2 , Georg Griesinger  3 , Axelle Pintiaux  4 , Dirk Timmerman  5 , Bart C J M Fauser  6 , Christopher Lademacher  7 , Jean Combalbert, Hamid R Hoveyda, Steven Ramael
Affiliations
Randomized Controlled Trial

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome

Graeme L Fraser et al. J Clin Endocrinol Metab. .

Abstract

Context: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility.

Objective: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS.

Methods: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed.

Results: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated.

Conclusion: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.

Keywords: dynorphin A neurons; gonadotropin-releasing hormone; kisspeptin; neurokinin 3 receptor; neurokinin B; polycystic ovary syndrome.

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Figures

Figure 1.
Figure 1.
Patient disposition. aPatient experienced depressed mood, mood swings, headache, and decreased libido considered by the investigator to be possibly related to treatment.
Figure 2.
Figure 2.
A, Adjusted mean (SE) percentage change from baseline in total testosterone levels during treatment with fezolinetant vs placebo. B, Adjusted mean (SE) change from baseline in LH during treatment with fezolinetant vs placebo. C, Adjusted mean (SE) change from baseline in FSH during treatment with fezolinetant vs placebo. D, Effects of fezolinetant on LH-to-FSH ratio. All ITT population. Changes in these hormone levels were analyzed post hoc using an analysis of covariance model with treatment group as a fixed factor and baseline value as a covariate. aP < .05; bP < .01; cP < .001 vs placebo. Between-treatment statistical comparisons were not made on absolute LH-to-FSH ratios. Abbreviations: FSH, follicle-stimulating hormone; ITT, intent-to-treat; LH, luteinizing hormone.
Figure 3.
Figure 3.
Effects of fezolinetant on A, adjusted mean change in E2 based on ANCOVA; B, endometrial thickness over time; and C, menses frequency, ITT population. aP < .05; bP < .01. Change in E2 is based on least squares mean percentage change from the ANCOVA model with treatment group as a fixed factor and baseline value as a covariate. ANCOVA, analysis of covariance; E2, estradiol; ITT, intent-to-treat.
Figure 4.
Figure 4.
Effect of fezolinetant on A, AMH and B, adjusted mean change in ovarian volume based on transvaginal ultrasound at week 12, ITT population. AMH, antimüllerian hormone; ITT, intent-to-treat.
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