Dataset Information

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

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.

SUBMITTER: Fraser GL

PROVIDER: S-EPMC8372662 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Vasomotor symptoms (VMS; eg, hot flashes, night sweats) are caused by a loss of thermoregulatory control. The thermoregulatory center in the brain is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. The activity of KNDy neurons is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen negative-feedback. Declining estrogen levels at menopause disturb this balance, leading to VMS. Fezolinetant is an antagonist at NK3R that acts to moderate KNDy neuron function for the treatment of VMS (1). The aim of the current trial was to evaluate fezolinetant dose levels and treatment regimen in VMS. In this phase 2b, double-blind trial (NCT03192176), menopausal women age >40−65 y with moderate/severe VMS (≥50/wk) were randomized to one of the following: fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo (PBO). Coprimary efficacy outcomes were frequency and severity of moderate/severe VMS at wk 4 and 12. Secondary efficacy outcomes included changes in moderate/severe VMS frequency and severity by study wk. Of 356 women randomized, 352 received ≥1 dose study drug (safety population; mean [SD] age: 54.6 [4.7] y; 73% white) and 287 (81%) completed the study: PBO: 37/44 (84%); fezolinetant: 250/312 (80%). The most common reasons for discontinuation were withdrawal of consent (6.7%) and AEs (5.9%). All fezolinetant dose groups demonstrated reductions in VMS frequency and severity at wk 4 and 12. Significant dose responses were observed in all coprimary efficacy endpoints. The differences from PBO in least squares (LS) mean changes from baseline in moderate/severe VMS frequency per day at wk 4 were −1.9, −3.0, −2.8, and −3.5 for 15, 30, 60, and 90 mg BID, respectively, and −2.3, −3.0, and −2.4 for 30, 60, and 120 mg QD, respectively, with a common SE of 0.8 (all P<.05). The differences from PBO in LS mean change from baseline in moderate/severe VMS frequency per day at wk 12 were −1.8, −2.1, −2.3, and −2.6 for 15, 30, 60, and 90 mg BID, respectively, and −2.1, −2.6, and −2.1 for 30, 60, and 120 mg QD, respectively, with a common SE of ~0.7 (all P<.05). Dose response was apparent in frequency and severity as early as at wk 1. The majority of TEAEs were mild or moderate in severity. There were no deaths or serious treatment-related TEAEs. This study demonstrates that fezolinetant is a safe and effective nonhormonal treatment for rapid reduction of moderate/severe menopausal VMS. 1Fraser GL, et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes [abstract OR16-5]. Endocr Rev. 2017;38(3).

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Project description:ObjectiveIn the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs).MethodsIn this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs).ResultsOf 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6).ConclusionsOral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.