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. Design This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). Setting The study was conducted at 5 European clinical centers. Patients Women with PCOS participated in the study. Intervention Interventions included fezolinetant 60 or 180 mg/d or placebo for 12 weeks. Main Outcome Measure The primary efficacy endpoint was change in total testosterone. Gonadotropins, ovarian hormones, and safety/tolerability were also assessed. Results Seventy-three women were randomized, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/d were −0.80 (0.13) and −0.39 (0.12) nmol/L versus −0.05 (0.10) nmol/L with placebo (P<0.0001 and P<0.05, 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) versus −3.16 (1.04) IU/L with placebo (P<0.0001 and P=0.0022); corresponding changes in follicle-stimulating hormone (FSH) were −1.46 (0.32) and −0.92 (0.30) versus −0.57 (0.26) IU/L (P=0.0336 and P=0.3770), underpinning a dose-dependent decrease in the LH-to-FSH ratio versus placebo (P<0.001). Circulating levels of progesterone and estradiol did not change significantly versus placebo (P>0.1). Fezolinetant was well tolerated. Conclusions Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ra

The role of gonadotropin‐releasing hormone neurons in polycystic ovary syndrome

“…153 No clear changes in circulating estradiol concentrations or ovulatory function were observed in this relatively short-term study. 153 The success of longer-term NK3R antagonism in PCOS remains to be determined. The potential impact of chronic NK3R antagonism on gonadotropin surge generation and ovulation is unknown.…”

“…For example, a study in adults with PCOS suggested that the selective NK3R antagonist pavinetant (formerly MLE4901 and AZD4901) administered at a dose of 80 mg day and LH:FSH ratio by almost 60%. 153 Although LH pulse frequency was not assessed in this study, reductions in LH:FSH ratio and testosterone were sustained for 12 weeks of treatment. 153 No clear changes in circulating estradiol concentrations or ovulatory function were observed in this relatively short-term study.…”

“…153 Although LH pulse frequency was not assessed in this study, reductions in LH:FSH ratio and testosterone were sustained for 12 weeks of treatment. 153 No clear changes in circulating estradiol concentrations or ovulatory function were observed in this relatively short-term study. 153 The success of longer-term NK3R antagonism in PCOS remains to be determined.…”

Review of human genetic and clinical studies directly relevant to GnRH signalling

“…The investigators argued that a 12-week duration of treatment in this trial may be inadequate to change these parameters as positive clinical outcomes in PCOS clinical trials are typically detected after 6-9 months of treatment. 117,123 Taken together, neurokinin receptor antagonism may negate differential hypersecretion of LH (i.e., excessive secretion of LH in comparison to FSH), and by extension, prevent excessive ovarian androgen production, a cardinal feature of PCOS.…”

“…As in other studies, NK3R antagonist treatment resulted in lower LH levels while not affecting those of FSH, thus reducing LH/FSH ratio. Fezolinetant is now in phase 3 development for the treatment of vasomotor symptoms in postmenopausal women 117 …”