A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause

Abstract

Objective: Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. Methods: Menopausal women aged >40-65 years with moderate/severe VMS (≥50 episodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90 mg BID or 30, 60, 120 mg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS × 2] + [number of severe VMS × 3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (≥50% reduction in moderate/severe VMS frequency) was a key secondary outcome. Results: Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by −1.9 to −3.5/day at week 4 and −1.8 to −2.6/day at week 12 (all P < 0.05 vs placebo). Mean difference from placebo in VMS severity score was −0.4 to −1 at week 4 (all doses P < 0.05) and −0.2 to −0.6 at week 12 (P < 0.05 for 60 and 90 mg BID and 60 mg QD). Response (50% reduction) relative to placebo was achieved by 81.4% to 94.7% versus 58.5% of participants at end of treatment (all doses P < 0.05). Treatment-emergent adverse events were largely mild/moderate; no serious treatment-related treatment-emergent adverse events occurred. Conclusions: Fezolinetant is a well-tolerated, effective nonhormone therapy that rapidly reduces moderate/severe menopausal VMS. Video Summary: http://links.lww.com/MENO/A572; video script available at http://links.lww.com/MENO/A573.

Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA)

“…These reductions in VMS were accompanied by improvements in PROs (MENQoL, HFRDIS, and GCS), with marked changes from baseline observed at the first measurement time point; improvements were maintained throughout the 12-week treatment period. Consistent with the reported efficacy of fezolinetant to reduce the frequency and severity of VMS (ie, the occurrence of hot flashes and/or night sweats), 18 , 19 this manuscript reflects notable improvements in PRO measure domains that have a strong association with VMS, including the MENQoL vasomotor function domain, HFRDIS total score, and GCS VMS score. Improvements on the MENQoL and HFRDIS exceeded previously published MID/CID values for all fezolinetant groups and placebo.…”

“…Primary safety results have been reported. 19 Rates of reported adverse events were similar across treatment groups, with no major dose-related events that would potentially skew results on PROs.…”

“…In this phase 2b, dose-ranging study, treatment with fezolinetant not only reduced the frequency and severity of VMS on the previously reported primary endpoints, 19 it resulted in higher responder rates and improvements in PROs in a population of postmenopausal women with a considerable baseline burden of moderate/severe VMS. Across all fezolinetant dose groups, more than 80% of the participants experienced a reduction in moderate or severe VMS of ≥ 50%, and more than half of the women achieved a ≥ 90% reduction.…”

“…Methodology, including detailed inclusion/exclusion criteria of this phase 2b, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study (NCT03192176), has been published, along with primary efficacy and safety outcomes. 19 Briefly, healthy postmenopausal women >40-65 years of age with ≥50 moderate/severe VMS episodes per week during a 35-day screening period were randomized to treatment with one of seven fezolinetant dosing regimens (15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD) or placebo for 12 weeks. Participants recorded their VMS episodes daily in an e-diary and completed PRO measures consisting of the Menopause-Specific Quality of Life (MENQoL) questionnaire, the Hot Flash-Related Daily Interference Scale (HFRDIS), and the Greene Climacteric Scale (GCS) at baseline and weeks 4, 8, and 12.…”

“… 18 Also, in a phase 2b, dose-ranging clinical trial (VESTA), fezolinetant significantly reduced moderate/severe VMS frequency and severity compared with placebo in postmenopausal women. 19 The majority of women who received fezolinetant (81%-95%) experienced a 50% or greater reduction from baseline in moderate/severe VMS frequency. VMS symptoms improved as early as the first week on treatment and were maintained throughout the 12-week duration.…”