NMPA Review Tests 45mg Bridging After East Asia 30mg Miss and HTA Splits

China NMPA Accepts NDA for Astellas' VEOZA for Menopausal VMS

Astellas Pharma Inc. announced that China's National Medical Products Administration (NMPA) has accepted a New Drug Application (NDA) for VEOZA™ (fezolinetant 45 mg) for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. This submission is supported by data from the global Phase 3 BRIGHT SKY™ program, a new bridging study conducted in China, and previous clinical studies in China. Fezolinetant, a non-hormonal selective neurokinin 3 (NK3) receptor antagonist, was generally well tolerated across all programs. VMS, commonly known as hot flashes and night sweats, significantly impacts women's quality of life, with 55% of women aged 40-65 in East Asia experiencing moderate to severe symptoms. VEOZA is already approved in 50 countries worldwide.

• Astellas has achieved a significant regulatory milestone with the acceptance of the New Drug Application for VEOZA (fezolinetant 45 mg) by China's NMPA. This marks a crucial step towards potentially expanding access to a non-hormonal treatment option for moderate to severe vasomotor symptoms (VMS) in a region where a substantial proportion of women, specifically 55% of those aged 40-65 in East Asia, experience these debilitating menopausal symptoms, highlighting a significant unmet medical need.
• The NDA submission is robustly supported by a comprehensive clinical development program. This includes data from the global Phase 3 BRIGHT SKY™ program, which involved over 1,000 women across the U.S., Canada, and Europe, alongside a new bridging study specifically conducted in China, and additional previously completed clinical studies within China, such as the Phase 2 study (NCT06812754) and Phase 3 MOONLIGHT 1 (2693-CL-0305) and MOONLIGHT 3 (2693-CL-0307) trials. Across these studies, fezolinetant demonstrated general tolerability with common adverse events including headache and abdominal pain.
• Fezolinetant is a first-in-class, non-hormonal, selective neurokinin 3 (NK3) receptor antagonist. Its mechanism involves blocking neurokinin B binding on kisspeptin/neurokinin/dynorphin (KNDy) neurons, which are critical in regulating the brain’s temperature control center. By modulating this pathway, fezolinetant effectively reduces the frequency and severity of moderate to severe VMS, offering a targeted approach to symptom management. The drug is already approved in 50 countries globally, underscoring its established efficacy and safety profile in other markets.

Understanding the Global Burden of Moderate to Severe VMS

Vasomotor symptoms affect around 70% of perimenopausal and postmenopausal women and are moderate or severe in around one-third of these women. Pooled prevalence estimates from a systematic review and meta-analysis of 41 studies (n = 28,955) ranged from 54.29% in Africa to 74.23% in the Americas and Europe. Heterogeneity was high across analyses (toI2 > 97%), and prevalence was higher in postmenopausal than perimenopausal women in all regions except South Asia and nearby regions.

Prevalence of moderate-to-severe vasomotor symptoms in postmenopausal women was 40%, 34%, and 16% in Europe, the US, and Japan, respectively, among 25,161 women completing the screening survey, of whom 11,771 were postmenopausal and 3,460 met inclusion criteria and completed the full questionnaire. In a European cohort of 11,452 women completing the screening survey, of whom 5178 were postmenopausal and 2035 completed the full questionnaire, prevalence of moderate-to-severe vasomotor symptoms ranged from 31 % in France to 52 % in Italy.

Moderate-to-severe vasomotor symptoms were associated with impact on health-related quality of life, with hot flashes and night sweats having a greater impact on daily activities than on working activities. The knowledge base does not have sufficient information on this aspect.

Addressing Unmet Needs in Vasomotor Symptom Management

Current treatment approaches for moderate to severe vasomotor symptoms associated with menopause require balancing the potential benefits and risks of treatment. Although estrogen remains the most effective medication to reduce hot flashes, options are scarce for those who cannot or do not want to take hormone therapy.

• Hormonal therapy safety concerns and restricted eligibility: Safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. In the WHI trial, age trends were less clear for CEE + medroxyprogesterone acetate, owing to increased risks of breast cancer, stroke, and venous thrombosis in all age groups, and rational use requires evaluating the patient for the presence of any contraindications to HT, as well as the time since menopause onset and baseline risks of cardiovascular disease and breast cancer.

• Tolerability and adverse event-related discontinuation with pharmacologic and hormonal interventions: Adverse events may cause 10-20% of individuals to withdraw from SSRI/SNRI treatment. Dropouts due to adverse events were more frequent in women randomized to gabapentin than in controls (RR = 2.09 [95% CI, 1.13-3.85]), with dizziness/unsteadiness: RR = 6.94 [95% CI, 3.19-15.13] and fatigue/somnolence: RR = 4.78 [95% CI, 2.23-10.25]. Dry mouth was reported by 52.1% of participants given oxybutynin and 5.3% of participants given placebo, leading to discontinuation of oxybutynin in 6.8% of participants. Eszopiclone [RR = 3.84 (95% CI: 1.14-12.87)] and oral combined hormone therapy [RR = 2.51 (95% CI: 1.04-6.07)] were associated with higher rates of adverse event-related discontinuation.

• Significant placebo effect and limited comparative evidence: Most of these trials are limited by a significant placebo effect, which frequently equals the effectiveness of the medication being evaluated. Across all blinded pharmacological interventions in men with prostate cancer undergoing castration therapy, the relative reduction in hot flash frequency ranged from -21% to -84%, and the placebo effect was between -19% and -30%. Direct head-to-head comparison with hormonal therapies and nonhormonal therapies for vasomotor symptoms, assessment of sleep outcomes, and evaluation of efficacy and safety beyond 1 year are key areas where additional data are still needed.

• Symptom relapse after treatment discontinuation: Vasomotor symptoms recur after discontinuation of hormonal therapy. Among women whose VMS improved with escitalopram, approximately one third relapsed swiftly after discontinuation of the medication, with 34.2%, 38.6%, and 37.3%, respectively, having relapse of VMS frequency, severity, and bother.

• Limitations of complementary and alternative therapies and drug interactions: Complementary and alternative medication trials are fraught with additional limitations, namely, a large placebo effect, greater homogeneity of participants, lack of validated tools, and lack of robust reporting of adverse effects. Primrose oil, Chinese herbal medicine, acupuncture, and yoga have mixed results, the concerns related to hepatotoxicity preclude the use of black cohosh, and exercise, relaxation, and paced respiration have no proven benefit thus far in reducing hot flashes. Caution should also be exercised when prescribing strong cytochrome P450 2D6 inhibitors, such as paroxetine or fluoxetine, to women who are taking tamoxifen.

Clinical Evidence Supporting Fezolinetant's Efficacy and Safety

Pooled analyses of the SKYLIGHT 1 and 2 fezolinetant trials and the OASIS 1 and 2 elinzanetant trials define the pivotal Phase 3 evidence in moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Both programs used double-blind, randomized, placebo-controlled designs with VMS frequency and severity assessed from baseline to weeks 4 and 12.

Fezolinetant's Place in the Evolving VMS Treatment Landscape

Trial data over the past five years have established oral neurokinin receptor antagonists as effective nonhormonal options for moderate-to-severe vasomotor symptoms (VMS) in postmenopausal women. Fezolinetant, an oral neurokinin-3 receptor antagonist, significantly reduced VMS frequency at both 4 weeks (Cohen's d = -0.56; 95% confidence interval [CI], -0.79, -0.34; P < 0.001) and 12 weeks (Cohen's d = -0.34; 95% CI, -0.45, -0.14; P < 0.001) in a meta-analysis of six studies with 3657 patients, with significantly improved health-related functioning and global clinical summary scores, particularly with the 90 mg twice per day dosage. A second meta-analysis of six trials with a total of 3291 women reported that fezolinetant at 30 mg QD or 45 mg QD substantially decreased the frequency and severity of VMSs per 24 hours compared to placebo after 4 and 12 weeks of therapy, with the 45 mg daily dosage over 12 weeks exhibiting significant efficacy. There were no statistically significant differences between fezolinetant and placebo concerning the occurrence of any treatment-emergent (odds ratio [OR] = 1.01, P = 0.81) or serious (OR = 1.57, P = 0.90) adverse events, and fezolinetant at 90 mg BID, 30 mg QD, or 45 mg QD did not show a significant difference in the rate of treatment-emergent adverse events (TEAEs), headache, and TEAEs leading to permanent discontinuation compared to placebo. Given fezolinetant's potential for liver enzyme elevations, it is essential to monitor liver function at baseline and regularly thereafter (monthly for the first 3 months and at 6 and 9 months).

Elinzanetant, the first drug that can act on both NK-1 and 3 receptors by selectively antagonizing them, has extended this class with dual targeting. In a systematic review of five RCTs with 1699 participants, elinzanetant demonstrated a statistically significant difference in reducing both frequency and severity of VMSs at week 4 compared to placebo (MD = -2.75, 95% CI: [-3.83, -1.67], P < 0.00001; MD = -0.29, 95% CI: [-0.35, -0.22], P < 0.00001, respectively), maintained at week 12 for both frequency (MD = -2.30, 95% CI: [-3.00, -1.59], P < 0.00001) and severity (MD = -0.35, 95% CI: [-0.43, -0.28], P < 0.00001). Compared to placebo, elinzanetant was associated with a higher incidence of TEAEs (RR = 1.12, 95% CI: [1.03, 1.22], P < 0.01), TEAEs causing permanent discontinuation of the study drug (RR = 2.18, 95% CI: [1.45, 3.28], P = 0.0002), drug-related TEAEs (RR = 1.92, 95% CI: [1.53, 2.41], P < 0.00001), headache (RR = 2.19, 95% CI: [1.38, 3.49], P = 0.0009), somnolence (RR = 2.96, 95% CI: [1.42, 6.17], P = 0.004), and fatigue (RR = 3.39, 95% CI: [1.77, 6.49], P = 0.0002), with no statistically significant difference in serious TEAEs (RR = 1.70, 95% CI: [0.82, 3.54], P = 0.15). A Bayesian network meta-analysis of 17 RCTs reported that elinzanetant 120 mg significantly reduced daily VMS frequency versus paroxetine 7.5 mg (MD: -2.11 [-3.31, -0.92]), desvenlafaxine 50-200 mg (MD: -2.77 to -1.72), and gabapentin 1200-1800 mg (MD: -2.22 to -2.31), significantly reduced VMS severity versus desvenlafaxine 50 mg (MD: -0.37 [-0.56, -0.17]), reduced nighttime awakenings significantly more effectively than paroxetine (MD: -0.82 [-1.26, -0.39]) and all desvenlafaxine regimens, and significantly improved sleep disturbance (PROMIS SD-SF-8b) score versus fezolinetant 45 mg (MD: -2.67 [-3.92, -1.42]), while change in MENQoL did not differ significantly.

The position of older nonhormonal pharmaceutical therapies has been reexamined in parallel with these developments. A meta-analysis of six randomized clinical trials with 1486 women demonstrated that 79% of the mean treatment response for hot flash frequency is accounted for by a placebo response, resulting in a mean true drug effect of 21% at most, and 68% of the mean treatment response for hot flash severity is accounted for by a placebo response, resulting in a maximum true drug effect of 32% for paroxetine mesylate. In a pilot double-blind randomized trial in women with surgical menopause, paroxetine 20 mg/day showed greater reduction in total Menopause Rating Scale score compared with placebo at 12 weeks (mean 16.9 ± 7.7 vs. 22.6 ± 6.1; mean difference -5.7, 95% CI -8.6 to -2.8; P < 0.001) and greater improvement in SF-36 scores (91.0 ± 6.4 vs. 86.9 ± 4.8; mean difference 4.1, 95% CI 1.7 to 6.5; P = 0.001), with adverse events (headache, fatigue, drowsiness) more frequent with paroxetine but mild and transient and no serious events. A randomized, double-blind, placebo-controlled study of a patented multi-ingredient botanical neurokinin inhibitor (BNI) in 74 randomized participants reported that BNI supplementation reduced VMS frequency by 2.2 hot flashes per day more than placebo (p = 0.003), corresponding to a 47.7% relative decrease, with HFRDIS improved in the BNI group (p = 0.037), no significant differences in MENQOL or PSQI, no changes in serum estradiol or liver function abnormalities, and no difference in adverse events between groups.

Fezolinetant's China NDA: A New Horizon for Non-Hormonal VMS Care

The acceptance of Astellas's New Drug Application for VEOZA (fezolinetant) by China's NMPA signals a pivotal moment for women experiencing moderate to severe vasomotor symptoms (VMS) in East Asia. This region, where over half of women aged 40-65 report significant VMS, represents a substantial unmet medical need. For years, menopausal hormone therapy (MHT) has been the primary treatment, yet its use is often limited by contraindications, perceived risks, or patient preference. Fezolinetant, as a non-hormonal selective neurokinin 3 (NK3) receptor antagonist, offers a scientifically grounded alternative by directly addressing the neurobiological pathways implicated in VMS.

Clinical evidence from global Phase 3 trials (SKYLIGHT 1 and 2) consistently demonstrates fezolinetant's ability to rapidly and significantly reduce the frequency and severity of VMS, with improvements observed as early as day one and maintained over 52 weeks. This efficacy extends to improving sleep quality, a common comorbidity of VMS. The drug's generally well-tolerated safety profile, with adverse events largely mild to moderate, further supports its potential as a valuable option.

However, the path to market leadership in China is not without its nuances. While global data are robust, the MOONLIGHT I study, specifically conducted in East Asian women, did not show a statistically significant reduction in VMS frequency or severity compared to placebo. This finding, despite other regional studies showing efficacy, underscores the importance of understanding ethnic and cultural variations in VMS presentation and treatment response. Additionally, the known risk of liver enzyme elevations requires careful patient monitoring, a factor that will be crucial in clinical practice. As other NK3 receptor antagonists like elinzanetant emerge, the competitive landscape for non-hormonal VMS treatments will intensify, demanding clear differentiation and robust real-world evidence. Astellas's ability to navigate these factors will determine fezolinetant's ultimate success in this critical market.