Shaping the future of menopause management with neurokinin-targeted therapies

Introduction

Menopause is a pivotal time high­lighted by the cessation of menses, but it is not a disease or condition.¹ However, people who have gone through menopause are more vul­nerable to certain health conditions (e.g., heart disease, osteoporosis).¹ There are several symptoms of menopause, with the most common being vasomotor symptoms (VMS) commonly referred to as hot flashes and night sweats.² Bothersome VMS affect up to 80% of postmenopausal persons.² Most individuals experi­encing VMS rate their symptoms as being moderate to severe, and VMS last an average 7 to 10 years.³ VMS also have a significant impact on daily activities such as child care, exercise, housework and, to a lesser extent, employment.³

Hormone therapy (HT) to manage VMS continues to be the most effec­tive treatment, yet some patients may be unable (due to contraindications) or unwilling to take HT.² This high­lights the ongoing need for nonhor­monal therapy options to manage VMS.² The emergence of neurokinin (NK)-targeted therapies has trans­formed the management of VMS. The first-in-class medication fezolinetant was approved by the FDA in May 2023 as nonhormonal therapy to manage VMS.⁴ Elinzanetant is an additional NK-targeted therapy currently being reviewed by the FDA to manage VMS.⁵ These medications may shift the paradigm of menopause symp­tom management.

Understanding vasomotor symptoms and their impact

Pathophysiology

Research into the pathophysiology of VMS has led to advances in meno­pause management. Specifically, these include the discovery of spe­cialized hypothalamic neurons that have kisspeptin, NKB and dynorphin occurring in the same neuron (i.e., KNDy neurons) and of hypothalamic NKB receptors and their impact on the thermoregulatory autonomic sys­tems.⁶ NKB/NK3 receptor signaling is critical to the pathophysiology of hot flashes, and thermoregulatory changes occur within this system in response to estrogen deficiency.⁶

Prevalence and duration

The Study of Women’s Health Across the Nation (SWAN) was a multisite, multiracial, multiethnic, longitu­dinal cohort study enrolling 3,302 women across the United States.⁷ Data recorded from the interviews and self-administered question­naires employed in the study sup­ported that the incidence of VMS in postmenopausal women was 80%.7 Additionally, VMS symptoms per­sisted for a median of 7.4 years.⁷ A 34% prevalence of moderate to severe VMS also has been described in the US.⁸ In the SWAN, Black women had a significantly higher adjusted odds ratio (OR) for frequent VMS associ­ated with menopause compared with their White counterparts (OR, 1.63; 95% CI, 1.21-2.20; p-value < 0.01).⁹

VMS were associated with women having less than a college education (adjusted OR [aOR], 1.91; 95% CI, 1.40-2.61), being smokers (aOR, 1.63; 95% CI, 1.25-2.12), having a higher body mass index (aOR, 1.03 per unit of increase; 95% CI, 1.01-1.04 per unit of increase), or reporting anxi­ety symptoms at baseline (aOR, 3.10; 95% CI, 2.33-4.12).⁹

Clinical impact

SWAN’s participants also answered questions about cognitive perfor­mance that involved verbal learn­ing, verbal fluency, memorization and intelligence.⁷ Compared with findings from the premenopausal group, outcomes of the perimeno­pausal group showed a temporary decrease in scores on the Continu­ous Recognition Paradigm of Kimura (CRP) (a measure of visual recogni­tion memory) (p-value = 0.02) and on verbal fluency (a measure of ver­bal production, semantic memory and language) (p-value = 0.02).⁷ Age-related cognitive decline begins after menopause and is unrelated to the timing of cessation of menses.⁷ In a prospective study of 274 community-dwelling women who were in later perimenopause or who were postmenopausal, VMS occur­ring during sleep were associated with a significantly lower ratio of amyloid beta 42 to amyloid beta 40 (OR, 1.18; 95% CI, 1.05-1.33; p-value = 0.006; multivariable).⁹ Over the course of the menopause transition, participants in SWAN experienced increases in lipids, body fat distribution, metabolic syn­drome risk and vascular health.⁹ In an analytic sample from SWAN, an increased risk of incident diabetes was noted among those with more frequent VMS (HR, 1.45; 95% CI, 1.11-1.95) as compared with those with infrequent VMS (HR, 1.30; 95% CI, 1.00-1.70) when adjusted for covariates.¹⁰ An analysis regarding the impact of VMS frequency from participants in SWAN was also con­ducted to assess the risk of incidence cardiovascular disease (CVD).¹¹ Women with more frequent VMS (defined as at least six days over a two-week period) had a greater than two-fold increased risk for CVD com­pared with women without VMS. This relationship persisted when adjusted for additional characteristics such as HT use.¹¹

In a systematic review, five of the 12 studies included showed no over­all effect of VMS on fracture risk (z = 0.71; p-value = 0.48).12 Conversely, VMS appeared to be associated with low bone mineral density (z = 10.71; p-value < 0.00001).¹²

With an 80% prevalence of VMS and more severe VMS occurring in 34% of patients, it is unsurprising that the occurrence of VMS results in frequent use of healthcare ser­vices and a large economic burden.⁸ In a study evaluating health insur­ance claims in 252,273 women with untreated VMS matched to non-VMS controls, women with untreated VMS had significantly higher direct use of healthcare resources for all causes than did controls in pharmacy claims (incidence rate ratio [IRR], 1.21; 95% CI, 1.20-1.22; p-value < 0.0001), outpatient visits (IRR, 1.82; 95% CI, 1.81-1.83; p-value < 0.0001), emer­gency department use (IRR, 1.32; 95% CI, 1.29-1.36; p-value < 0.0001) and other visits (IRR, 1.69; 95% CI, 1.66- 1.72; p-value < 0.0001).¹³ In addition, patients with untreated VMS had a higher all-cause work loss (IRR, 1.57; 95% CI, 1.51-1.63; p-value < 0.0001).¹³

Conventional strategies to manage vasomotor symptoms

Current treatment landscape: hormone therapy

The Menopause Society recognizes HT as the most effective therapy for managing VMS of menopause; fur­ther, HT is FDA approved as first-line therapy for moderate to severe VMS of menopause.¹⁴ During the meno­pause transition, less estrogen is pro­duced by the ovaries; HT is a way of replacing this lost estrogen lost and relieving menopausal symptoms.¹⁴ Both oral and transdermal HT are contraindicated for use by patients with unexplained vaginal bleeding; liver disease; prior estrogen-sensitive cancer including breast cancer; prior coronary heart disease, stroke, myo­cardial infarction or venous throm­boembolism (VTE) or a personal history of or inherited risk of throm­boembolic disease.¹⁴ The potential risks of HT include breast cancer (absolute risk, six events per 10,000 women per year) with use of combi­nation conjugated equine estrogen (CEE)-medroxyprogesterone ace­tate (MPA) therapy and endometrial hyperplasia or endometrial cancer with use of inadequately opposed estrogen therapy.¹⁴ With use of CEE monotherapy, the absolute risk of deep-vein thrombosis (DVT) was five per 10,000 women per year and of pulmonary embolism (PE) was three per 10,000 women per year.¹⁴ With use of combination CEE-MPA ther­apy, the absolute risk of DVT was 10 per 10,000 women per year and of PE was six per 10,000 women per year.¹⁴

Gallbladder disease is also a poten­tial risk.¹⁴ Common adverse effects (AEs) of HT include nausea, bloating, weight gain, fluid retention, mood swings, breakthrough bleeding, head­aches and breast tenderness.¹⁴

After the results of two large national and international studies — the Women’s Health Initiative (WHI) in the US and the Million Women Study in the United Kingdom — were reported, there was a significant decline in the use of HT.¹⁵ This was mainly driven by the risk of CV events and breast cancer found in the stud­ies.¹⁵ Despite subsequent subgroup analyses of the WHI reporting that the patients at highest risk for these events were older or that risk was due to the type and dose of HT pre­scribed, patient reluctance to begin HT continues.¹⁵

Current treatment landscape: nonhormonal approaches

Several nonhormonal prescription therapies have been evaluated for reducing VMS.

Use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) has produced mild to mod­erate improvements in VMS.¹⁵ For the use of SSRIs to treat VMS, the FDA has only approved 7.5 mg/day of paroxe­tine mesylate given orally.¹⁵ In clini­cal trials, use of this agent improved VMS severity and frequency and sleep disruption, and it did not impact weight or libido.¹⁵ SSRIs and SNRIs have several associated cautions and warnings, such as one concern­ing serotonin syndrome and a black box warning for suicidal thoughts; in addition, use of these agents may result in nausea or dizziness.¹⁵

Gabapentin is FDA approved as an antiepileptic drug, but it is often prescribed for neuropathic pain syn­dromes.¹⁵ The results of clinical trials have demonstrated improved VMS frequency and severity with gabapen­tin.¹⁵ Gabapentin use has been asso­ciated with several AEs including diz­ziness, headache and disorientation; as such, gabapentin may be a good choice for women with sleep disrup­tions due to VMS.¹⁵

Similar to gabapentin, prega­balin given for the management of VMS has resulted in reduced VMS frequency and severity; however, it has similar AEs and is a schedule V controlled substance, which may be a barrier to access.¹⁵

Clonidine may also be beneficial in reducing VMS, but it is less beneficial than are SSRIs, SNRIs and gabapen­tin.¹⁵ Clonidine is not often used due to intolerability related to hypoten­sion, lightheadedness, headache, dry mouth, dizziness, sedation and con­stipation due to its central agonism of the alpha-2 adrenergic receptor.¹⁵

There are limitations to the use of both HT and existing nonhormonal therapies; these include AEs and con­traindications. Emerging therapeutic options also may address newly dis­covered pathophysiological mecha­nisms of VMS of menopause. As pre­viously discussed, The Menopause Society recognizes HT as the most effective therapy to manage VMS.¹⁵ Use of SSRIs, SNRIs, gabapentin and oxybutynin is recommended by The Menopause Society for the manage­ment of VMS.¹³ Use of clonidine, suv­orexant and pregabalin, however, is not recommended.¹⁵

Emerging neurokinin-targeted therapies: fezolinetant and elinzanetant

Hypothalamic neurons responding to kisspeptin, NKB, and dynorphin (known as the KNDy neurons) also impact VMS.¹⁵ As estradiol levels decline during the menopause tran­sition, VMS are triggered by hyperac­tivity of the KNDy neuron that results in hypersecretion of NKB, disruption of the thermoregulatory center of the hypothalamus and, subsequently, VMS.¹⁵ NK-targeted therapies, spe­cifically NKB antagonists, target this area of hypersecretion and lead to a decrease in VMS.¹⁵ These agents rep­resent a targeted therapy that may reduce VMS without leading to the risks of HT.¹⁵

Fezolinetant is currently the only FDA-approved NK-targeted therapy.¹⁵ Fezolinetant was evaluated in three SKYLIGHT trials and the DAYLIGHT trial.¹⁶

SKYLIGHT-1 (NCT04003155) was a randomized, double-blind, pla­cebo-controlled, 12-week, phase 3 trial with a 40-week treatment exten­sion.¹⁶ Moderate to severe VMS fre­quency significantly improved after four weeks; the change in least squares (LS) means for use of 30 mg of fezolinetant was -1.87 (SE, 0.42; p-value < 0.001) and for use of 45 mg of fezolinetant was -2.07 (SE, 0.42; p-value < 0.001).¹⁶ At 12 weeks, the change for 30 mg of fezolinetant was -2.39 (SE, 0.44; p-value < 0.001) and for 45 mg of fezolinetant was -2.55 (SE, 0.43; p-value < 0.001).¹⁶ A signif­icant improvement in VMS severity was also seen with both fezolinetant doses.¹⁶ The most common treat­ment-emergent AEs (TEAEs) were headache (45 mg, 6%; 30 mg, 5%; pla­cebo, 7%), increased blood glucose (3%, 3% and 0%, respectively), abdom­inal pain (2%, 1% and 1%) and arthral­gia (1%, 2% and 1%).¹⁴ In addition, an increased blood phosphokinase level, nasopharyngitis and increased levels of liver enzymes (alanine aminotrans­aminase, gamma-glutamyl transfer­ase) were also seen.¹⁶

SKYLIGHT-2 (NCT04003142) was a multinational, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in women with moderate to severe VMS.¹⁷ Mod­erate to severe VMS frequency sig­nificantly improved in women tak­ing fezolinetant after four weeks as compared with the placebo group; the change in LS means for those using 30 mg of fezolinetant was -1.82 (SE, 0.46; p-value < 0.001) and for those using 45 mg of fezolinetant was -2.55 (SE, 0.46; p-value < 0.001).¹⁷ Compared to the placebo group at 12 weeks, the change in LS means in those using the 30-mg dose was -1.86 (SE, 0.55; p-value < 0.001) and in those using the 45-mg dose was -2.53 (SE, 0.55; p-value < 0.001).¹⁷

A significant improvement in VMS severity was also seen with both fezolinetant doses.¹⁷ The most com­mon TEAEs were upper respiratory infection (45 mg, 3%; 30 mg, 3%; placebo, 4.2%), headache (3.6%, 3% and 2.4%, respectively), dry mouth (2.4%, 2.4% and 0%), arthralgia (0.6%, 3% and 0.6%), diarrhea (1.2%, 0.6% and 2.4%), nasopharyngitis (0%, 1.8% and 2.4%), nausea (2.4%, 1.8% and 0%) and weight increases (0.6%, 3% and 0.6%).¹⁷ A few instances of elevated liver function test (LFT) results occurred with use of each fezolinetant dose (45 mg, 1.8%; 30 mg, 1.2%).¹⁷

SKYLIGHT-4 (NCT04003389) was a randomized, placebo-controlled, 52-week study focusing on long-term safety and tolerability of both the fezolinetant 30- and 45-mg doses.¹⁸ In SKYLIGHT-4, TEAEs were similar between the placebo and fezolin­etant groups.¹⁸ The most common TEAE was headache (45 mg, 9%; 30 mg, 8.5%; placebo, 9.2%), and the inci­dence of elevations in LFTs was low.¹⁸

The DAYLIGHT trial (NCT05033886) was a phase 3b, randomized, dou­ble-blind, placebo-controlled trial to assess the efficacy and safety of fezo­linetant in patients unable to take hormone therapy.¹⁹ At week 24, there was a significant reduction in the fre­quency of moderate to severe VMS compared to placebo (LS mean dif­ference, -1.93; 95% CI, -2.64 to -1.22; p-value < 0.001) and severity of VMS (LS mean difference, -0.39; 95% CI, -0.57 to -0.21; p-value < 0.001).¹⁹ In addition to VMS, this study demon­strated a significant improvement in sleep quality (reduction in distur­bance) as well.¹⁹ In a pooled analysis of the SKYLIGHT 1 and SKYLIGHT 2 trials, use of the 45-mg dose led to improvements from baseline on the Menopause-Specific Quality of Life total scores (week 4, -0.57; 95% CI, -0.75 to -0.39) (week 12: -0.47; 95% CI, -0.66 to -0.28).²⁰

Elinzanetant use is not yet FDA approved, but its new drug applica­tion was accepted by the FDA.

Fezolinetant is an antagonist of NK3R; elinzanetant targets both the NK1 receptor (NK1R) and NK3R.21 Dual NK1R/NK3R inhibition may lead to improved VMS and sleep dis­turbances.¹⁹ Elinzanetant was eval­uated in the OASIS 1, 2 and 3 trials (NCT05042362, NCT05099159 and NCT05030584). The OASIS 1 and OASIS 2 trials were phase 3 random­ized, placebo-controlled studies to assess the efficacy and safety of 120 mg of elinzanetant in individuals with severe VMS.¹⁹ In both OASIS 1 and OASIS 2, significant improve­ments in VMS frequency and sever­ity were seen (LS mean changes in daily VMS frequency vs placebo from baseline to week 4: OASIS 1, -3.3 [95% CI, -4.5 to -2.1; p-value < 0.001]); OASIS 2, -3.0 [95% CI, -4.4 to -1.7; p-value < 0.001]).²¹ At week 12, LS mean changes from baseline vs pla­cebo for OASIS 1 was -3.2 (95% CI, -4.8 to -1.6; p-value < 0.001) and for OASIS 2 was -3.2 (95% CI, -4.6 to -1.9; p-value < 0.001).²¹ Daily reductions in VMS frequency vs placebo from baseline to week 1 were also statis­tically significant in both trials.²¹ Headache was the most frequently reported TEAE in OASIS 1 (elinzane­tant, 7%; placebo, 2.6%) and OASIS 2 (9% vs 2.5%, respectively).¹⁹ In OASIS 1, fatigue was reported in 7% of the elinzanetant group vs 1.5% of the placebo group, and arthralgia was reported in 5% vs 5.2%, respectively; in OASIS 2, fatigue was reported in 5.5% vs 1.5%, and arthralgia was reported in 2.5% vs 1.0%.²¹

Although the results of OASIS-3 are not yet published, a recent abstract by the principal investiga­tors supported significant reductions in VMS with elinzanetant with a favorable safety profile.²²

Comparison of therapies

Although HT is still considered the most effective therapy for VMS, fezo­linetant appears to have advantages over other nonhormonal options. A recent network meta-analysis was conducted using phase 3 pooled data from the fezolinetant trials and com­parator publications.²³ Tibolone was the only HT included in the review. Oral use of 2.5 mg of tibolone was more effective than was 45 mg of fezolinetant (mean difference, -0.41; 95% CI, -0.61 to -0.20).²¹ Fezolinetant appeared to be more effective than was 50 mg of the nonhormonal treat­ment desvenlafaxine (mean differ­ence, 0.28; 95% CI, 0.07-0.48).²³

Implications for treatment guidelines and health economics

In the most recent guideline update by The Menopause Society on non­hormonal therapy, NK-targeted thera­pies (in the form of fezolinetant) were added as a level 1 recommendation.² Emerging data regarding the efficacy of these agents may shift clinical deci­sion-making in managing VMS.

Health economics and outcomes research

Long-term trial data on fezolinetant are lacking, but outcomes of an anal­ysis of long-term cost-effectiveness in improving quality-adjusted life-years (QALY) favored fezolinetant over no therapy.²⁴ The annual cost of fezolin­etant is expected to be about $6,000 annually, whereas the cost per QALY gained is $360,000.²⁴ Authors in this study did not recommend a VMS frequency threshold for approval of fezolinetant, as VMS may have a significant impact on QALY at dif­ferent thresholds.²⁴ There are limited data on the potential cost benefit of NK-targeted therapies compared with conventional options.

Conclusion

VMS are prevalent in postmeno­pausal persons. In many individuals, VMS can be moderate to severe and may last for upwards of 10 years from the last menstrual period. HT is still considered the most effective man­agement strategy for VMS; however, patients may be unable or unwilling to take HT. NK-targeted therapies represent a novel and transformative approach to management of VMS in patients not on HT. The newly FDA-approved agent fezolinetant and other NK-targeted therapies such as elinzanetant, which is being reviewed by the FDA, represent a way to manage VMS in a population of patients who, if left untreated, would have high use of healthcare resources and all-cause work loss.

References

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