Advances in vasomotor symptom treatments

Non-hormonal options are available for women who cannot or prefer not to use menopausal hormone therapy to treat vasomotor symptoms (VMS). This article summarises advances in treatment options for VMS.

Dr Sheryl Kingsberg (MacDonald Women’s Hospital/University Hospitals Cleveland Medical Center, Ohio, USA) reviews the VMS treatment landscape, and how emerging therapies can meet unmet needs. View transcript.

Newly approved and investigational treatments for VMS are shown in Figure 1.

Figure 1. Newly approved and investigational treatments for vasomotor symptoms.^1-13 *Newly approved for VMS. ^†Investigational treatment for VMS. ^‡Prescribed off-label for VMS. NK3R, neurokinin 3 receptor; NK1/3R, neurokinin 1/3 receptor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; VMS, vasomotor symptoms.

Non-hormonal agents

Neurokinin B antagonism (NK3R antagonists)

Identification of specialised hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons that use neurokinin B (NKB) signalling on the neurokinin 3 receptor (NK3R) has advanced the understanding of the pathophysiology of VMS.¹⁴ NK3R antagonism inhibits NKB binding on the KNDy neuron, which is hypothesised to restore KNDy neuronal function in the hypothalamic thermoregulatory neutral zone.¹⁴

Fezolinetant

Fezolinetant, a non-hormonal selective NK3R antagonist was approved in 2023 for moderate-to-severe VMS due to menopause by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).^1,2 Approval for fezolinetant was based on the BRIGHT SKY programme, which consisted of the SKYLIGHT 1, 2, and 4 clinical trials.

SKYLIGHT 1, 2, 4

SKYLIGHT 1

At the recommended dose of 45 mg/day, fezolinetant significantly reduced the VMS frequency versus placebo at week 4 (difference in change, –2.07; P<0.001) and week 12 (–2.55; P<0.001), and VMS severity at week 4 (–0.19; P=0.002) and week 12 (–0.20; P=0.007). Improvements in VMS frequency and severity were maintained from week 1 over 52 weeks. Treatment-emergent adverse events (TEAE) were observed in 75 participants (43%) taking fezolinetant 45 mg and 78 (45%) taking placebo during the first 12 weeks. Incidence of liver enzyme elevations was low (fezolinetant 45 mg, n=0; placebo, n=1) and was generally asymptomatic and resolved during treatment.¹⁵

SKYLIGHT 2

Fezolinetant 45 mg significantly reduced VMS frequency at week 4 (–2.55; P<0.001) and week 12 (−2.53; P<0.001) compared with placebo. For VMS severity compared with placebo, the difference at week 4 was −0.29 (P<0.001) and at week 12 was −0.29 (P<0.001). VMS improvements were maintained from week 1 over 52 weeks. Serious TEAEs were reported by 1% (fezolinetant 45 mg) and 0% (placebo). Three participants taking fezolinetant had liver elevations >3 times upper limit of normal, as did one taking placebo, which supports the hepatic safety of fezolinetant, with no cases of Hy's law to suggest drug-induced liver injury.¹⁶

SKYLIGHT 4

In this 52-week safety trial, no safety signals for fezolinetant were observed, and the incidence of endometrial hyperplasia or malignancy was within prespecified limits. TEAEs were observed in 67.9% of the fezolinetant 30 mg group, 63.9% of the fezolinetant 45 mg group, and 64.1% of the placebo group. TEAEs leading to discontinuation were similar across the trial groups. Liver enzyme elevations were more than three times the upper limit of normal in eight of 590 participants on fezolinetant 30 mg, 12 of 589 participants on fezolinetant 45 mg, and six of 583 participants on placebo.¹⁷

Dr Kingsberg summarises non-hormonal treatments for VMS and why they are a needed option for women. View transcript.

Elinzanetant (NT-814)

Elinzanetant is an antagonist of the neurokinin pathway targeting NK1 and NK3 receptors.^3,4

RELENT-1

In this 14-day, phase 2 clinical trial investigating 50, 100, 150, and 300 mg daily of elinzanetant, reduction from baseline at week 2 in moderate-to-severe hot flash frequency was 37% in the placebo group and an additional 24% (P=0.048; 50 mg), 59% (P=0.155; 100 mg), 84% (P<0.001; 150 mg), and 66% (P=0.022; 300 mg) for elinzanetant. For waking due to night sweats, reduction was 20% (P=0.059; 50 mg), 55% (P=0.135; 100 mg), 81% (P<0.001; 150 mg), and 63% (P=0.031; 300 mg) for elinzanetant, and 32% for placebo.³

SWITCH-1

A 12-week, phase 2b clinical trial evaluated optimal dosing of elinzanetant at 40, 80, 120 or 160 mg daily compared with placebo. At 40 mg and 80 mg, reductions in VMS were not significantly different from placebo; for 120 mg, a significant reduction was observed at 4 and 12 weeks; for 160 mg, VMS were significantly reduced at 4 weeks but not at 12 weeks. No serious AEs were observed.¹⁸

OASIS 1, OASIS 2

Phase 3 double-blind, placebo-controlled studies investigating the efficacy and safety of elinzanetant 120 mg in women with moderate-to-severe VMS. Compared with placebo, elinzanetant significantly reduced VMS frequency at week 4, which was sustained at week 12 (OASIS 1, –3.22; P<0.0001; OASIS 2, –3.24; P<0.0001), and the same was observed for VMS severity (OASIS 1, –0.40; P<0.0001; OASIS 2, –0.29; P<0.0001). In OASIS 1 and 2, compared with placebo at week 12, elinzanetant significantly improved sleep disturbances (P<0.0001 in both studies) and menopause-related quality of life (QoL; P=0.0001 in OASIS 1; P=0.0059 in OASIS 2). The safety profile was favourable in both trials.¹⁹

Elinzanetant is currently in development for VMS and does not have regulatory approval for any indication.

Serotonin and norepinephrine reuptake inhibitors

Venlafaxine

A clinical trial compared the efficacy and tolerability of 0.5 mg/day oral 17β-oestradiol and 75 mg/day venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), in perimenopausal and postmenopausal women with VMS. At week 8, VMS frequency decreased to 3.9 per day (52.9% reduction) for oestradiol and 4.4 per day (47.6% reduction) for venlafaxine. Oestradiol achieved the highest treatment satisfaction (70.3%), whereas satisfaction for venlafaxine was intermediate (51.1%). Both interventions were well tolerated.⁶ Venlafaxine does not interact with the cytochrome P450 system.²⁰ Venlafaxine is not FDA or EMA indicated for VMS.

Venlafaxine is being further investigated in the phase 4 OPTION-VMS observational study, along with other agents in the serotonergic family (citalopram, escitalopram, and desvenlafaxine) and other non-hormonal treatments used in clinical practice.¹³

Anticholinergics

Oxybutynin

Oxybutynin is approved by the FDA and EMA for urge incontinence overactive bladder.^21,22

A 12-week, phase 2 clinical trial that compared 15 mg oxybutynin with placebo showed reductions for oxybutynin in frequency and severity of moderate-to-severe VMS through week 12. Women on oxybutynin showed improved sleep and QoL, with persistent treatment response at 12 weeks. Oxybutynin was associated with dry mouth and urinary difficulties.¹¹ Compared with placebo, using 2.5 or 5 mg oxybutynin twice daily can reduce hot flush frequency and severity, and benefit most hot flush-related daily interference scale measures and QoL.²³

An ongoing phase 3 head-to-head study is comparing the efficacy and safety of paroxetine versus oxybutynin in reducing frequency and severity of VMS, especially in patients with breast cancer taking aromatase inhibitors.²⁴

Oxybutynin is used off-label for VMS and should be prescribed with care for older women, given its anticholinergic side effects, including risk for impaired cognition.²⁵

Hormonal therapy

Estetrol

Estetrol (E4) is a human fetal oestrogen that activates the nuclear oestrogen receptor α (ERα), stimulating a cascade of coregulator activators and repressors in a similar manner to oestradiol (E2) and oestriol (E3).²⁶ In preclinical mouse models, E4 appears to act synergistically with endogenous oestrogens in bone, vasculature, vaginal tissues, and endometrium, with fewer toxic effects on liver and breast than E2.²⁶

In a two-part trial, the phase 2 stage established that E4 15 mg was the minimum effective daily dose for reducing VMS frequency and severity at weeks 4 and 12, compared with placebo (P<0.05). In phase 3, the E4 15 mg and 20 mg doses were associated with significant reductions in VMS frequency (up to 80%) and severity (up to 51%) at weeks 4 and 12 for moderate-to-severe VMS, compared with placebo (P<0.05).²⁷

The E4Comfort Study is investigating the effect of E4 15 mg or 20 mg or placebo on the severity and frequency of VMS and treatment tolerability in postmenopausal women who have undergone hysterectomy and those who have not.²⁸

E4 is not approved for VMS.

Read: How clinicians can meet unmet patient needs in VMS