A yearlong phase 3 trial shows elinzanetant can cut hot flashes by nearly three-quarters while maintaining a strong safety profile, positioning it as a promising new option for women seeking alternatives to hormone therapy.
Study: Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause. Image credit: New Africa/Shutterstock.com
A recent study in JAMA Internal Medicine investigated the safety and efficacy of elinzanetant for treating moderate to severe vasomotor symptoms (VMS) in menopausal women, in a phase 3 Randomized Clinical Trial (RCT).
Vasomotor symptoms and conventional treatments
VMS, commonly known as hot flashes, are disruptive menopause-associated symptoms that women experience during the day or night, along with sweating and sleep disturbance. Up to 80% women experience VMS, and up to 60% report sleep disturbances, both of which adversely influence their quality of life.
Although hormone therapy (HT) is commonly recommended to alleviate menopausal symptoms, it is not suitable for all women. In many countries, antidepressants are also used to treat VMS. Previous research has shown that these treatments have modest efficacy compared to a placebo. Additionally, various factors, including tolerability issues, lead to increasing treatment discontinuation rates, particularly during the first three months. Since VMS can last a mean of seven to ten years, an alternative effective intervention is urgently needed.
During and after the menopausal transition, estrogen levels deplete, leading to hypertrophy and hyperactivity of hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons. This hyperactivity is accompanied by an overexpression of neurotransmitters, including neurokinin B (NKB) and substance P (SP). This hyperactivation correlates with the thermoregulatory disruption in VMS. SP and NK-1 receptors may have a role in peripheral vasodilatation and primary insomnia.
In many countries, the NK-3 receptor antagonist fezolinetant has been approved for the treatment of moderate to severe VMS due to menopause. Recent phase 3 trials, OASIS-1 and OASIS-2, have assessed the safety and efficacy of elinzanetant, an antagonist of NK-1 and NK-3 receptors. During the 26-week study period, a significant reduction in VMS frequency was observed, with reductions evident by week one of receiving elinzanetant treatment.
About the study
The current study documented the 52-week OASIS-3 study, the first Phase 3 clinical trial to assess the safety and efficacy of elinzanetant for treating VMS beyond 6 months of use in postmenopausal women. OASIS-3 was conducted at 83 sites across North America and Europe between August 27, 2021, and February 12, 2024.
Naturally or surgically postmenopausal women, between the ages of 40 and 65 years, were selected. All women sought treatment to alleviate moderate to severe VMS. Participants with abnormal liver parameters, endometrial polyps, hyperplasia, disordered proliferative endometrium, or malignant neoplasm were excluded. Unlike OASIS-1/-2, OASIS-3 had no minimum VMS frequency requirement, broadening generalizability.
Eligible candidates were randomly assigned in a 1:1 ratio to either the treatment or placebo groups. The treatment group participants received 120 mg of elinzanetant orally for the entire 52-week study duration.
All participants maintained an electronic hot flash daily diary (HFDD). They also completed the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality Of Life (MENQOL) questionnaire total score over 52 weeks. For safety assessment, participants were asked to spontaneously report any adverse events (AEs) they experienced during the study.
Study findings
A total of 1,524 women were screened, of whom 628 were randomized to the elinzanetant and placebo groups. The mean age of the participants was 54.7 years. At baseline, the demographic characteristics of the participants of both groups were well balanced.
At baseline, women in the elinzanetant and placebo arms experienced 6.7 and 6.8 moderate to severe VMS events per day, respectively. After 12 weeks (the primary endpoint time point) of intervention, the mean change was −5.4 for the elinzanetant arm and −3.5 for the placebo arm.
The current study estimated the least-squares (LS) mean difference in the change from baseline for elinzanetant compared with placebo at week 12 to be −1.6. In addition, descriptive analyses indicated that at a similar time, the mean percentage changes were −73.8% for elinzanetant and −47.0% for placebo. Notably, after 50 weeks of intervention, participants experienced a mean of 1.4 and 3.5 moderate to severe VMS events per day in the elinzanetant and placebo arms, respectively.
Secondary and exploratory outcomes were analyzed descriptively, including sleep and MENQOL over 52 weeks and VMS over 50 weeks. The trial was not powered to detect between-group differences on these endpoints.
Baseline mean Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form SF 8b total T-scores were 57.4 for elinzanetant and 58.0 for placebo. Mean baseline MENQOL total scores were 4.1 for elinzanetant and 4.4 for placebo.
At the end of the study period, 70.0% and 61.1% of women in the elinzanetant and placebo arms, respectively, experienced at least one treatment-emergent AE (TEAE). Approximately, 89% of the TEAEs in the elinzanetant arm and 89.6% in the placebo arm were mild or moderate in intensity. In both the study arms, the commonly reported TEAEs were headache, nasopharyngitis, COVID-19, fatigue, and somnolence.
A relatively low discontinuation rate was recorded at 12.5% in the elinzanetant arm and 4.1% in the placebo arm, though discontinuation was higher in the treatment group, mainly due to adverse events. No endometrial hyperplasia or malignant endometrial neoplasms were observed in the endometrial biopsy in both arms. Only two participants in the elinzanetant arm had clinically significant abnormal mammogram reports.
After the 52-week study period, serum concentrations of estradiol, luteinizing hormones, progesterone, and follicle-stimulating hormones did not significantly change. Furthermore, body weight and composition remained stable in both groups at the end of the study period. Some liver enzyme elevations occurred in both arms (a few met predefined monitoring criteria), but there were no Hy’s law cases, and the independent board concluded no hepatotoxic signal.
Conclusions
The current study highlighted a favorable efficacy and safety profile of elinzanetant after 52 weeks of treatment. This treatment resulted in a reduction in the number of daily VMS events compared to the placebo. Notably, elinzanetant was found to be well-tolerated in menopausal women with moderate to severe VMS.
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