Elinzanetant, a novel neurokinin-1,3 receptor antagonist, reduced menopausal hot flash frequency by over 65% in two phase 3 trials, offering a promising nonhormonal treatment option for vasomotor symptoms.

Elinzanetant significantly reduced the frequency and severity of vasomotor symptoms (VMS) in postmenopausal women compared with placebo in two phase 3 randomized clinical trials. Findings from the OASIS 1 and OASIS 2 studies, published in JAMA, also demonstrated improvements in sleep disturbances and menopause-related quality of life with elinzanetant.

Elinzanetant, as a dual neurokinin receptor antagonist, works on two receptors in the brain to improve hot flashes, night sweats, sleep, and overall mood. This mechanism of action provides a new alternative for women who cannot tolerate or do not wish to take hormone therapy due to potential side effects or contraindications.

Methods

OASIS 1 and 2 were conducted across 77 sites each from August 2021 to November 2023. Eligible participants had 50 or more moderate to severe hot flashes weekly during screening.

The primary endpoints were mean changes in VMS frequency and severity from baseline to weeks 4 and 12, measured by an electronic daily diary. Key secondary endpoints included changes in sleep disturbances (measured by the PROMIS Sleep Disturbance Short Form 8b) and menopause-related quality of life (assessed by the Menopause-Specific Quality of Life questionnaire) from baseline to week 12.

Statistical analyses used mixed models with repeated measures. A multiplicity adjustment strategy controlled the overall type I error rate at a 1-sided α level of .025 for confirmatory testing.

The multicenter, double-blind studies, conducted at multiple locations (including UVA Health) across the United States, Europe, and Israel, randomized postmenopausal women aged 40 to 65 years with moderate-to-severe VMS to receive oral elinzanetant at 120 mg daily or placebo for 12 weeks. After 12 weeks, all participants received elinzanetant for an additional 14 weeks.

Key Findings

In OASIS 1 (n = 396), elinzanetant reduced mean daily VMS frequency from baseline by 7.5 at week 4 and 8.7 at week 12, compared with reductions of 4.4 and 5.5 with placebo, respectively. OASIS 2 (n = 400) showed similar results. The differences versus placebo were statistically significant at both time points (P<.001). Notably, statistically significant reductions in hot flash frequency and severity were observed as early as the first week in both trials.

Elinzanetant also significantly decreased VMS severity and improved sleep disturbance scores and menopause-specific quality of life compared with placebo at 12 weeks (P<.001 for all).

By week 12, over 70% of elinzanetant-treated participants achieved at least a 50% reduction in VMS frequency in both trials; this increased to over 80% by week 26.

"The effectiveness for relief of hot flashes in highly symptomatic women, along with improvements in sleep and mood across multiple trials and [the] favorable safety profile of elinzanetant, suggests it has potential as a non-estrogen treatment for women with bothersome menopausal symptoms," remarked JoAnn V. Pinkerton, MD, UVA Health's Director of Midlife Health and the first author of the JAMA paper.

The most common adverse events observed with elinzanetant were headache (7.0%-9.0%) and fatigue (5.5%-7.0%). No liver toxicity or endometrial hyperplasia cases were observed.

Further Results

Baseline OASIS 1 and 2 participant characteristics included:

• Mean age: 54.6 years in both trials
• Race: 75.9%-86.0% White, 12.5%-19.3% Black or African American
• Mean body mass index: 27.7-28.0 kg/m²
• Prior hysterectomy: 34.5%-42.2%
• Prior oophorectomy: 12.0%-25.6%
• Mean duration of amenorrhea: 4.5-5.0 years
• Mean daily VMS frequency: 13.4-14.7 for elinzanetant, 14.3-16.2 for placebo
• Mean VMS severity score (0-3 scale): 2.5-2.6 for both groups
• Mean PROMIS SD SF 8b total T score: 60.2-61.7 (moderate sleep disturbance).

In terms of VMS frequency, in OASIS 1, the mean change from baseline at week 4 was –7.5 (standard deviation [SD] = 5.8) with elinzanetant and –4.4 (SD = 6.7) with placebo; at week 12, it was –8.7 (SD = 6.7) with elinzanetant and –5.5 (SD = 10.2) with placebo. In OASIS 2, the mean change from baseline at week 4 was –8.6 (SD = 9.2) with elinzanetant and –6.1 (SD = 8.9) with placebo; at week 12, it was –10.0 (SD = 10.3) with elinzanetant and –7.2 (SD = 8.5) with placebo.

Least square mean differences vs placebo in terms of VMS frequency were:

• Week 4: –3.3 (95% confidence interval [CI] = –4.5 to –2.1) in OASIS 1, –3.0 (95% CI = –4.4 to –1.7) in OASIS 2
• Week 12: –3.2 (95% CI = –4.8 to –1.6) in OASIS 1, –3.2 (95% CI = –4.6 to –1.9) in OASIS 2 (All P<.001).

The percentage change from baseline in terms of VMS frequency in OASIS 1 at week 4 was –55.9% with elinzanetant and –31.4% with placebo; at week 12, it was –65.2% with elinzanetant and –42.2% with placebo. In OASIS 2, the percentage change from baseline in terms of VMS frequency at week 4 was –57.9% with elinzanetant and –35.7% with placebo; at week 12, it was –67.0% with elinzanetant and –45.9% with placebo.

Least square mean differences vs placebo in terms of VMS severity were:

• Week 4: –0.3 (95% CI = –0.4 to –0.2) in OASIS 1, –0.2 (95% CI = –0.3 to –0.1) in OASIS 2
• Week 12: –0.4 (95% CI = –0.5 to –0.3) in OASIS 1, –0.3 (95% CI = –0.4 to –0.1) in OASIS 2 (All P<.001).

In terms of sleep disturbances, the differences in least square means vs placebo at week 12 were –5.6 (95% CI = –7.2 to –4.0) in OASIS 1 and –4.3 (95% CI = –5.8 to –2.9) in OASIS 2 (both P<.001).

In terms of menopause-related quality of life, the differences in least square means vs placebo at week 12 were –0.4 (95% CI = –0.6 to –0.2) in OASIS 1 and –0.3 (95% CI = –0.5 to –0.1) in OASIS 2 (both P<.001).

Mean changes from baseline in MENQOL VMS domain score at week 12 were –2.86 (SD = 2.11) with elinzanetant and 1.50 (SD = 1.80) with placebo in OASIS 1; in OASIS 2, changes were –2.70 (SD = 1.99) with elinzanetant and –1.64 (SD = 1.93) with placebo.

The percentage of participants achieving a ≥ 50% reduction in VMS frequency at week 4 were 62.8% and 62.2% (elinzanetant) vs 29.2% and 32.3% (placebo) in OASIS 1 and 2, respectively, at week 12, rates were 71.4% and 74.7% (elinzanetant) vs 42.0% and 48.3% (placebo), and at week 26, rates were 81.6% and 81.5% (elinzanetant).

Safety

Treatment-emergent adverse events over 12 weeks were seen in 51.3% of patients taking elinzanetant and 48.5% taking placebo in OASIS 1; in OASIS 2, rates were 44.3% with elinzanetant and 38.2% with placebo. In OASIS 1, serious adverse events occurred in 2.0% of patients taking elinzanetant and 1.0% of those taking placebo; in OASIS 2, rates were 0.5% with elinzanetant and 0.5% with placebo. Discontinuations due to adverse events in OASIS 1 occurred in 8.5% of patients taking elinzanetant and 6.7% of those taking placebo; in OASIS 2, rates were 6.5% with elinzanetant and 2.0% with placebo.

Conclusions

These phase 3 results suggested elinzanetant may offer an efficacious nonhormonal treatment option for menopausal VMS with a favorable safety profile. The onset of action was rapid, with significant reductions in VMS frequency observed as early as week 1. Improvements were maintained throughout the 26-week treatment period, with further benefits observed in participants who switched from placebo to elinzanetant after week 12.

The researchers emphasized the significant impact of menopausal symptoms on women's lives, including effects on workplace productivity and relationships. The development of new nonhormonal treatments like elinzanetant addresses an unmet need for effective management of these symptoms.

Longer-term safety data from the ongoing 52-week OASIS 3 trial are still pending.

Conflict of interest disclosures can be found in the study.