Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause

Key Points

Question

What are the efficacy and safety of elinzanetant, 120 mg, in postmenopausal individuals with moderate to severe vasomotor symptoms (VMS)?

Findings

In 2 pivotal phase 3 clinical trials, elinzanetant demonstrated statistically significant reductions in VMS frequency and severity vs placebo. Elinzanetant also significantly improved sleep disturbances and menopause-related quality of life vs placebo; the safety profile was favorable.

Meaning

Elinzanetant is an efficacious and well-tolerated selective neurokinin-1,3 receptor antagonist for the treatment of moderate to severe VMS associated with menopause. Elinzanetant also improves sleep disturbances and menopause-related quality of life.

Abstract

Importance

Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed.

Objective

To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms.

Design, Setting, and Participants

Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023).

Intervention

Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks.

Main Outcomes and Measures

Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12.

Results

Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency vs placebo at week 4 (OASIS 1: −3.3 [95% CI, −4.5 to −2.1], P < .001; OASIS 2: −3.0 [95% CI, −4.4 to −1.7], P < .001) and at week 12 (OASIS 1: −3.2 [95% CI, −4.8 to −1.6], P < .001; OASIS 2: −3.2 [95% CI, −4.6 to −1.9], P < .001). Elinzanetant also improved VMS severity vs placebo at week 4 (OASIS 1: −0.3 [95% CI, −0.4 to −0.2], P < .001; OASIS 2: −0.2 [95 CI, −0.3 to −0.1], P < .001) and week 12 (OASIS 1: −0.4 [95% CI, −0.5 to −0.3], P < .001; OASIS 2: −0.3 [95% CI, −0.4 to −0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable.

Conclusions and Relevance

Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS.

Trial Registration

ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159

These 2 clinical trials evaluate the efficacy and safety of elinzanetant for the treatment of moderate to severe vasomotor symptoms associated with menopause.

Introduction

Women experience a variety of symptoms during their menopausal transition, including vasomotor symptoms (VMS, also known as hot flashes) and sleep disturbances, reported by up to 80% and 60%, respectively.^1,2,3 Menopausal symptoms can negatively impact quality of life, reducing the capacity for daily activities and work productivity,^4,5,6 and may be associated with long-term negative health outcomes such as cardiovascular events, depressive symptoms, cognitive decline, and other adverse brain outcomes.^{7,8,9,10,11,12,13}

There are currently different treatment options that address the needs of individuals with menopausal symptoms. Hormone therapy and the selective serotonin reuptake inhibitor paroxetine salt, 7.5 mg, are approved for the treatment of VMS in some countries, while other selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are used off label.^14,15,16,17 However, many women have contraindications, have tolerability issues leading to discontinuation, or prefer not to take these treatments.^4,17,18 Recently, the nonhormonal neurokinin (NK)-3 receptor antagonist fezolinetant was approved by the US Food and Drug Administration (FDA), European Commission, and Switzerland SwissMedic for the treatment of moderate to severe VMS due to menopause.^19,20,21

Hypothalamic kisspeptin/neurokinin/dynorphin (KNDy) neurons play a role in thermoregulation.²² KNDy neurons express a number of receptor/ligand systems, including NK-1 and NK-3 receptors and their respective ligands, substance P (SP), and neurokinin B (NKB). Declining estrogen levels during and after the menopause transition lead to hypertrophy and hyperactivity of KNDy neurons, accompanied by elevated gene expression of neurotransmitters including NKB and SP.^22,23,24,25 This hyperactivation has been related to disruption of thermoregulation, which may trigger VMS.²² Recent data showed the involvement of NK-3 receptors in this disruption; fezolinetant, an NK-3–specific receptor antagonist, demonstrated reductions in VMS in postmenopausal individuals.^26,27 SP and NK-1 receptors may have a role in peripheral vasodilatation and primary insomnia.^28,29

Elinzanetant is a nonhormonal compound in development for the treatment of VMS associated with menopause that specifically targets both NK-1 and NK-3 receptors.^30,31 Based on clinical data, it was hypothesized that the dual inhibition of NK-1 and NK-3 receptors would reduce VMS and may have an effect on sleep disturbances associated with menopause.³⁰ Indeed, elinzanetant demonstrated significant reductions in VMS frequency and severity compared with placebo, as well as improvements in different aspects of sleep and menopause-related quality of life in the phase 2b SWITCH-1 trial.³⁰ The aim of the OASIS 1 (NCT05042362) and 2 (NCT05099159) phase 3 randomized, placebo-controlled studies was to assess the efficacy and safety of elinzanetant, 120 mg, in individuals experiencing moderate to severe VMS associated with menopause.

Methods

Study Design

OASIS 1 and 2 were pivotal, multicenter, multinational, double-blind, randomized, placebo-controlled, phase 3, 26-week intervention trials. The trials had similar designs and identical primary and key secondary end points in accordance with regulatory guidance to ensure the results were reliable and reproducible.³² The trial protocol and statistical analysis plan are in Supplement 1 and Supplement 2, respectively. The trials were conducted in parallel but involved different study sites mainly located in the US and Europe (eTables 1 and 2 in Supplement 3). The trials were conducted in accordance with the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines and reported using the CONSORT reporting guideline. Institutional review board and ethics committee approval were obtained for all study sites. Feedback from menopausal participants was collected to ensure that the patient voice was incorporated in aspects of the study design and assessments.³³ Detailed methodology of the OASIS 1 and 2 trials has been described in a previous publication.³³ Herein, we present the results from both OASIS 1 and 2 trials side by side to demonstrate the reproducibility of findings.

Participants

OASIS 1 and 2 included naturally or surgically (bilateral oophorectomy with or without hysterectomy) postmenopausal participants, aged 40 to 65 years and experiencing 50 or more moderate to severe VMS over 7 days during screening (Table 1 and Figure 1). Exclusion criteria included abnormal liver parameters (including alanine aminotransferase or aspartate aminotransferase >2 × upper limit of normal), disordered proliferative endometrium, endometrial hyperplasia or polyps, and current or history of malignancy within the last 5 years (except basal and squamous cell skin tumors).³³ Written informed consent was obtained from all participants prior to study start. Race and ethnicity were determined during the visit by participant and site personnel together and documented in the case report form as part of the demographic characteristics using fixed categories (ethnicity: Hispanic or Latino, not Hispanic or Latino, not reported and race: American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; White; not reported).

Table 1. Baseline Demographics of the Full Analysis Set in the OASIS 1 and 2 Trials.

Parameter	OASIS 1		OASIS 2
	Elinzanetant, 120 mg (n = 199)	Placebo (n = 197)	Elinzanetant, 120 mg (n = 200)	Placebo (n = 200)
Age, mean (SD), y	54.6 (4.9)	54.5 (4.9)	54.8 (5.0)	54.4 (4.5)
Race, No. (%)
American Indian or Alaska Native	1 (0.5)	1 (0.5)	1 (0.5)	1 (0.5)
Asian	2 (1.0)	1 (0.5)	0	1 (0.5)
Black or African American	38 (19.1)	38 (19.3)	35 (17.5)	25 (12.5)
White	151 (75.9)	154 (78.2)	163 (81.5)	172 (86.0)
Multiple	3 (1.5)	0	1 (0.5)	0
Not reported	4 (2.0)	3 (1.5)	0	1 (0.5)
Hispanic or Latino, No. (%)	17 (8.5)	14 (7.1)	13 (6.5)	24 (12.0)
BMI, mean (SD)	27.8 (4.8)	27.7 (4.5)	27.8 (4.8)	28.0 (4.7)
Smoking history, No. (%)
Never	150 (75.4)	115 (58.4)	117 (58.5)	135 (67.5)
Former	26 (13.1)	33 (16.8)	41 (20.5)	33 (16.5)
Current	23 (11.6)	49 (24.9)	42 (21.0)	32 (16.0)
Hysterectomy, No. (%)	84 (42.2)	82 (41.6)	69 (34.5)	74 (37.0)
Oophorectomy, No. (%)	51 (25.6)	49 (24.9)	24 (12.0)	40 (20.0)
Duration of being amenorrheic, mean (SD), ya	5.0 (4.4)	4.5 (4.0)	5.0 (4.4)	4.6 (3.8)
Moderate to severe vasomotor symptom baseline characteristics
Frequency, average daily, mean (SD)	13.4 (6.6)	14.3 (13.9)	14.7 (11.1)	16.2 (11.2)
Severity, average daily, mean (SD)b	2.6 (0.2)	2.5 (0.2)	2.5 (0.2)	2.5 (0.2)
PROMIS SD SF 8b total T score assessing severity of sleep disturbances, mean (SD)c	61.0 (7.7)	60.2 (7.2)	61.7 (6.2)	60.7 (7.2)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); PROMIS SD SF 8b, Patient-Reported Outcomes Measurement Information System Short Form 8b.

^a Calculated for participants in the safety analysis set who had no hysterectomy or oophorectomy reported in the medical history.

^b Score range: 0-3 (0 indicates no moderate or severe ; 2, moderate; and 3, severe vasomotor symptoms). Higher scores indicate greater vasomotor symptom severity.

^c Score range: 28.9-76.5 (<55 indicates normal; 55-60, mild; 60-70, moderate; and >70, severe sleep disturbance). Higher scores indicate greater severity of sleep disturbance.

Figure 1. Recruitment, Randomization, and Participant Flow in the OASIS 1 and OASIS 2 Trials.

“Did not complete study” indicates did not complete all phases of the trial including the last visit (follow-up).

^aSix participants withdrew consent and 1 was not rescreened per protocol.

^bThree participants (0.8%) in OASIS 1 were randomized but did not receive treatment intervention and were, therefore, excluded from the safety analysis sets. One participant in the placebo group of each trial incorrectly received elinzanetant initially, and both were assigned to the elinzanetant groups for analyses based on the safety analysis set.

^cNo information provided by investigator.

^dWithdrew because of work.

Randomization

In both trials, eligible participants were randomized in a 1:1 ratio to receive elinzanetant, 120 mg, or identical-appearing placebo once daily orally for 12 weeks. After 12 weeks, all participants received elinzanetant, 120 mg, for a further 14 weeks, followed by a 4-week posttreatment follow-up. Randomization was performed centrally using an interactive voice/web response system and stratified by North America and the rest of the countries. Investigators, participants, and study personnel remained blinded throughout the trials. The interactive voice/web response system was programmed with blind-breaking instructions in the event of an emergency.

Efficacy Assessments

The phase 3 end point strategy was developed in alignment with regulatory recommendations and clinical practice.^32,33,34 Efficacy end points in both trials were assessed using patient-reported outcome instruments collected on an electronic handheld device. Considerable research has been conducted to confirm the fitness for use of the patient-reported outcome instruments in assessing key efficacy end points in phase 3 VMS trials.^35,36,37 Primary and key secondary end points were identical across the OASIS 1 and 2 trials (eTable 3 in Supplement 3). The prespecified primary end points included mean change in frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12, as measured by the electronic hot flash daily diary. The prespecified key secondary end points included mean change in moderate to severe VMS frequency from baseline to week 1 also measured by the hot flash daily diary, as well as mean changes in the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b total T score and the Menopause-Specific Quality of Life (MENQOL) questionnaire total score from baseline to week 12. The proportion of participants with at least a 50% reduction in VMS frequency at weeks 4 and 12 was an exploratory end point. For additional secondary and exploratory end points, see the statistical analysis plan in Supplement 2 (results not reported here).

The electronic hot flash daily diary was used to record the frequency and severity of VMS twice daily (in the morning when getting up and in the evening when going to bed) on a dedicated handheld device, similar to diaries used in other clinical trials in participants with VMS.³⁸ Participants were trained on the use of the handheld device for timely and accurate data entry during screening. Participants recorded whether or not they had hot flashes, followed by rating the total number of mild, moderate, and severe hot flashes they experienced. Mild hot flashes were defined as a sensation of heat without sweating, moderate as a sensation of heat with sweating but able to continue activity, and severe as a sensation of heat with sweating that causes cessation of activity.³² Possible ranges were 0 to 180 for the VMS frequency score and 0 to 3 for the VMS severity score.

The PROMIS SD SF 8b questionnaire is a short form derived from the 27-item PROMIS SD item bank.^39,40,41 It assesses the degree of sleep disturbance over the past 7 days, with the 8 items particularly investigating restless sleep, satisfaction with sleep, refreshing sleep, difficulties falling asleep, staying asleep, getting to sleep, amount of sleep, and sleep quality. Items were scored on a 5-point Likert scale, and the 8 single item scores were summed to yield total raw scores (range, 8-40), which were converted to total T scores for analysis of the key secondary end point (range, 28.9-76.5). Higher scores indicated more disturbed sleep. A T score of 50 (SD, 10) represented the mean sleep disturbance score in a reference population. T scores of 55 or greater, 60 or greater, and 70 or greater represented mild, moderate, and severe levels of sleep disturbances, respectively, in the reference population.^42,43 Participants completed the questionnaire at baseline and weeks 1 through 4, 8, 12, 16, 26, and 30.

The 29-item MENQOL questionnaire assesses the presence and degree of bother associated with menopausal symptoms over the past week.⁴⁴ Participants indicated whether or not they experienced a particular symptom and rated its level of bother on a 7-point scale (range, 0-6, with higher scores indicating a higher level of bother). The 29 items assess 4 domains of symptoms and functioning: VMS (items 1-3), psychosocial (items 4-10), physical (items 11-26), and sexual (items 27-29) domains. Responses to single items were used to calculate 29 individual item scores. The 4 domain scores were calculated as a mean of converted single-item scores (range, 1-8, with higher scores indicating a higher level of bother), and the mean of the 4 domain scores yielded the MENQOL total score. Participants completed the questionnaire at baseline and weeks 4, 8, 12, 16, 26, and 30. The development and validation of PROMIS SD SF 8b and MENQOL and their use in VMS clinical trials have been described previously.^{30,33,35,36,37,44,45,46,47,48}

Safety

Safety was assessed throughout the trials by documenting adverse events (AEs), which were coded using the Medical Dictionary for Regulatory Authorities. Safety assessments also included laboratory assessments, transvaginal ultrasonography, and endometrial biopsies, among others. Consistent with FDA guidance, participants meeting the prespecified criteria for close liver observation, including those with increases in alanine aminotransferase and aspartate aminotransferase levels greater than 3 times the upper limit of normal, were followed up. These cases were assessed in a blinded fashion by an independent external liver safety monitoring board to identify potential drug-induced liver injury.⁴⁹ An independent data and safety monitoring board monitored the general safety of the participants in the trials.

Statistical Analysis

A planned sample size of 370 participants per trial was derived based on simulations using the t test and Wilcoxon rank-sum test, considering an assumed drop-out rate of 10% in the first 3 months. Treatment effects and characteristics of the distributions were assumed from phase 2 SWITCH-1 results and a fixed level of correlation of 0.3 was anticipated between the end points. The trials were planned to achieve a power of at least 90% for all primary and key secondary end points considering the multiple testing strategy.

Statistical analysis was performed using SAS (release 9.4; SAS Institute Inc) and ValidR (R version 3.5.2⁵⁰; Mango Solutions Ltd). Efficacy analyses were performed on the full analysis set where all randomized participants were included. Participants in the full analysis set were analyzed according to the randomized intervention (intention to treat). Safety analyses were performed on the safety analysis set that included all participants who received at least 1 dose of study intervention. Participants in the safety analysis set were analyzed according to the intervention they received.

The primary and key secondary end points were analyzed for each trial using a mixed model with repeated measures on the change from baseline at different weeks. Fixed effects in the model included baseline values of the respective end point, treatment, region, and week, as well as the interaction terms baseline by week and treatment by week. Prior to modeling, missing and collected data that occurred in the presence of intercurrent events were handled in alignment with the predefined estimand, as provided in eTable 4 in Supplement 3.⁵¹ A multiplicity adjustment strategy for each trial was defined using the graphical approach,⁵² controlling the overall type I error rate at a 1-sided α level of .025 for confirmatory statistical superiority testing. All presented P values are from 1-sided statistical testing. Full details of the statistical analysis, including assessed model diagnostics and sensitivity analysis, are provided in the statistical analysis plan in Supplement 2.

Results

Participants

OASIS 1 was conducted between August 27, 2021, and November 27, 2023, across 77 sites in the US, Europe, and Israel. OASIS 2 was conducted between October 29, 2021, and October 10, 2023, across 77 sites in Canada, the US, and Europe (eTables 1 and 2 in Supplement 3). The participant disposition is summarized in Figure 1. Baseline demographics were generally balanced between treatment groups in both trials, with slight imbalances in smoking history in opposite directions in the 2 studies (Table 1).

VMS

At baseline, OASIS 1 participants in the elinzanetant and placebo groups experienced a mean (SD) of 13.4 (6.6) and 14.3 (13.9) VMS per 24 hours, respectively; similar numbers of VMS, 14.7 (11.1) and 16.2 (11.2), respectively, were observed in OASIS 2. In OASIS 1, mean (SD) descriptive changes from baseline to week 4 were −7.5 (5.8) and −4.4 (6.7) in the elinzanetant and placebo groups, respectively, corresponding to a mean (SD) percentage change from baseline of −55.9% (34.1%) and −31.4% (33.8%). At week 12, these changes were −8.7 (6.7) and −5.5 (10.2), respectively, with mean (SD) percentage changes of −65.2% (35.3%) and −42.2% (43.3%). In OASIS 2, similar trends were seen, with mean (SD) changes from baseline to week 4 of −8.6 (9.2) and −6.1 (8.9), corresponding to mean (SD) percentage changes of −57.9% (34.7%) and −35.7% (37.4%). Mean (SD) changes to week 12 were −10.0 (10.3) and −7.2 (8.5) and mean (SD) percentage changes were −67.0% (34.9%) and −45.9% (38.1%), respectively (Figure 2; eFigures 1 and 2, eTables 5 and 6 in Supplement 3).

Figure 2. Change From Baseline in Average Daily Vasomotor Symptom (VMS) Frequency and Severity by Treatment Group and Study.

Score range 0-3 (0 indicates no moderate or severe vasomotor symptoms [at baseline] and no mild, moderate, or severe vasomotor symptoms [post baseline]; 1, mild; 2, moderate; and 3, severe symptoms; higher scores indicate greater vasomotor symptom severity). Data shown are means (95% CIs). Zoomed-in presentation along the y-axis for illustration purposes. Only outliers within the displayed scale are visible. Connecting lines over time join arithmetic means by treatment group. A boxplot presentation of the full distribution is provided in eFigure 1 in Supplement 3 and the descriptive summary and data range are available in eTable 5 in Supplement 3. Placebo-elinzanetant, 120 mg, refers to the participants receiving placebo who were switched to receive elinzanetant after week 12. Efficacy analyses were performed on the full analysis set. The circles indicate outside values.

At baseline, OASIS 1 participants in the elinzanetant and placebo groups experienced a mean (SD) of 2.6 (0.2) and 2.5 (0.2) in VMS severity, respectively; in OASIS 2, baseline severity was 2.5 (0.2) and 2.5 (0.2), respectively. Reductions were also seen for VMS severity from baseline to weeks 4 and 12 in both studies based on descriptive statistics, with greater mean numerical reductions in the elinzanetant groups than the placebo groups (Figure 2; eFigure 3 and eTable 7 in Supplement 3).

In both trials, reductions in VMS frequency and severity from baseline to weeks 4 and 12 were statistically significantly greater for elinzanetant vs placebo. Least square (LS) mean changes in daily VMS frequency vs placebo from baseline to week 4 were −3.3 (95% CI, −4.5 to −2.1; P < .001) for OASIS 1 and −3.0 (95% CI, −4.4 to −1.7; P < .001) for OASIS 2. At week 12, LS mean changes from baseline vs placebo were −3.2 (95% CI, −4.8 to −1.6; P < .001) for OASIS 1 and −3.2 (95% CI, −4.6 to −1.9; P < .001) for OASIS 2. Reductions in daily VMS frequency vs placebo from baseline to week 1 were statistically significant in both trials (OASIS 1: −2.5 [95% CI, −3.4 to −1.6], P < .001; OASIS 2: −1.7 [95% CI, −2.7 to −0.6], P = .001). LS mean changes in daily VMS severity vs placebo from baseline to week 4 were −0.3 (95% CI, −0.4 to −0.2; P < .001) in OASIS 1 and −0.2 (95% CI, −0.3 to −0.1; P < .001) in OASIS 2. At week 12, changes from baseline vs placebo were −0.4 (95% CI, −0.5 to −0.3; P < .001) in OASIS 1 and −0.3 (95% CI, −0.4 to −0.1; P < .001) in OASIS 2.

At week 4, 62.8% and 62.2% of participants in the elinzanetant group achieved at least a 50% reduction in VMS frequency in OASIS 1 and 2, respectively, compared with 29.2% and 32.3% in the placebo group. At week 12, 71.4% and 74.7% in the elinzanetant group achieved at least a 50% reduction in OASIS 1 and 2, respectively, compared with 42.0% and 48.3% in the placebo group.

Sleep Disturbances

Participants reported improvements from baseline in sleep disturbances (assessed by the PROMIS SD SF 8b total T scores) across both treatment groups (Figure 3; eFigure 4 and eTable 8 in Supplement 3); differences were statistically significant at week 12 vs placebo in both trials (difference in LS means for OASIS 1: −5.6 [95% CI, −7.2 to −4.0], P < .001; OASIS 2: −4.3 [95% CI, −5.8 to −2.9], P < .001). Improvements were also observed with PROMIS total raw scores, based on descriptive analyses (eTable 9 in Supplement 3).

Figure 3. Change From Baseline in PROMIS SD SF 8b Total T Score^a and MENQOL Total Score^b by Treatment Group and Study.

A reduction in Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS SD SF 8b) total T score and Menopause-Specific Quality of Life (MENQOL) questionnaire total score corresponded to an improvement in symptoms. Efficacy analyses were performed on the full analysis set. Connecting lines over time join arithmetic means by treatment group. The circles indicate outside values.

^aFor PROMIS SD SF 8b, the score ranges from 28.9 to 76.5 (<55, normal; 55-60, mild; 60-70, moderate; and >70, severe sleep disturbance). Higher scores indicate greater severity of sleep disturbance.

^bFor MENQOL, the score ranges from 1 to 8; higher scores indicate greater bother; and 0.9-point within-patient change represent a clinically meaningful difference.

Menopause-Related Quality of Life

Participants reported improvements in menopause-related quality of life (assessed by the MENQOL total score) from baseline (Figure 3; eFigure 5 and eTable 10 in Supplement 3). Improvements seen in the elinzanetant group from baseline to week 12 were statistically significant vs placebo (difference in LS means for OASIS 1: −0.4 [95% CI, −0.6 to −0.2], P < .001; OASIS 2: −0.3 [95% CI, −0.5 to −0.1], P = .0059).

Based on descriptive analyses, the largest changes from baseline were observed in the VMS domain. At week 12, the mean (SD) changes from baseline in the VMS domain score in the elinzanetant group were −2.86 (2.11) in OASIS 1 and −2.70 (1.99) in OASIS 2. In the placebo group, the mean changes from baseline were −1.50 (1.80) and −1.64 (1.93), respectively, at week 12.

Efficacy During Weeks 13 Through 26

Reductions in the frequency and severity of VMS, PROMIS SD SF 8b total T score, and MENQOL total score in the elinzanetant group were maintained throughout the 26-week treatment period. Further improvements in these measures were also observed in the group that switched from placebo to elinzanetant after week 12 (eTables 5-10 and eFigures 2-5 in Supplement 3) based on descriptive analyses.

By week 26, more than 80% of participants had achieved at least a 50% reduction in VMS frequency in the elinzanetant group (81.6% and 81.5% in OASIS 1 and 2, respectively) and in those who switched to elinzanetant after week 12 (84.5% and 86.7% in OASIS 1 and 2, respectively).

Safety

In OASIS 1, treatment-emergent adverse events (TEAEs) were reported in 51.3% of participants in the elinzanetant group and 48.5% in the placebo group over the 12-week placebo-controlled treatment period (Table 2; eTables 11 and 12 in Supplement 3). In OASIS 2, 44.3% and 38.2% of participants reported TEAEs in the elinzanetant and placebo groups, respectively. In both trials, most TEAEs were of mild or moderate intensity, and there were few serious AEs (eTables 11 and 12 in Supplement 3).

Table 2. Treatment-Emergent Adverse Events (TEAEs) in the 12-Week Placebo-Controlled Period in the Safety Analysis Set.

No. of participants with TEAEa	No. (%)
	OASIS 1		OASIS 2
	Elinzanetant, 120 mg (n = 199)	Placebo (n = 194)	Elinzanetant, 120 mg (n = 201)	Placebo (n = 199)
Any TEAE	102 (51.3)	94 (48.5)	89 (44.3)	76 (38.2)
Serious TEAEs	4 (2.0)	2 (1.0)	1 (0.5)	1 (0.5)
Study drug-related TEAEsb	43 (21.6)	28 (14.4)	40 (19.9)	18 (9.0)
TEAEs leading to study discontinuation	17 (8.5)	13 (6.7)	13 (6.5)	4 (2.0)
Most frequently reported TEAEs
Headache	14 (7.0)	5 (2.6)	18 (9.0)	5 (2.5)
Fatigue	14 (7.0)	3 (1.5)	11 (5.5)	3 (1.5)
Arthralgia	10 (5.0)	10 (5.2)	5 (2.5)	2 (1.0)

^a Coded using Medical Dictionary for Regulatory Activities version 26.1 for OASIS 1 and version 26.0 for OASIS 2.

^b The relationship between study drug and TEAE was assessed by the investigator based on their clinical judgment, considering alternative causes and the temporal relationship between study drug administration and the occurrence of the TEAE.

Across both trials, headache and fatigue (Medical Dictionary for Regulatory Activities preferred term) occurred more frequently in the elinzanetant groups during the 12-week, placebo-controlled treatment period (7.0%-9.0% vs 2.5%-2.6% for headache and 5.5%-7.0% vs 1.5% for fatigue) (Table 2). Both fatigue and headache were reported less frequently by participants in the placebo group after switching to elinzanetant compared with those initially randomized to elinzanetant (2.2%-3.6% for headache and 0.6%-1.7% for fatigue during weeks 13-26) (eTable 13 in Supplement 3). Most events were of mild intensity, and none were severe. Based on a post hoc analysis, for fatigue, the highest reported daily relative frequency (up to 5%) was observed during the first weeks, which was then reduced to less than 3% after week 13. For headache, the highest daily relative frequency (up to 5.5%) was reported around week 7 to 8 and reduced to less than 2% toward the end of the treatment period.

There were no cases of liver enzyme elevations meeting criteria for liver injury as assessed by the liver safety monitoring board. There were no cases of endometrial hyperplasia or malignant neoplasm in either trial as assessed by 3 independent pathologists. There were no clinically relevant changes in vital signs or laboratory parameters throughout the study, and no new safety signals were observed throughout either trial (eTable 13 in Supplement 3).

Discussion

OASIS 1 and 2 are the first phase 3 trials evaluating the efficacy and safety of elinzanetant—a nonhormonal, selective NK-1 and NK-3 receptor antagonist—in postmenopausal individuals with moderate to severe VMS. Results from both studies are consistent with regard to the primary and key secondary end points and in line with previous results of the phase 2 study SWITCH-1,³⁰ thereby demonstrating the reproducibility of and increasing confidence in these findings. In both OASIS 1 and 2 trials, elinzanetant achieved statistically significant reductions from baseline in VMS frequency and severity vs placebo as well as improvements in sleep disturbances and menopause-related quality of life.

A reduction of at least 2 moderate to severe VMS per day above placebo (14 per week) has been identified by the FDA as a clinically meaningful reduction on a group level.^53,54 Considering this, elinzanetant reached a clinically meaningful reduction in daily VMS frequency compared with placebo as early as week 1 in OASIS 1, and at weeks 4 and 12 in both trials. In addition, a reduction from baseline in VMS frequency of at least 50% has been described in the literature as a relevant improvement on an individual level.⁵⁵ Based on descriptive analyses, more than 70% of participants in the elinzanetant group achieved a response by week 12, and more than 80% of participants achieved a response by the end of treatment using this threshold. These results have clinically relevant implications because VMS often pose significant impacts on menopausal individual’s overall health, everyday activities, sleep, quality of life, and work productivity.^{4,5,6,8,9,10,11,12}

Nighttime VMS can affect sleep quantity and quality, but sleep disturbances experienced during menopause can occur independently of VMS.⁵⁶ Sleep disturbances can substantially impair quality of life during menopause^1,3,4 and additionally have implications for women’s physical health as they age.¹³ Individuals experiencing menopausal sleep disturbances often use sleep medications such as benzodiazepines,⁵⁷ which can be associated with increased risk of falls as well as dependence or overuse.^58,59 Studies have reported mixed results regarding the efficacy of hormone therapy in addressing sleep problems among those with and without VMS.^60,61,62 A small, double-blind, randomized crossover study in healthy male volunteers showed the involvement of SP (NK-1 receptor ligand) in sleep. After intravenous infusion of SP, both polysomnography and subjective sleep ratings indicated a significant decrease in sleep quantity and quality.⁶³ Improvements in wakefulness after sleep onset in primary insomnia have been shown for an NK-1–specific receptor antagonist.²⁹ However, a role for SP/NK-1 receptors in sleep disturbance associated with menopause has not previously been established. Elinzanetant demonstrated significant reductions in sleep disturbance and improvements in sleep quality in the SWITCH-1 study.³⁰ In OASIS 1 and 2, at baseline, participants were on average experiencing moderate sleep disturbances according to the PROMIS SD SF 8b total T score classification established in a reference population (eTable 8 in Supplement 3).⁴² Following treatment with elinzanetant, mean scores were reduced to the normal range according to the cut points published for the reference population; while scores in the placebo group only fell within the mild sleep disturbance range.⁴² These data confirm that elinzanetant, as a selective dual NK-1,3 receptor antagonist, improves sleep disturbances in menopausal women.

A decrease in MENQOL total score of at least 0.9 from baseline has been identified as a clinically relevant response to treatment.³⁴ On average, both elinzanetant, 120 mg, and placebo demonstrated a clinically relevant improvement in menopause-related quality of life from baseline to week 12 using this threshold.³⁷ However, elinzanetant demonstrated statistically significant greater improvements in menopause-related quality of life compared with placebo. Further improvements up to 26 weeks were also observed in the participants who switched to elinzanetant after week 12. Consistent with reported findings from SWITCH-1, the MENQOL total score in OASIS 1 and 2 is considered to be predominantly driven by the VMS domain score. This is consistent with the impact of elinzanetant on reducing VMS frequency and severity. The improvements in the VMS domain are suggested to have a beneficial effect on other aspects of quality of life over time.

Elinzanetant maintained a favorable safety profile in line with its phase 2b clinical trial.³⁰ The most frequently reported adverse events in the elinzanetant group during the 12-week placebo-controlled period were headache and fatigue. In participants who switched from placebo to elinzanetant after week 12, few cases of headache and fatigue were reported. No incidences of endometrial hyperplasia or malignant neoplasm were seen in either trial.

Increases in liver enzymes were closely monitored in the OASIS trials due to previous concerns of elevations in liver transaminases with NK-3 receptor antagonists.^26,27,64 No incidences of liver toxicity were observed with elinzanetant in the OASIS 1 and 2 trials. Overall, the safety profile of elinzanetant was favorable when compared with placebo in the OASIS 1 and 2 studies over 12 weeks and with extended use up to 26 weeks. Additional safety data will be available from the 52-week, placebo-controlled OASIS 3 study (NCT05030584).

The OASIS 1 and 2 trials had a number of strengths. Both were randomized, double-blind, multinational, and placebo-controlled trials specifically designed to evaluate the efficacy of elinzanetant for the treatment of VMS, while also assessing the effect of elinzanetant on sleep disturbances and menopause-related quality of life. Results demonstrated high reproducibility, with treatment effects consistent across all primary and key secondary end points over time.

Limitations

The OASIS 1 and 2 trials had some limitations. First, all data for the primary and key secondary end points were collected electronically using diaries or questionnaires (patient-reported outcomes). Such measures are appropriate for measuring end points such as VMS, sleep disturbance, and menopause-related quality of life, which are highly influenced by participant perception. In addition, these can be associated with considerable participant burden. The subjective nature of patient-reported outcomes, together with regression to the mean symptom burden over time and the caring effect experienced during the study, may help explain the placebo response seen in these and other similar clinical trials.^65,66 Of note, this is an aspect common to studies investigating VMS treatments, with a recent meta-analysis demonstrating VMS placebo responses typically ranging from 34% to 67%.⁶⁷

Second, the OASIS 1 and 2 trials included only individuals with VMS who were naturally or surgically postmenopausal. Similar to other VMS trials, the participants were primarily White, with 12% to 19% Black or African American and less than 10% Hispanic or Latino. Significant unmet needs remain for other populations of individuals experiencing VMS, such as perimenopausal individuals and those experiencing VMS due to endocrine therapy for breast cancer. OASIS 4 (NCT05587296) will assess the efficacy and safety of elinzanetant among individuals with or at high risk of breast cancer receiving tamoxifen or aromatase inhibitors.

Third, the participants in the OASIS 1 and 2 trials were not required to have sleep disturbances to be included. Although significant reductions in sleep disturbances were seen compared with placebo, further characterization is needed to assess the effect of elinzanetant in populations with sleep disturbances associated with menopause.

Conclusions

OASIS 1 and 2 were 2 similar pivotal phase 3 trials performed across different sites and countries that separately demonstrated the efficacy of elinzanetant for the treatment of VMS associated with menopause. Elinzanetant demonstrated a rapid improvement in VMS frequency at 1 week and robust improvements in VMS severity, sleep disturbances, and menopause-related quality of life, and has a favorable safety profile. Elinzanetant has the potential to provide a well-tolerated and efficacious nonhormonal treatment option to address the unmet health needs of many menopausal individuals with moderate to severe VMS.

Supplement 1.

Trial Protocol

Supplement 2.

Statistical Analysis Plan

Supplement 3.

eTable 1. OASIS 1 Sites Summary

eTable 2. OASIS 2 Sites Summary

eTable 3. Primary and Key Secondary Endpoints

eTable 4. Main Estimand: Intercurrent Events and Strategies to Address Them

eTable 5. Mean Change From Baseline in Average Daily Moderate-to-Severe Vasomotor Symptom Frequency Over Time by Treatment Arm and Study

eFigure 1. Change From Baseline in Average Daily Vasomotor Symptom Frequency in OASIS 1 (Top) and OASIS 2 (Bottom)

eFigure 2. Mean Change From Baseline in Average Daily Moderate-to-Severe Vasomotor Symptom Frequency Over Time in OASIS 1 (Top) and OASIS 2 (Bottom)

eTable 6. Percentage Change From Baseline in Average Daily Moderate-to-Severe Vasomotor Symptom Frequency Over Time by Treatment Arm and Study

eTable 7. Mean Change From Baseline in Average Daily Vasomotor Symptom Severity Over Time by Treatment Arm and Study

eFigure 3. Mean Change From Baseline in Average Daily Vasomotor Symptom Severity Over Time in OASIS 1 (Top) and OASIS 2 (Bottom)

eTable 8. Mean Change From Baseline in PROMIS SD SF 8b Total T-Scores Over Time by Treatment Arm and Study

eTable 9. Mean Change From Baseline in PROMIS SD SF 8b Total Raw Scores Over Time by Treatment Arm and Study

eFigure 4. Mean Change From Baseline in PROMIS SD SF 8b Total T-Scores Over Time in OASIS 1 (Top) and OASIS 2 (Bottom)

eTable 10. Mean Change From Baseline in MENQOL Total Score Over Time by Treatment Arm and Study

eFigure 5. Mean Change From Baseline in MENQOL Total Score Over Time in OASIS 1 (Top) and OASIS 2 (Bottom)

eTable 11. Treatment-Emergent Adverse Events in OASIS 1 by Treatment Arm and During Elinzanetant Exposure

eTable 12. Treatment-Emergent Adverse Events in OASIS 2 by Treatment Arm and During Elinzanetant Exposure

eTable 13. Summary of Treatment-Emergent Adverse Events During Elinzanetant Period (Weeks 13–26) and Treatment-Emergent Adverse Events During Elinzanetant Exposure (Weeks 1–26)

Supplement 4.

Data Sharing Statement