Nonhormonal drug for hot flash scores big in two phase III trials

The novel neurokinin-1 and -3 receptor antagonist elinzanetant appears to reduce the frequency and severity of vasomotor symptoms (VMS), as well as improve sleep and menopause-related quality of life, as shown in two pivotal phase III trials.

In postmenopausal participants between 40 and 65 years of age who were experiencing moderate-to-severe VMS, VMS frequency dropped significantly with elinzanetant than with placebo at week 4 (OASIS 1: −3.3; OASIS 2: −3.0; p<0.001 for both) and week 12 (OASIS 1: −3.2; OASIS 2: −3.2; p<0.001 for both). Likewise, VMS severity decreased more with elinzanetant vs placebo at week 4 (OASIS 1: −0.3; OASIS 2: −0.2; p<0.001 for both) and week 12 (OASIS 1: −0.4; OASIS 2: −0.3; p<0.001 for both). [JAMA 2024;332:1343-1354]

At week 4, significantly more participants in the elinzanetant arm achieved at least a 50-percent reduction in VMS frequency than in the placebo group in OASIS 1 (62.8 percent vs 29.2 percent) and 2 (62.2 percent vs 32.3 percent). These numbers further increased at week 12 (OASIS 1: 71.4 percent vs 42.0 percent; OASIS 2: 74.7 percent vs 48.3 percent).

“A reduction of at least two 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. 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,” the investigators noted. [https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204516Orig1s000CrossR.pdf]

“In addition, a reduction from baseline in VMS frequency of at least 50 percent has been described in the literature as a relevant improvement on an individual level… 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,” they added. [Menopause 2024;31:512-521; Menopause 2023;30:887-897; Menopause 2024;31:202-208; Am J Obstet Gynecol 2023;230:342.e1-342.e8; Neurology 2023;100:e133-e141]

Sleep and quality of life

Beyond the primary endpoints, elinzanetant outperformed placebo on secondary endpoints.

Sleep disturbances, as assessed by the PROMIS SD SF* 8b total T scores, at week 12 decreased by −5.6 with the investigational drug vs placebo in OASIS 1 (p<0.001) and by −4.3 in OASIS 2 (p<0.001). The same was true for menopause-related quality of life, as measured by the MENQOL** total score, with a between-group difference of −0.4 in OASIS 1 (p<0.001) and −0.3 in OASIS 2 (p=0.0059).

Safety

“Elinzanetant maintained a favourable safety profile in line with its phase IIb clinical trial,” the investigators said. [Menopause 2023;30:239-246]

Over the 12-week treatment period, treatment-emergent adverse events (TEAEs) occurred in 51.3 percent of participants in the elinzanetant group and 48.5 percent in the placebo group in OASIS 1 and in 44.3 percent and 38.2 percent, respectively, in OASIS 2.

The most frequently reported TEAEs with elinzanetant were headache (7.0–9.0 percent vs 2.5–2.6 percent) and fatigue (5.5–7.0 percent vs 1.5 percent). Few cases of headache and fatigue were documented among participants who switched from placebo to elinzanetant after week 12. There were no cases of endometrial hyperplasia or malignant neoplasm seen in either trial.

“OASIS 1 and 2 are the first phase III trials evaluating the efficacy and safety of elinzanetant … in postmenopausal individuals with moderate to severe VMS. Results from both studies are consistent with regard to the primary and key secondary endpoints and in line with previous results of the phase II study SWITCH-1, thereby demonstrating the reproducibility of and increasing confidence in these findings,” the investigators said. [Menopause 2023;30:239-246]

OASIS 1 included 396 participants (mean age 54.6 years), while OASIS 2 comprised 400 (mean age 54.6 years). These participants were randomly assigned to receive elinzanetant 120 mg orally daily for 26 weeks (OASIS 1: n=199; OASIS 2: n=200) or matching placebo for 12 weeks followed by elinzanetant 120 mg for 14 weeks (OASIS 1: n=197; OASIS 2: n=200). In total, 78.0 percent and 81.0 percent of participants completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean VMS over 24 hours were 13.4 vs 14.3 in OASIS 1 and 14.7 vs 16.2 in OASIS 2. The respective baseline VMS severity was 2.6 vs 2.5 in OASIS 1 and 2.5 vs 2.5 in OASIS 2.

*Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form
**Menopause-Specific Quality of Life