Elinzanetant a promising nonhormone treatment option for VMS, sleep problems

The selective neurokinin (NK)-1,3 receptor antagonist elinzanetant appears to be beneficial in the treatment of vasomotor symptoms (VMS) and associated sleep disturbance in postmenopausal women, as shown in the results of the phase IIb SWITCH-1 trial.

Elinzanetant targets the receptors NK-3 and NK-1, which have been implicated in the aetiology of VMS and sleep disturbances associated with menopause, according to the investigators.

Compared with placebo, elinzanetant 120 and 160 mg led to substantial reductions in the mean daily frequency of moderate-to-severe VMS. The reductions associated with the 120-mg dose were significant at weeks 4 (−3.93; p<0.001) and 12 (−2.95; p=0.01), while those associated with the 160-mg dose were significant only at week 4 (−2.63; p=0.01) but not week 12 (−1.78; p=0.13). [Menopause 2023;doi:10.1097/GME.0000000000002138]

Both doses also yielded clinically meaningful improvements in measures of sleep (night-time awakenings, Insomnia Severity Index [ISI], and Pittsburgh Sleep Quality Index [PSQI]) and quality of life (Menopause-specific Quality-of-Life intervention version [MenQoL-I]).

“Reductions in VMS frequency compared with placebo at the 120-mg dose were similar to those seen with hormone therapy and NK-3R antagonists and met the threshold for clinical relevance of a reduction of two or more per day beyond that achieved by placebo,” the investigators noted. [Menopause 2020;27:382-392; Lancet 2017;389:1809–1820; Obstet Gynecol 2018;132:161–170; Menopause 2009;16:1116-1124]

As for safety, all doses of elinzanetant were well tolerated. A total of 235 treatment-emergent adverse events (TEAEs) occurred in 67.8 percent (103 of 152) of participants in the elinzanetant groups, while 80 TEAEs were documented in 60 percent (28 of 47) of participants in the placebo group. TEAEs were mostly mild or moderate in severity, with headache, somnolence, and diarrhoea being the most common across all treatment groups.

“The findings of this study further support the potential of NK signaling for the rapid treatment of VMS. Elinzanetant 120 mg and 160 mg led to meaningful reductions in VMS frequency after only 1 week of treatment. This is consistent with results from RELENT-1, in which similarly rapid reductions in VMS frequency were shown with a 150-mg dose of elinzanetant, and studies of NK-3R antagonists that demonstrate maximum efficacy within weeks,” according to the investigators. [Menopause 2020;27:382-392; Lancet 2017;389:1809-1820]

Elinzanetant may exert effects on VMS via suppression of KNDy neuron hyperactivation and on peripheral vasodilatation through NK-1R antagonism in peripheral blood vessels, they pointed out. [Menopause 2018;25:862-869]

“The 120-mg dose offers clinically important efficacy across a range of menopause-related symptoms with the most favourable benefit/risk profile. Elinzanetant demonstrated a generally dose-ordered response across all efficacy outcomes with no additional benefit observed with the 160-mg dose, suggesting a plateau of effect at 120 mg,” the investigators said.

SWITCH-1 sets the groundwork for a full safety and efficacy study, with elinzanetant 120 mg chosen as the dose that will be further evaluated in a phase III program, they added.