Long-Term Data Support Non-Hormonal Drug for Hot-Flash Management

CHICAGO — The non-hormonal drug elinzanetant reduced the frequency of moderate-to-severe hot flashes in postmenopausal women, and seemed to have a favorable safety profile, according to long-term OASIS 3 trial data.

Women with moderate-to-severe vasomotor symptoms (VMS) treated with elinzanetant for 12 weeks had an average of 1.6 hot flashes per day compared to 3.4 per day with placebo (least-squares mean difference between elinzanetant and placebo from baseline -1.6, 95% CI -2.0 to -1.1, P<0.0001), reported James A. Simon, MD, of George Washington University and IntimMedicine Specialists in Washington, in a poster presentation at the Menopause Society annual meeting.

This is consistent with earlier findings from OASIS 1 and 2, which showed significant reductions in VMS frequency at weeks 4 and 12 compared to placebo. The reductions were maintained up to week 50, Simon said. Safety assessments at week 52 showed no Hy’s law (a measure of drug-induced liver injury) cases, and no indication of cholestatic injury.

“This is a new, very promising treatment for hot flashes — non-hormonal — that persists in its efficacy for 52 weeks and seems to have very minimal, if any, liver effects,” Simon told MedPage Today. “That’s historic.”

Safety assessments also found no cases of endometrial hyperplasia or malignant neoplasm, no hepatotoxicity signal, and changes in bone mineral density consistent with expected age-related loss.

Elinzanetant is an investigational dual neurokinin-1 and 3 (NK-1 and 3) receptor antagonist being evaluated by the FDA (the developer submitted a New Drug Application in August) for the treatment of moderate to severe VMS associated with menopause. NK-3 may be involved in the disrupted thermoregulation that accompanies declining estrogen during menopause, and NK-1 may play a role in sleep and peripheral vasodilation. Fezolinetant (Veozah), an approved drug in the same category, recently underwent a label update requiring liver blood testing after the agency received a postmarket report of liver injury.

Non-hormonal options may be a good option for women who are untreated for menopause symptoms or who have contraindications for hormone therapy option, wrote Stephanie Faubion MD, MBA, of the Mayo Clinic in Jacksonville, Florida, and colleague, in a JAMA editorial accompanying the OASIS 1 and 2 results.

“It is important to note that menopause symptoms such as VMS rarely exist in isolation, and often co-occur in symptom clusters,” Faubion stated. “Thus, drugs that can target multiple symptoms associated with menopause are more appealing than the need for multiple treatments to separately address VMS, sleep and mood disturbances, weight gain, and brain fog, for example.”

The OASIS 3 trial enrolled 628 naturally or surgically postmenopausal women who experienced moderate to severe VMS. They were randomized to receive either once daily 120-mg elinzanetant or placebo orally. The mean age was around 55, around 80% of the women were white, and the mean frequency of VMS was around seven per day. Participants recorded VMS in a daily diary.

Secondary patient-reported outcomes (PROs) included the mean change from baseline in sleep disturbances, measured with the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b total T-score, and in quality of life, measured by the Menopause-Specific Quality of Life (MENQOL) total score.

On PROMIS SD SF 8b, the mean changes from baseline to week 52 were -9.4 and -5.7 for elinzanetant and placebo groups, respectively, from baseline means of 57.4 and 58. On the MENQOL, mean changes were -1.3 and -1.1 for elinzanetant versus placebo, from baseline scores of 4.1 and 4.4.

Of the women in the elinzanetant and placebo groups, 70% and 61.1%, respectively, experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs experienced by more than 5% of participants in any treatment group were headache, COVID-19, and fatigue. In the treatment and placebo groups, 4.2% and 1.9% of participants had serious TEAEs. No TEAEs were considered by the investigators to be treatment-related.

Study limitations included the primarily white patient population and the use of PROs. The trial did not include perimenopausal women or those with VMS from endocrine therapy due to breast cancer. OASIS 4 will assess safety and efficacy of elinzanetant among those on anticancer therapy and with a high risk of breast cancer.