Elinzanetant Significantly Improves Vasomotor Symptoms

CHICAGO — The nonhormonal investigational drug elinzanetant led to significant improvement in hot flashes as well as sleep disturbance and quality of life, according to data from three randomized controlled trials presented at The Menopause Society 2024 Annual Meeting on September 12 in Chicago. Two phase 3 trials, OASIS 1 and 2, were also published in JAMA, and the longer-term OASIS 3 trial was presented as a poster at the conference.

Elinzanetant is a selective neurokinin (NK) receptor antagonist, similar to fezolinetant, the first drug in this class approved by the US Food and Drug Administration (FDA) for vasomotor symptoms in May 2023. This class of medications targets the estrogen-sensitive kisspeptin/NK B/dynorphin (KNDy) neurons thought to play a role in thermoregulation and hot flashes during menopause. While fezolinetant targets only the NK-3 receptor, elinzanetant is a dual NK receptor antagonist that targets both NK-1 and NK-3. Bayer submitted a New Drug Application for elinzanetant to the FDA on August 1.

For those in whom hormone therapy is contraindicated, “it’s always been difficult for women with really severe symptoms to have a safe and effective therapy,” lead author JoAnn Pinkerton, MD, a professor of OB/GYN at the University of Virginia in Charlottesville, Virginia, told Medscape Medical News. “The nonhormonal therapies we’ve used mostly off-label — the antidepressants, gabapentin, clonidine, oxybutynin — do help the hot flashes, but they don’t work nearly as effectively as these new NK receptor antagonists, and having one that looks like it might have a broader use for hot flashes, night sweats, mood, and sleep is just really exciting.”

Pinkerton said approximately 80% of the women in the OASIS 1 and 2 studies had at least a 50% reduction in hot flashes. “It was a very strong, dramatic positive finding, but the improvements in sleep and mood have really encouraged us to go further,” she said.

Declining estrogen levels during and after menopause can cause hypertrophy and hyperactivity of the KNDy neurons, which has been linked to thermoregulation disruptions that may trigger hot flashes, James Simon, MD, a clinical professor of OB/GYN at The George Washington University School of Medicine & Health Sciences and medical director of IntimMedicine in Washington, DC, told attendees. He presented pooled data from OASIS 1 and 2. The NK-1 receptor, targeted by elinzanetant but not fezolinetant, is also thought to play a role in insomnia and possibly in mood.

“Oftentimes the focus on a lot of these drugs is hot flashes, hot flashes, hot flashes, but we know hot flashes do not occur in isolation,” Chrisandra Shufelt, MD, professor and chair of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Florida, told Medscape Medical News. Elinzanetant is “an interesting compound because it actually works on sleep, and that was critical because sleep disturbance precedes” many other menopausal symptoms, said Shufelt, who was not involved in the study.

“I think it is an outstanding option for women who don’t have the opportunity to get hormones,” Shufelt said, and she was particularly pleased to see there were no safety concerns for the liver in the trial data. The FDA issued a warning on September 12 about the risk for rare liver injury with fezolinetant, but the early signals that had been seen in fezolinetant data were not seen in these elinzanetant data.

The OASIS 1 and 2 trials enrolled postmenopausal women, aged 40-65 years, who had at least 50 moderate to severe vasomotor occurrences per week.

“A moderate hot flash is a hot flash that is also associated with sweating, and a severe hot flash is a moderate hot flash that stops a woman in her tracks,” Simon said. “Namely, it’s severe enough with sweating and central nervous system effects that she is interrupted in whatever it is that she’s doing at the time.”

Exclusion criteria for the trials included a history of arrhythmias, heart block, or QT prolongation; abnormal lab results; history of malignancy within the past 5 years; uncontrolled or treatment-resistant hypertension, hypothyroidism or hyperthyroidism; unexplained postmenopausal bleeding; clinically relevant abnormal mammogram findings; or disordered proliferative endometrium, endometrial hyperplasia, polyp, or endometrial cancer.

The predominantly White (80%) women were an average 54 years old, with an average body mass index (BMI) of 27.8, and were an average 3.5 years from their last period. For the first 12 weeks of the trials, 399 women were assigned to receive 120 mg once daily of oral elinzanetant and 397 were assigned to once daily placebo. Then the women taking placebo switched to elinzanetant for the final 14 weeks of the study.

The endpoints included mean change in frequency and severity of vasomotor symptoms at weeks 1, 4, and 12 as well as change in sleep disturbance and quality of life at week 12. Sleep was assessed with the Patient-Reported Outcomes Measurement Information System Sleep Disturbance–Short Form score, which ranges from 28.9 to 76.5, with a higher number denoting greater sleep disturbance. The Menopause-Specific Quality of Life ranges from 1 to 8, with a higher score indicating poorer quality of life.

Daily frequency of vasomotor symptoms was 14 per day at baseline in the elinzanetant group, decreasing by 4.8 per day at week 1, 8 per day at week 4, and 9.4 per day at week 12. In the placebo group, women had an average 15.2 occurrences per day at baseline, which decreased by 3.2 at week 1, 5.2 at week 4, and 6.4 at week 12. Comparing the groups at 12 weeks, those receiving elinzanetant had 3.2 fewer daily vasomotor symptoms than those receiving placebo (P < .0001).

The severity of vasomotor symptoms also improved more in the elinzanetant group than in the placebo group over 12 weeks, after which severity improved further in those who switched from placebo to elinzanetant (P < .0001).

Sleep disturbance scores, starting at a mean 61.5 in the elinzanetant group and 60.5 in the placebo group, fell 10.7 points in the elinzanetant group and 5.3 points in the placebo group at 12 weeks, for a difference of 4.9 points (P < .0001). Sleep then further improved in those who switched from placebo to elinzanetant. Quality of life scores improved 1.37 points (from 4.52 at baseline) in the elinzanetant group and 0.96 points (from 4.49 at baseline) in the placebo group, for a mean difference at 12 weeks of 0.36 (P < .0001).

Though no head-to-head data exist comparing elinzanetant and fezolinetant, Simon told Medscape Medical News the side effects with fezolinetant “tend to be gastrointestinal, whereas the side effects for elinzanetant tend to be central nervous system,” such as drowsiness and lethargy.

The women who are the best candidates for elinzanetant, Pinkerton told Medscape Medical News, include those who have had an estrogen-sensitive cancer, such as breast or endometrial cancer, or who have fear of it, a family history, or are otherwise high risk. Other ideal candidates include those with a history of venous thromboembolism, people who have migraine with aura (due to concerns about increased risk for stroke), and those who have endometriosis or large fibroids.

“Then the last group might be women who took hormone therapy in their 50s and want to continue, but they’re trying to go off, and they have a recurrence of their hot flashes or night sweats or sleep issues,” Pinkerton said. “This might be a great group to switch over.”

OASIS 3 assessed the drug for 1 year and “supported the results of OASIS 1 and 2, demonstrating efficacy over a longer study duration and in a population with a vasomotor symptom profile representative of that seen in clinical practice,” Nick Panay, BSc, MBBS, director of the Menopause & PMS Centre at Queen Charlotte’s Hospital & Imperial College London, London, England, and his colleague reported.

Among 628 postmenopausal women aged 40-65, the predominantly White (78.5%) women were an average 54 years old, with an average BMI of 27.6, and were an average 5 years past their last period. Half received 120 mg elinzanetant and half received a placebo for 52 weeks.

At 12 weeks, the women receiving elinzanetant reported an average 1.6 moderate to severe vasomotor symptoms per day, down from 6.7 at baseline. Daily average symptoms in the placebo group fell from 6.8 at baseline to 3.4 at 12 weeks, for a difference of 1.6 fewer occurrences per day in the elinzanetant group (P < .0001).

Sleep disturbances also improved, falling 9.4 points from a baseline 57.4 in the elinzanetant group and 5.7 points from a baseline 58 in the placebo group. Quality of life scores improved from 4.1 to 2.8 (−1.3 change) in the elinzanetant group and from 4.4 to 3.3 (−1.1 change) in the placebo group.

In addition to looking at treatment-emergent adverse events, the safety assessments also included endometrial biopsies; bone mineral density in the femoral neck, hip, and lumbar spine; weight; and labs. Adverse events related to the study drug occurred in 30.4% of those in the elinzanetant group and 14.6% of those in the placebo group. The most commonly reported adverse events were headache (9.6% elinzanetant vs 7% placebo), fatigue (7% vs 10.2%), and sleepiness (5.1% vs 1.3%). A higher proportion of women taking elinzanetant (12.5%) than those taking placebo (4.1%) discontinued the study.

No serious adverse events deemed to be treatment-related occurred in either group, and no endometrial hyperplasia or malignant neoplasm occurred in either group. Bone mineral density changes in both groups were within the expected range for the women’s age, and their weight remained stable over the 52 weeks.

Six women taking elinzanetant and four taking placebo met predefined criteria for close liver observation, but none showed hepatotoxicity or evidence of possible drug-induced liver injury.

The research was funded by Bayer. Pinkerton has run a trial funded by Bayer and is a consultant for Bayer and Pfizer. Shufelt had no disclosures. Simon had grant/research support, consulting/advisory board participation, and/or speaking disclosures with AbbVie, Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies, Camargo Pharmaceutical Services, Covance, Daré Bioscience, DEKA M.E.L.A S.r.l., Femasys, Ipsen, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mayne Pharma, Mitsubishi Tanabe Pharma Development America, Mylan/Viatris Inc, Myovant Sciences, ObsEva SA, Pfizer, Pharmavite, QUE Oncology, Scynexis, Sebela Pharmaceuticals, Sprout Pharmaceuticals, TherapeuticsMD, Vella Bioscience, and Viveve Medical, and he is a stockholder in Sermonix Pharmaceuticals.

Tara Haelle is a Dallas-based medical journalist.