Elinzanetant significantly reduces menopausal hot flash frequency

Mary Jane Minkin, MD

This past week, Bayer announced favorable results in the topline phase 3 study OASIS 3 of the novel neurokinin-1,3 receptor antagonist elinzanetant. The results go along with the favorable results seen in the OASIS 1 and 2 studies. The naturally occurring neurokinin receptor antagonists are estrogen; when estrogen levels go down with menopause, the neurokinins can then bind to the receptors, leading to hypertrophy in this area of the hypothalamus and leading to hot flashes.

The biochemistry here has been a breakthrough for management of vasomotor symptoms for postmenopausal women. Prior to the approval of the first neurokinin receptor antagonist earlier this year — fezolinetant, a neurokinin 3 receptor antagonist — the only officially FDA approved non-estrogenic medication for hot flashes was a small dose of the selective serotonin reuptake inhibitor, paroxetine (Paxil, GlaxoSmithKline). Data on the neurokinin receptor antagonists not only show significant efficacy, but also relatively rapid response to the medications. Safety profiles have been good.

Fezolinetant has been approved for relief of vasomotor symptoms. The ongoing trials of elinzanetant are looking at hot flashes and sleep disturbances. Subsequent ongoing studies are looking at the safety and efficacy of elinzanetant among breast cancer survivors, one of the significant  groups in whom estrogens have a relative contraindication. The studies focus on women aged 40 to 65 years.

The neurokinin receptor antagonists will also be helpful to medical endocrinologists managing menopausal vasomotor symptoms. Because they are not estrogenic, they do not require concomitant administration of progestins. Side effect profiles have shown minimal problems. However, they do not provide relief of other menopausal symptoms, namely genitourinary syndrome of menopause, and do not protect against bone loss. But it does give practitioners another powerful tool for hot flash relief.

Nanette Santoro, MD

These findings indicate that elinzanetant is heading for FDA approval as an effective non-hormonal treatment for vasomotor symptoms. The OASIS series of studies has proven that it is effective, and the newest study, which is not yet published, will likely prove its safety over 52 weeks.

Elinzanetant is a member of the class of neurokinin receptor antagonists and would be the second in this class to get approval. Unlike fezolinetant (Veozah, Astellas), which interacts with the neurokinin-3 receptor, elinzanetant interacts with both the neurokinin-1 and neurokinin-3 receptors. The neurokinin receptors mediate hot flashes, and blocking them bypasses the estrogen receptor and stops hot flashes at their point of origin — in the brain. Neurokinin receptor antagonists blockade is an exciting new advance because it seems to be able to reduce hot flashes as effectively as estrogen, and we have not had FDA-approved non-hormone agents that have been this effective.

Overall, this is great news for women who suffer from hot flashes. More treatments that do not involve hormones, that are as effective as hormones and that do not have off-target adverse effects — which most non-hormone options have because they are antidepressants, are sedating, cause dry mouth, etc — will provide menopausal women with more and better options. It is not clear how or whether dual blockade of the neurokinin-1 and neurokinin-3 receptors will provide advantages or disadvantages over neurokinin-3 blockade. Further studies will be needed to determine these nuances.