Bayer Submits NDA to FDA for Elinzanetant, a First-in-Class Dual NK1/NK3 Receptor Antagonist, for Moderate-to-Severe Menopausal Vasomotor Symptoms

Recently, Bayer has submitted a New Drug Application (NDA) to the U.S. FDA, seeking approval for the investigational therapy elinzanetant to treat moderate to severe vasomotor symptoms (VMS, also known as hot flashes) associated with menopause. If approved, this would be the second non-hormonal drug for treating hot flashes.

This application is based on the positive results of the OASIS 1, 2, and 3 studies, which evaluated the efficacy and safety of elinzanetant compared to placebo. The study results showed that elinzanetant (120 mg oral dose once daily) significantly reduced the frequency and severity of moderate to severe VMS and demonstrated a favorable safety profile. In the elinzanetant group, headache and fatigue were the most common treatment-emergent adverse events (TEAEs).

Elinzanetant is the first dual neurokinin-1,3 (NK-1,3) receptor antagonist administered orally once daily. It addresses VMS by modulating estrogen-sensitive neurons (KNDy neurons) in the hypothalamus.

Bayer acquired KaNDy Therapeutics in 2020 for approximately $875 million (including a $425 million upfront payment and $450 million in milestone payments), obtaining this potential "first-in-class" therapy.

NK3 Receptor Antagonists Emerging with Market Potential for Menopausal Hot Flashes

Vasomotor Symptoms (VMS), commonly known as hot flashes and night sweats, occur in postmenopausal women. Menopause is a normal and natural change in a woman’s life, typically occurring between the ages of 45 and 55. Approximately 80% of menopausal women experience hot flashes, which include sweating, flushing, and chills lasting several minutes. Among them, about one-third suffer from moderate to severe vasomotor symptoms for up to a decade.

Vasomotor symptoms severely trouble perimenopausal women in both their life and work, but traditional treatment methods still have limitations. Currently, the most commonly used treatment for alleviating menopause-related VMS is menopausal hormone therapy. However, menopausal hormone therapy has many contraindications, a treatment window period, and studies have proven that it may also increase the risk of breast cancer, cardiovascular diseases, and thromboembolism.

Neurokinin 3 Receptor (NK3R) Participates in the Brain's Mechanism for Regulating Body Temperature. Studies show that antagonists targeting NK3R can block the signaling pathway of Neurokinin B (NKB), modulate neural activity in the hypothalamic temperature regulation center, and thereby reduce the frequency and severity of moderate to severe vasomotor symptoms during menopause. Currently, multiple pharmaceutical companies are developing NK3 receptor antagonists for hot flashes in menopausal women, providing a new treatment option for patients who cannot or choose not to undergo hormone therapy.

According to research data from the U.S. Female Founders Fund, it is estimated that there will be 1.1 billion menopausal women globally by 2025, and the menopause market will reach a scale of $600 billion. In menopause management, effective drug treatment is crucial. The impact of menopausal syndrome on women's health is becoming increasingly evident, but there is also a lack of effective drugs in this field, which means the market potential in this area is enormous.

Bayer to Be Strong Competitor of Astellas, Led by China's Hansoh and GenSci Pharmaceuticals

At this stage, only one NK3 receptor antagonist for the treatment of VMS has been approved and launched, which is Astellas' small-molecule oral drug Fezolinetant (brand name Veozah). Other NK3 receptor antagonists under development include Bayer's Elinzanetant (NDA) and Sanofi's Osanetant (Phase 2), while the clinical trials of Sojournix’s SJX-653 (Phase 2), Daiichi Sankyo’s CS-003 (Phase 2), and Millendo’s Pavinetant (Phase 2) have all been terminated. In China, Hansoh’s HS-10384 is leading the domestically produced track, having entered Phase 3 clinical trials, with Jin Sai Pharmaceutical’s GS1-144 following closely behind in Phase 1 clinical stage.

Fezolinetant was initially developed by the Belgian pharmaceutical company Ogeda and acquired by Astellas for 500 million euros (approximately 534 million US dollars) in 2017. In May 2023, the US Food and Drug Administration (FDA) approved Veozah (fezolinetant) for the treatment of moderate to severe vasomotor symptoms (VMS) caused by menopause. Veozah is the first neurokinin-3 (NK3) receptor antagonist approved by the FDA for treating such patients and also the first non-hormonal therapy approved by the FDA for moderate to severe vasomotor symptoms (VMS) due to menopause. The global VMS market holds vast and continuously growing potential. It is predicted that fezolinetant sales could reach up to 1.5 billion US dollars by 2027 and hit 2.5 billion US dollars by 2029.

Currently, Fezolinetant has gained a first-mover advantage. Whether Fezolinetant can quickly capture the market will depend on its subsequent real-world efficacy and marketing strategies. Meanwhile, Fezolinetant also faces competition from Elinzanetant. If Elinzanetant successfully enters the market, whether NK1/NK3 dual-target receptor antagonists are superior to single-target NK3 receptor antagonists will inevitably lead to fierce competition, where efficacy will determine the winner.

In addition, NK3 is currently under development.Receptor AntagonistThe track for VMS is not yet crowded, but in the future, competition will gradually intensify with the joint efforts of generic drugs and innovative drugs. Pharmaceutical companies in China that have laid out plans in this area should seize the window period and bring their products to market as soon as possible.

Reference Source:       

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2.Kimball A Johnson and others, Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT, The Journal of Clinical Endocrinology & Metabolism, 2023;, dgad058.       

3.S. Lederman, F.D. Ottery, A. Cano, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study, Lancet, 401 (2023) 1091-1102.    

4.Simon, JA; Anderson, RA; Ballantyne, E, et al. (2023). Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1). Menopause; 30 (3): 239–246. 26     

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