Oral investigational drugs currently in phase I or phase II for the amelioration of menopausal symptoms

ABSTRACT

Introduction: Menopausal symptoms have a substantial effect on the quality of life of many women; hence, investigations for the amelioration of menopausal symptoms continue to be necessary. The two main approaches to the amelioration of symptoms are hormone therapy (HT) and non-hormonal therapy.

Areas covered: This review provides a background for understanding the types of menopausal symptoms and their underlying physiology. The early clinical development of natural estrogen (estetrol, E4), neurokinin 3 receptor (NK3R) antagonists, and other non-hormonal therapies are covered. The status and outcome of these novel treatment modalities are also discussed.

Expert opinion: The recent observation in the Women’s Health Initiative (WHI) trials that HT was not associated in the long-term with all-cause mortality, brings renewed interest in the development of new treatment modalities in postmenopausal women. Estetrol (E4), a native estrogen with selective action in tissues, is a potential next-generation HT with improved cardiovascular and breast safety. NK3R antagonists may become an interesting new modality for the amelioration of hot flushes in women with contraindications to estrogens.

Trial registration: ClinicalTrials.gov identifier: NCT00163033.

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Trial registration: ClinicalTrials.gov identifier: NCT02865538.

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Trial registration: ClinicalTrials.gov identifier: NCT03518138.

KEYWORDS:

• E4
• estetrol
• hormone therapy
• menopausal symptoms
• NK3R antagonist

Article highlights

• Menopausal symptoms have a substantial deleterious effect on the quality of life of women.

• Current early clinical development of new oral treatments includes the investigations of natural estrogen (estetrol, E4), neurokinin 3 receptor (NK3R) antagonists, and other non-hormonal therapies.

• Based on all the evidence available today, hormone-replacement therapy remains the most effective treatment for menopausal symptoms.

• Estetrol (E4) is a natural estrogen, exclusively produced by the human fetal liver, and is coined a Native Estrogen with Selective action in Tissues.

• NK3R plays a key role in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis and gonadotropin-releasing hormone GnRH activity.

• NK3R antagonists such as fezolinetant (ESN364) and NT-814 seem to be a promising new treatment option for hot flushes.

• Other potential treatment modalities include the neuroprotectant MT-8554, the non-hormonal FP-101, and (for breast cancer survivors) the C-X-C chemokine receptor type 4 (CXCR4) modulator Q-122.

• The current early clinical development of both hormonal and non-hormonal treatment modalities shows that there is a renewed interest in the amelioration of menopausal symptoms.

This box summarizes key points contained in the article.

Acknowledgments

Medical writing support was provided by Jan Egberts and Mireille Gerrits at Terminal 4 Communications, Hilversum, the Netherlands. The authors thank representatives of Mithra Pharmaceuticals, Millendo Therapeutics, and QUE Oncology for their review of the information on the drug in development contained herein.

Declaration of interest

J-M Foidart is a Consultant for Mithra Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has an affiliation with TherapeuticsMD Inc (TXMD). Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Mithra Pharmaceuticals, Liège, Belgium