MICA: Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Hot flushes (or flashes) are transient episodes of sweating and intense heat sensation associated with a chronic decrease in circulating sex steroid levels. Hot flushes are experienced by up to 70% of women during the menopausal transition and postmenopause, and negatively impact on quality of life. Hot flushes are also experienced by many patients undergoing sex steroid deprivation therapy for breast and prostate cancer. Hormone replacement therapy (HRT) is the most effective treatment for menopausal hot flushes. Unfortunately, current recommendations are that HRT be used at the lowest possible dose for the shortest possible duration due to associated risks of breast cancer, stroke, venous thromboembolism and coronary artery disease. Furthermore, HRT is contraindicated in many patients. Hence alternative therapies to HRT are needed for menopausal flushing.

Neurokinin B (NKB) is a member of the tachykinin family of peptides. NKB is encoded by the TAC3 gene and binds preferentially to the neurokinin 3 receptor (NK3). Recent human and animal data have demonstrated that NKB signalling is an essential component in mediating menopausal flushing. We performed for the first time a double-blinded, placebo-controlled pilot study which demonstrated that NKB infusion induced hot flush symptoms in women. These data suggest that NK3 receptor antagonists could be a novel and effective therapy for menopausal flushing.

The aim of the proposed research is to carry out a study to determine if a Neurokinin 3 Receptor Antagonist is effective in treating hot flushes in menopausal women.

AstraZeneca have developed a NK3 receptor antagonist (AZD2624) and shown that it is safe when administered to humans. AstraZeneca have agreed to work with the University researchers by providing their NK3 receptor antagonist (AZD2624) at no cost for this proposed research. The proposed study will determine how effective an NK3 receptor antagonist (AZD2624) is in treating hot flush symptoms in post menopausal women.

If the proposed study shows that an NK3 receptor antagonist is an effective new treatment for menopausal flushing then this could provide a new treatment for hot flushes without the potential risks of hormonal administration. This would be beneficial for the following groups of patients:
1. The major clinical application would be as a second-line therapy for patients with contraindication to HRT (ischaemic heart disease, cerebrovascular disease, previous thrombosis or high thrombotic risk), or in patient preference for non-hormonal therapy due to previous or anticipated adverse effects. In practice, 25% of women aged 50 or over, cannot take the pill due to a contraindication. Therefore, our solution would benefit an estimated 5 million women per year a third of whom have 'troublesome' flushing symptoms.
2. Patients previously treated with HRT for 5 years, who require further treatment for flush symptoms which may persist for a total of 10 years i.e. 5 years beyond the point at which HRT would usually be discontinued.
3. Women with flushes induced by hormonal deprivation therapy for breast cancer.
4. Women with a contraindication to HRT due to the diagnosis of previous breast cancer.
5. Men with flushes induced by hormonal deprivation therapy for prostate cancer.

Technical Summary

Hot flushes affect 70% of menopausal women, with up to 20% of these women describing them as 'intolerable'. Furthermore hot flushes can last up to 20 years, therefore having a significant and long-lasting effect on quality of life. Hormone Replacement Therapy is the mainstay of treatment but confers an increased risk of breast cancer, stroke and thromboembolism. Hence current guidelines recommend a limited duration of therapy and in several cases HRT is contra-indicated. Other options such as SSRIs and Clonidine are less effective than HRT. The reducing use of HRT worldwide highlights an unmet need to develop non-hormonal alternative treatments.

Neurokinin B (NKB) is a recently identified hypothalamic neuropeptide. Recent studies in humans, monkeys and rodents indicate that NKB signalling within the hypothalamus mediates menopausal hot flushes. Furthermore we have recently demonstrated that administration of NKB to women elicits hot flush symptoms. We therefore hypothesise that NK3 receptor (the primary receptor for NKB) antagonism is a novel treatment for menopausal hot flushes.

To test this hypothesis we propose a randomised, double-blinded, placebo-controlled, 2-way crossover study in 42 menopausal women with untreated hot flushes. Participants will receive 28 days of either oral AZD2624 or placebo in random order separated by a 14 day washout period. The primary outcome will be number of hot flushes. Secondary outcomes will include hot flush severity (FDA scale), quality of life and sternal skin conductance (measure of sweating). The study will be carried out by a team who have extensive experience in clinical trials hormonal administration and menopausal hot flushing.

Planned Impact

This work will benefit for patients, the pharmaceutical industry and the research community of researchers into menopausal disorders as detailed below:

Patients: This work will directly benefit patients with flush symptoms and a contraindication to HRT (ischaemic heart disease, cerebrovascular disease, previous thrombosis or high thrombotic risk), or a preference for non-hormonal therapy. In practice, 25% of women aged 50 or over, cannot take the pill due to a contraindication. Therefore, our solution would benefit an estimated 5 million women per year (Archer et al. 2011) a third of who have 'troublesome' flushing symptoms (Kronenberg et al. 1990; Bachmann 1999). This work would also provide a novel therapy for patients previously treated with HRT for 5 years, women with flushes induced by hormonal deprivation therapy for breast cancer, women with a contraindication to HRT due to the diagnosis of previous breast cancer, and men with flushes induced by hormonal deprivation therapy for prostate cancer.

Pharmaceutical industry: Our host department has an established record of maximising the impact and benefit of its research on peptide hormones. The department was the first to demonstrate that the peptide GLP-1 reduced food intake in man. GLP-1 analogues were later developed as pharmaceutical agents for use in type 2 diabetes mellitus. The department also established a spin out company Thiakis to develop analogues of oxyntomodulin as potential therapeutic agents for obesity. Subsequently Thiakis was sold to Wyeth pharmaceuticals for £10 million, with £100 million potential performance related payments. The host department therefore has the experience to translate results from this study into advanced pharmaceutical development, which could benefit the UK's pharmaceutical industry.

UK research community of researchers into menopausal disorders: This collaborative project would stimulate further developments in the treatment of menopausal disorders, by provoking other researchers to exchange their expertise with researchers in other disciplines.

Publications

10 25 50

publication icon
Narayanaswamy S (2016) Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men. in The Journal of clinical endocrinology and metabolism

publication icon
Prague JK (2021) Neurokinin 3 receptor antagonists - prime time? in Climacteric : the journal of the International Menopause Society

 
Description BBC filming, July 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBC filming
Year(s) Of Engagement Activity 2018
 
Description BRC open day at Imperial (2016) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Clinical and non-clinical team members gave demonstrations and hosted exhibits featuring key aspects of our research and recent findings and relating them to everyday problems (including infertility and obesity).
Year(s) Of Engagement Activity 2016
 
Description Management of Menopausal Hot Flashes: Hormonal and Nonhormonal Therapy, Oct 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Management of Menopausal Hot Flashes: Hormonal and Nonhormonal Therapy
Year(s) Of Engagement Activity 2018
 
Description Management of menopausal hot flashes - hormonal and non-hormonal therapy American Society for Reproductive Medicine Annual Meeting Oct 2018, Denver USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk- Management of menopausal hot flashes - hormonal and non-hormonal therapy
American Society for Reproductive Medicine Annual Meeting Oct 2018, Denver USA
Year(s) Of Engagement Activity 2018
 
Description Metabolic effects of kisspeptin 1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Talk-Metabolic effects of kisspeptin
1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018
Year(s) Of Engagement Activity 2018
 
Description Neurokinin B antagonism - novel therapy for menopausal flushing, British Endocrine Society meeting Glasgow, Nov 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk Presentation- Neurokinin B antagonism - novel therapy for menopausal flushing, British Endocrine Society meeting Glasgow, Nov 2018
Year(s) Of Engagement Activity 2018
 
Description Neurokinin and hot flushes, 2018 International Congress of Endocrinology (ICE 2018), Cape Town, South Africa December 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk from Neurokinin and hot flushes
2018 International Congress of Endocrinology (ICE 2018), Cape Town, South Africa December 2018
Year(s) Of Engagement Activity 2018
 
Description Nk3r Data meeting, Denver Colorado-Oct 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Nk3r Data meeting, Denver Colorado-Oct 2018
Year(s) Of Engagement Activity 2018
 
Description Opportunities for clinical academic training, Clinical Update Meeting, Society for Endocrinology, 21st March 2016, Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Clinical Update Meeting, Society for Endocrinology, 21st March 2016, Birmingham
Year(s) Of Engagement Activity 2016
 
Description Plenary Lecture: Kisspeptin / neurokinin B Pathways: Regulating Emotion and Treatment of Menopausal Symptoms American Endocrine Society meeting, Chicago April 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk-Plenary Lecture: Kisspeptin / neurokinin B Pathways: Regulating Emotion and Treatment of Menopausal Symptoms
American Endocrine Society meeting, Chicago April 2018
Year(s) Of Engagement Activity 2018
 
Description Talk at Annual Academic Meeting/ Blair Bell Research Society, Royal College of Obstetricians and Gynaecologists, London Jan 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Royal College of Obstetricians and Gynaecologists, London
Year(s) Of Engagement Activity 2018
 
Description The future of clinical academic training at Tony Gordon's conference in Great Hall, King's College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The future of clinical academic training at Tony Gordon's conference in Great Hall, King's College London-Feb 2018
Year(s) Of Engagement Activity 2018
 
Description The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research, Moller Centre Cambridge, Nov 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research
Moller Centre Cambridge, Nov 2016
Year(s) Of Engagement Activity 2016
 
Description Translating Novel Hormones into New Therapies for Reproductive Disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk/Seminar Translating Novel Hormones into New Therapies for Reproductive Disorders
Year(s) Of Engagement Activity 2019
 
Description Update on clinical kisspeptin studies Kisspeptin 2017, Orlando USA, March 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Update on clinical kisspeptin studies
Kisspeptin 2017, Orlando USA, March 2016
Year(s) Of Engagement Activity 2016