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

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.

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.

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.