Neurokinin 3 Impact Case Study

Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes

Key features

• Study ran Feb 2016-Jan 2017

• Phase 2, randomised, double-blind, placebo-controlled, proof of concept study

• Funded by Medical Research Council and NIHR (partnered with Astrazeneca/Millendo therapeutics)

• NIHR recruited 34 participants at one site in good time and exceeding recruitment target

• Study performed at an NIHR Clinical Research Facility at Imperial College NHS Trust Hospital

• Principal Investigator: Waljit Dhillo, Professor of Endocrinology & Metabolism and an NIHR Research Professor • Neurokinin 3 was a stratified medicine study targeted specifically at post-menopausal women experiencing hot flushes

Most women will experience hot flushes when going through the menopause. They are often described as a sudden feeling of heat that seems to come from nowhere and spreads throughout the body. Some 70 per cent of women are affected. Hot flushes can last as long as 20 years, therefore having a significant and long-lasting effect on quality of life. Some women describe them as uncomfortable, disruptive and embarrassing.

The most effective treatment for hot flushes is hormone replacement therapy (HRT), which significantly improves symptoms. However, HRT is associated with an increased risk of breast cancer, thromboembolic disease and stroke. Current recommendations suggest a limited duration of HRT in all women, and advises against therapy in specific groups. Alternative treatments such as some antidepressants and herbal remedies, while effective, are still less effective than HRT. Neurokinin B (NKB) is a recently identified hypothalamic neuropeptide (a small protein-like molecule used by neurons to communicate with each other) that acts largely via the NK3 receptor. 

Neurokinin 3 receptor (NK3R) has been identified as a cause of hot flushes following a number of human and animal studies in recent years. Furthermore, it has recently been demonstrated that administration of Neurokinin B to women elicits hot flush symptoms comparable to those experienced by post-menopausal women.

The aim of the Neurokinin 3 study was to test the effectiveness of an oral NK3R antagonist (MLE4901) in reducing the frequency of menopausal hot flushes, without the need for oestrogen, as used in HRT. The study sought to recruit post-menopausal women experiencing seven or more hot flushes within a 24-hour period. Participants received four weeks of either NK3R antagonist or placebo twice daily, followed by a two week period to allow for the drug to be eliminated from the body.

Following this, the participants received four weeks of the intervention they did not receive first, again followed by a two week monitoring period. During the final week of both treatment periods, participants were asked to subjectively record hot flush frequency. Data was also collected on hot flush severity, bother and interference (via the Menopause-Specific Quality of Life questionnaire), as well as objectively measuring hot flushes via a skin conductance monitor.

Outcomes and findings

Women who received an oral NK3R antagonist over a four week period had an overall 73 per cent reduction in the frequency of hot flushes, some 45 per cent greater than the reduction that accompanied the placebo treatment.

The study also revealed improvements in physical and psychosocial symptoms, particularly related to improved sleep quality. Further analysis of this data identified that these improvements largely occurred within three days of treatment, and persisted throughout the four week trial period. The study highlights that there is rapid and sustained relief from hot flushes with NK3R antagonism, without the need for any exposure to oestrogen.

Treatment with a neurokinin 3 receptor antagonist could be practice changing. This study showed that it significantly relieved hot flush symptoms without the need for oestrogen exposure, and was well tolerated by participants.

Professor Waljit Dhillo Principal Investigator, Imperial College London

Value to the NHS

The study paves the way for further research into the use of NK3R antagonists as a potential novel and effective treatment for menopausal hot flushes, and as a viable alternative to hormone replacement therapy. The potential benefit to patients is significant, especially given the prevalence of hot flush symptoms and the symptomatic burden for post-menopausal women. Relief of hot flush symptoms will have a profound impact on improving patients’ quality of life.

In terms of cost implications, the use of alternative, less effective pharmacological and non-pharmacological agents can also be reduced in favour of NK3R antagonists in future. Due to the promise that NK3R antagonism has shown in ameliorating hot flush symptoms in our study, a number of biopharmaceutical companies are currently undertaking their own research into NK3R antagonists to build upon this data, with the aim to introduce this novel treatment to clinical practice within the next three to five years.

Key publications:

• Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Nash Z, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2017 May;389(10081):1809–20.

• Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Mohideen P, et al. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018 Aug;25(8):862–9.