Endocrine Abstracts (2017) 50 OC1.1 | DOI: 10.1530/endoabs.50.OC1.1

Neurokinin 3 receptor antagonism is a highly effective, novel treatment for menopausal hot flushes with rapid onset: a phase 2, randomised, double-blind, placebo-controlled trial

Julia Prague1, Rachel Roberts1, Alexander Comninos1, Sophie Clarke1, Channa Jayasena1, Zachary Nash1, Chedie Doyle1, Deborah Papadopoulou1, Stephen Bloom1, Pharis Mohideen2, Vivian Lin2, Theresa Stern3, Nicholas Panay4,5, Myra Hunter6, Johannes Veldhuis7, Lorraine Webber8, Les Huson9 & Waljit Dhillo1

1Department of Investigative Medicine, Imperial College London, London, UK; 2Millendo Therapeutics, Inc, Ann Arbor, Michigan, USA; 3TPS Pharmaceutical Consulting, Ann Arbor, Michigan, USA; 4Department of Gynaecology, Queen Charlotte’s and Chelsea Hospital and Chelsea and Westminster Hospital, London, UK; 5Institute of Reproductive and Development Biology, Imperial College London, London, UK; 6Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK; 7Endocrine Research Unit, Mayo Center for Translational Sciences, Rochester, New York, USA; 8Scientific Partnering & Alliances, Innovative Medicines & Early Developmental Biotech Unit, AstraZeneca, Melbourn, UK; 9NIHR/Wellcome Trust Imperial Clinical Research Facility, London, UK.

Background: Hot flushes (HF) affect 70% of menopausal women and can be debilitating. Oestrogen administration is effective but not without risk. Neurokinin B signalling is increased in menopausal women, and is likely critical in the aetiology of their HF. We therefore hypothesised that a neurokinin 3 receptor (NK3R) antagonist could attenuate menopausal flushing.

Design: This single-centre, phase 2, randomised, double-blind, placebo-controlled, crossover trial assessed the efficacy of an oral NK3R antagonist (MLE4901) on menopausal HF (Clinicaltrials.gov NCT02668185; funding MRC, NIHR). Of 68 women screened, 37 were randomised and included in an ITT analysis (aged 49–62 years, with >7 HF/24 h some of which were bothersome or severe). Participants received 4 weeks of MLE4901 and four weeks of placebo in random order separated by a 2 week washout period. Primary outcome was total number of HF during the fourth week of both treatment periods. Post-hoc time course analysis was conducted in a modified ITT population (minimum n=34) to ascertain the therapeutic profile of MLE4901.

Results: Primary outcome: MLE4901 significantly reduced the total weekly number of HF by 45% points compared to placebo (adjusted means: placebo 49.01 (CI: 40.81–58.56), MLE4901 19.35 (CI: 15.99–23.42), P<0.0001), and by 73% compared to baseline. By day 3 of treatment, MLE4901 reduced the frequency of HF by 72% compared to baseline (CI: −81.3 to −63.3, P<0.0001; 51% point decrease compared to placebo (CI: −63.5 to −38.4)), and this effect persisted throughout dosing. HF severity was also reduced by 38% compared to baseline by day 3 (CI: −46.1 to −29.1, P<0.001), as was HF bother by 39% (CI: −47.5 to −30.1, P<0.0001), and HF interference by 61% (CI: −79.1 to −43, P=0.0006); all continued to improve throughout dosing and were positively correlated (r=0.76–0.93, P<0.001). Treatment was well tolerated.

Conclusion: NK3R antagonist therapy (MLE4901) could be practice changing as it is well tolerated, and HF symptoms are rapidly relieved without oestrogen exposure. Larger scale studies of longer duration are imminent.

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