ECE2017 Guided Posters Female Reproduction (12 abstracts)
Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial
Julia Prague 1 , Rachel Roberts 1 , Alexander Comninos 1 , Sophie Clarke 1 , Channa Jayasena 1 , Zachary Nash 1 , Chedie Doyle 1 , Deborah Papadopoulou 1 , Stephen Bloom 1 , Pharis Mohideen 2 , Nicholas Panay 3, , Myra Hunter 5 , Johannes Veldhuis 6 , Lorraine Webber 7 , Les Huson 8 & Waljit Dhillo 1
1Department of Investigative Medicine, Imperial College, London, UK; 2Millendo Therapeutics, Inc., Michigan, USA; 3Department of Gynaecology, Queen Charlotte’s & Chelsea Hospital and Chelsea & Westminster Hospital, London, UK; 4Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; 5Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK; 6Mayo Clinic, Minnesota, USA; 7Scientific Partnering & Alliances, Innovative Medicines & Early Developmental Biotech Unit, Astrazeneca, Melbourn, UK; 8Division of Experimental Medicine, Imperial College, London, UK.
Background: Hot flushes affect 70% of menopausal women, can be long-lasting, and often severely impact on physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but not without risk. Neurokinin B is an important mediator of hot flushes in rodents and elevated hypothalamic expression occurs in menopausal women. Neurokinin B acts via the neurokinin 3 receptor. We therefore hypothesised that neurokinin 3 receptor antagonism could be a novel treatment for menopausal hot flushes.
Methods: This phase 2, randomised, double-blind, placebo-controlled, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes in an ambulatory setting (Clinicaltrials.gov NCT02668185). Sixty-eight women were screened between February and October 2016 in a single-centre, of which 37 were randomised and included in an ITT analysis. Twenty-eight participants (aged 49–62yrs, experiencing >7 hot flushes/24 h some of which were reported as bothersome or severe), completed the trial, and were included in a Per-Protocol analysis. They received 4 weeks of MLE4901 and placebo in random order separated by a washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. Primary outcome was total number of hot flushes during the final week of both treatment periods.
Findings: MLE4901 significantly reduced the total weekly number of hot flushes by 45% compared to placebo (adjusted means: placebo 49.01 (CI: 40.81–58.56), MLE4901 19·35 (CI: 15.99–23.42), P<0.0001) (ITT). MLE4901 also significantly reduced weekly hot flush severity, bother, and interference compared to placebo by 41% (P<0.0001), 45% (P<0.0001), and 58% (P<0.0001) respectively. Treatment was well tolerated.
Interpretation: Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated.
Funding: MRC (UK) (MR/M024954/1)
Volume 49
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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