Novel drug offers hope for menopausal hot flushes
A novel treatment targeting the neurokinin 3 receptor (NK3R) pathway with MLE4901, a NK3R antagonist, significantly reduces the frequency and severity of menopausal hot flushes, as well as the impact on daily life of menopausal women compared with placebo, according to a study presented at The Endocrine Society Annual Meeting (ENDO 2017) in Orlando, Florida, US.
“[Treatment with MLE4901] could be practice-changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure,” said lead author Dr Julia Prague of Imperial College London, UK.
At baseline, the study participants reported about 13 hot flushes per day and 85 events per week. After 4 weeks of treatment, the frequency of hot flushes was significantly reduced by 45 percent to 19 events during the final week in the MLE4901 group vs 49 events in the placebo group (p<0.0001). [Lancet 2017;doi:10.1016/S0140-6736(17)30823-1]
Objective assessment of hot flushes using a skin conductance monitor further confirmed the findings from participants’ subjective reporting, which corresponds to a 43 percent decrease (mean weekly frequency, 16.22 vs 26.91; p<0.0001).
Hot flushes were also 41 percent less severe with MLE4901 than with placebo (mean score, 3.27 vs 5.70; p<0.0001).
In addition, women taking MLE4901 experienced 45 percent less bothersome hot flushes (mean score, 2.92 vs 5.56; p<0.0001) and 58 percent less interference from hot flushes, as rated with the Hot Flash Related Daily Interference Scale (7.94 vs 26.48; p<0.0001).
The effects of menopausal symptoms on overall life quality, scored using the Menopause-Specific Quality of Life questionnaire, improved significantly with MLE4901 in terms of vasomotor symptoms (2.05 vs 3.98; p<0.0001), physical (2.42 vs 2.93; p=0.0002), and psychosocial domains (2.18 vs 2.58; p=0.0083).
Treatment was well tolerated with no serious adverse events. By day 28 following treatment with MLE4901, three women developed elevated liver enzyme (alanine aminotransferase reached 4.5–5.9 folds the upper limit of normal) although bilirubin level was normal, and the elevation eventually normalized within 3 months.
The phase II, single-centre, crossover trial randomized 37 menopausal women with ≥7 hot flushes per day to oral MLE4901 40 mg twice daily or placebo for 4 weeks followed by a 2-week washout period before switching over to the opposite treatment.
Due to the small number of participants and short duration of treatment, Prague acknowledged that “a larger and longer trial is needed to establish whether the treatment effect is long lasting in a greater number of individuals.”
Although the current gold standard for treating hot flushes using hormone replacement therapy is effective, it is contraindicated in some women and comes with long-term safety concerns, the researchers noted.
“NKB antagonists are an exciting development … Larger trials of clinically relevant duration examining benefits relative to established treatments are needed and might lead to a much needed addition to a very small toolbox of treatments for hot flushes,” according to Drs Jenifer Sassarini and Richard Anderson from the University of Glasgow and MRC Centre for Reproductive Health in Edinburgh, UK, respectively in a separate commentary. [Lancet 2017;doi:10.1016/S0140-6736(17)30886-3]