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NK3R antagonist reduces menopausal hot flash frequency, severity
In menopausal women, the neurokinin-3 receptor antagonist MLE4901 reduced the number and severity of bothersome hot flashes over 4 weeks compared with placebo, according to phase 2 study findings published in The Lancet.
“The current standards of therapy for [vasomotor symptoms], including hormone replacement therapy (HRT), selective serotonin reuptake inhibitors (SSRIs) and over-the-counter treatments, all have tradeoffs between safety and efficacy, such as an increased risk of breast and endometrial cancers,” Waljit S. Dhillo, PhD, professor of endocrinology and metabolism at Imperial College London, said in a press release. “While larger-scale studies of longer duration will be needed, this study has demonstrated the practice-changing capacity of MLE4901 for the treatment of [vasomotor symptoms] in that it has the potential to treat hot flush symptoms without the need for estrogen exposure.”
In a randomized, double blind, crossover trial, Dhillo, Julia K. Prague, MBBS, of the department of investigative medicine at Imperial College London, UK, and colleagues analyzed data from 28 menopausal women aged 40 to 62 years recruited between February and June 2016 who reported at least seven hot flashes every day and who had not taken any medication intended to improve hot flashes in the preceding 8 weeks. Researchers randomly assigned participants to receive 40-mg MLE4901 twice daily for 4 weeks (n = 16) followed by a matching placebo (n = 12) for 4 weeks, separated by a 2-week washout period, or to the two protocols in reverse order. Participants returned for weekly clinic visits and completed questionnaires regarding total hot flash frequency, severity, interference, associated menopausal symptoms and treatment adherence. A programmed Bahr Monitor was issued to record skin conductance during the first 48 hours of each week. Primary outcome was the total number of hot flashes during the fourth week of both treatment periods; 37 women were included in the intention-to-treat analysis.
Baseline menopausal symptoms were similar between groups; mean number of hot flashes per 24-hour period was13.09 in group 1 and 12.56 in group 2.
Researchers found that MLE4901 reduced the total weekly number of hot flashes by 45% compared with placebo; intention-to-treat adjusted means of weekly hot flashes were 19.35 vs. 49.01, respectively (P < .0001). Researchers observed a 52% decrease in weekly hot flashes in the per-protocol analysis with mean weekly 16.85 hot flashes with MLE4901 vs. 59.27 for placebo (P < .0001).
MLE4901 also reduced hot flash severity compared with placebo, with mean hot flash severity scores of 3.27 vs. 5.7, respectively, as well as hot flash bother (mean score, 2.92 vs. 5.56) and interference (mean score, 7.94 vs. 26.48). The reported subjective effect of decreased hot flashes was confirmed by skin conductance measurements; mean number of hot flashes per 24 hours was 16.22 with MLE4901 vs. 26.91 with placebo, a 43% decrease (P < .0001).
Researchers also noted improved psychosocial and physical symptoms, including improved sleep and less irritability.
No serious adverse events occurred. Three women developed a transient transaminase rise with a normal bilirubin 28 days after starting MLE4901, which normalized within 90 days, according to researchers.
“The results of this study provide a strong rationale for the expanded development of MLE4901 into patients with [vasomotor symptoms], for which there is a clear need for an effective non-hormonal treatment option,” said Julia C. Owens, PhD, president and chief executive officer of Millendo. – by Regina Schaffer
Disclosure: The UK Medical Research Council and the National Institute for Health Research funded this study. Prague reports no relevant financial disclosures. Please see the full study for the other authors’ relevant financial disclosures.