MLE4901, a drug used for treating hot flashes in menopausal women, has a unique mechanism of action; it targets the area of the brain responsible for inducing hot flashes. In a recently completed Phase 2 clinical trial, MLE4901 significantly decreased the incidence and severity of hot flashes.
Menopause occurs when the ovaries stop producing estrogen and progesterone and is diagnosed when a woman has not menstruated for 12 months. Declining estrogen levels are accompanied by symptoms such as hot flashes, vaginal dryness, urinary incontinence, lack of libido, irritability, and anxiety. Hot flashes are often reported as the most troublesome symptom; 70% of menopausal women report hot flashes and at least 10% of women find them intolerable.
A hot flash is exactly as it sounds–an intense feeling of heat. When a hot flash occurs blood vessels in the skin dilate, the surface temperature of the skin rises, and the patient feels overheated. Past studies have suggested that the neuropeptide neurokinin B (NKB) and its receptor (NK3R) are responsible for triggering hot flashes. Located in the hypothalamus, a region of the brain responsible for regulating temperature, NKB neurons change in response to a lack of sex hormones. When NKB is introduced intravenously to premenopausal women, hot flashes are induced.
Several treatment options for hot flashes exist, but none target the source of hot flashes directly. Hormone replacement therapy (HRT) attempts to reset the levels of estrogen and progesterone to premenopausal levels, but HRT is associated with an increased risk of breast cancer, blood clots, and stroke. Antidepressants, such as paroxetine, and herbal remedies, such as black cohosh have been used; however, some studies show no improvement of hot flashes compared with placebo.
Millendo Therapeutics is developing a drug called MLE4901 that blocks NK3R receptors to directly target the cause of hot flashes. The results of a Phase 2, randomized, double-blind clinical trial that compared MLE4901 with a placebo was conducted by researchers at the Imperial College of London and was recently published in The Lancet. The participants of the trial were menopausal women between 40- and 62-years-old who had greater than 7 hot flashes per day. Enrolled patients started a 2-week introductory period, followed by 4 weeks of either 40 mg MLE4901 by mouth 2 times a day or placebo. A 2-week washout period was used before switching patients to the alternate intervention (those taking the placebo began taking MLE4901, and those taking MLE4901 began taking the placebo).
The total number of hot flashes during week 4 was the main outcome. Researchers also compared the total number of hot flashes during week 4 of treatment to the total number of hot flashes during week 2 of the introductory phase. Secondary measures of outcome were the severity of hot flashes, hormone concentrations, and the objective measurement of hot flashes by a skin monitor.
Researchers screened 68 women and selected 45 to start the trial. During the 2-week introductory phase, 7 subjects were excluded; a total of 28 subjects completed the trial. The mean amount of daily hot flashes in the MLE4901-first group was 13.09, in the placebo-first group it was 12.56. Treatment with MLE4901 significantly reduced the weekly number of hot flashes at week 4 compared with placebo. Treatment with MLE4901 also significantly reduced the severity of hot flashes compared with placebo. Patient assessments revealed a significantly improved quality of life compared with the placebo. Three patients experienced an elevation in liver enzymes, but these patients did not show any symptoms of liver damage, and the elevation returned to normal in all cases.
The results of the study show that blocking NK3R receptors can significantly improve the quality of life for women suffering from hot flashes. The number of subjects and length of this trial were short; Phase 3 trials of MLE4901 will further examine this drug’s safety and efficacy in a greater number of patients. If MLE4901 proves to be both efficacious and safe then patients will finally have a treatment option that specifically targets the cause of hot flashes.
Written By: Corey Cunningham, PharmD