New class of drug effective in targeting menopausal symptoms: News from Endocrine Conference 2017.

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A new class of drug Neurokinin 3 (NK3) receptor antagonists is highly effective and low risk alternative to hormone replacement therapy(HRT) for treatment of menopausal hot flashes according to a study presented at the ENDO 2017, The endocrine society annual meeting from April 1–4, 2017, in Orlando, FL.

NK3 receptor blockers fezolinetant (Ogeda) and MLE4901 (Millendo Therapeutics) were found useful in reducing moderate to severe hot flashes in postmenopausal women.  

The study results of MLE4901 trial were also simultaneously published in Lancet.

About two-third of women are affected by hot flashes that reduce the quality of life and overall well-being. Approximately 20 million women in the United States currently experiencing VMS. HRT is effective alternative, but it is not without any side effects and cannot be used in patients with malignancies.

In this phase2, randomized, double-blind, placebo-controlled, single-center, crossover trial 37 women aged 40–62 years were assigned to take either 40 mg BD of the drug/placebo for 4 weeks and then received other treatment for 4 weeks after a 2 weeks’ gap in between.

The primary end point of study was number of hot flashes, the secondary endpoints were hot flush severity, bother, and interference with daily activities, gonadotrophins and LH concentrations.  

MLE4901 reduced the number and severity of hot flashes considerably as compared to placebo (p<0·0001 for both). 

The women also reported increased sleep, decreased fatigue and irritability. The drug was well tolerated except a small increase in transaminase without rise in serum bilirubin.

Studies during the last 2 decades have increasingly shown the role of NKB–NK3R signaling in the etiology of menopausal hot flushes.

Dr Julia K Prague, of Imperial College London, United Kingdom, said of MLE4901 in her presentation"Treatment with the NK3 receptor antagonist could be practice-changing, as it significantly relieves hot-flash symptoms without the need for estrogen exposure. Larger-scale studies of longer duration are now indicated and planned."

The other study presented at the conference evaluated the effect of fezolinetant, which was a 12-week double-blind, placebo-controlled, multicenter study involving 80, healthy postmenopausal women between 40-65 years.

The women were randomized to receive either fezolinetant (90 mg, BID) or placebo. Women receiving the NK3 antagonist experienced 50% less frequent hot flashes that were half as severe as women in the placebo group. (P < .001)

At a biochemical level these women showed a 50% decrease in LH levels. LH levels are biomarkers for reduction in hot flashes. Quality of life, sleep and irritability also improved, that continued after stopping the drug.

Both the drugs did not have any significant effect on libido, "That is to be expected, because after all this isn't estrogen replacement," said the lead author Dr Fraser.  He further added that the safety profile is extremely good and only two patients experienced mild side effects and the patients were able to reach the end of study.

Ogeda chief scientific officer Dr Graeme L Fraser, who presented the fezolinetant data, said that the company plans to further test the drug in women who have had breast, uterine, and ovarian cancer, for whom hormone-replacement therapy is contraindicated. "This really is a perfect fit for this population, where there is an important unmet need."

Pr. Herman Depypere (UZ Ghent), principal investigator said: "More than 80% of menopausal women develop hot flashes and 20% to 30% of this population seek treatment because their symptoms are severe and debilitating and negatively affect their quality-of-life. The Women's Health Initiative Study advises against the chronic use of HRT due to important safety concerns including the increased risks of cancer and cardiovascular events. The degree of relief demonstrated with fezolinetant (a non-HRT) in this study could represent an important breakthrough in the way we can manage menopause."

The results of both these studies call for larger studies for long period of time.

The conference abstract can be accessed here.

The article in Lancet can be accessed here.