News from NAMS 2018: Estetrol, the next generation hormone therapy linked to significant improvement in menopausal VMS

Estetrol (E4) (Donesta®) in daily oral dose of 15 mg appears to be the most effective dose for the treatment of menopausal VMS reports the results of Phase IIb (E4 Relief) clinical trial presented at the 29th Annual Meeting of the North American Menopause Society (NAMS), being held on 3-6 October 2018 in San Diego, CA.  

Estetrol (E4) is the first promising NEST™ or Native Estrogen with Selectively action in Tissues produced by the human fetal liver, crossing the placenta and excreted in maternal urine at relatively high levels during pregnancy. It has a half-life of 28 hours and exhibits a unique mode of action.

It acts as an estrogen agonist in the vagina, endometrium, bone, and cardiovascular system and shows a mixed agonist and antagonist estrogenic property in liver and breast tissue. This results in lower level of breast stimulation with no effect on hemostasis parameters and triglycerides levels.

This multicentric, randomized, placebo-controlled, double-blinded, dose-finding study Phase IIb clinical trial recruited post-menopausal women, aged 40-65years across many European countries. Women qualified to participate in the trial if they had ≥7 moderate to severe hot flushes (HF) per day, or ≥50 moderate to severe HF in the week and Transvaginal Ultrasound (TVUS) showed a bi-layer endometrial thickness ≤5 mm.

Women were randomized to receive 2.5; 5; 10; or 15 mg E4, or placebo, once-daily, for 12 weeks. The primary endpoints were decreased in frequency and severity of hot flashes (VMS), while effects on genitourinary symptoms, lipid and glucose metabolism, hemostatic and bone markers were secondary endpoints of interest. Menopause Rating Scale (MRS) assessed the health-related quality of life. Safety of the drug was assessed by measuring the endometrial thickness and bleeding episodes while on therapy. 

As a protective measure against endometrial hyperplasia, the patients receive 2 weeks of progestin therapy (Dydrogesterone 10 mg) after the cycle of E4 is complete.

Of the 257 women selected, 200 women completed the study. At the end of the study period, there was an 80% improvement in frequency and severity of hot flashes, vaginal dryness, and dyspareunia in the E4 15mg group as compared to placebo. The improvement in VMS started as early as the end of 2 weeks with a trend reaching significance at the end of 4 weeks.

All the 11 dimensions of MRS also showed improvement with a near 50% reduction in the total score. The drug was completely safe with no effect on total triglycerides and cholesterol panel, hemostatic parameters and endometrial hyperplasia.

Estetrol (E4) (Donesta®) could be the next breakthrough for treatment of the full spectrum of menopausal symptoms. It is wholly natural and safety profile differs from that of estrogen. It could be the next oral alternative for transdermal estrogen preparations because of more breast safety.

Maud Jost, E4 Program Director, commented: “The presentation of data from the E4 Relief trial provides further evidence of the potential of Estetrol in the treatment of menopausal symptoms. This is the second-high profile conference where our compelling data from our promising Donesta program is presented. Preparations are already underway to progress Donesta into Phase III trials, which if approved could provide an innovative alternative to the millions of women seeking treatment with an improved benefit and risk profile.” 

Mithra (Euronext Brussels: MITRA), is a company specialized in Women’s Health is headquartered in Liège, Belgium.

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