麻豆传媒

CHICAGO -- Daily treatment with a plant-based form of estrogen significantly eased vasomotor symptoms (VMS) in postmenopausal women, the primary efficacy analysis of a phase III trial showed.

In the so-called E4Comfort II study, two different doses of oral estetrol (E4) reduced the frequency of moderate to severe VMS versus placebo at weeks 4 and 12, reported Amanda Black, MD, MPH, of the University of Ottawa in Ontario.

The higher dose reduced the severity of VMS at both time points as well, and secondary outcome analyses showed improvements in patient-reported outcomes (PROs) and markers of bone health out to 1 year, according to data presented at the Menopause Society annual meeting.

Estetrol is a naturally occurring estrogen produced by the fetal liver. E4 is a plant-derived formulation of the hormone that is already on the market as one of the two ingredients in an FDA-approved contraceptive, E4/drospirenone (Nextstellis).

E4 is less potent than other estrogens but may offer an alternative to other hormone therapies because of its limited impact on hemostasis parameters and breast tissue, which remain risks for some women considering hormone therapy, said co-investigator Ekta Kapoor, MBBS, of the Mayo Clinic in Rochester, Minnesota, who presented the PRO data on the compound at the meeting.

"The most fascinating part is that potency wise, they say it's 10 times less potent than estradiol. But then again, it came through very strong in the studies," Kapoor told 麻豆传媒. "This does have some pharmacologic potency on top of the placebo effect, so to me, it's a very promising molecule."

Stephanie Faubion, MD, MBA, of the Mayo Clinic in Jacksonville, Florida, told 麻豆传媒 that although E4 is currently not approved for menopause symptoms, it could be another tool for clinicians. Faubion, who was not involved in the study, noted that "this form of estrogen may offer some safety benefits given its limited effect on clotting factors and the breast, and positive effects on bone parameters."

A second phase III trial of E4 -- -- met all its , significantly improving both VMS frequency and severity, according to then-developer Mithra Pharmaceuticals. In the multinational study, E4 also improved metabolic profiles.

Prior to its bankruptcy in June, Mithra had stated it would by the end of this year. Kapoor said she believes E4 is still on track for regulatory filing (the rights were to another drug company).

enrolled 579 postmenopausal women, ages 40-65, from North America, who experienced at least 7 VMS per day or at least 50 VMS per week at enrollment. Participants were randomized 1:1:1 to 15-mg E4, 20-mg E4, or placebo daily for 12 weeks for the efficacy analysis. Non-hysterectomized women received 200-mg progesterone for 14 consecutive days following E4 treatment for endometrial protection.

Primary efficacy outcomes included the frequency and severity of VMS at weeks 4 and 12. At both time points and with both doses, E4 significantly reduced the weekly frequency of moderate to severe VMS versus placebo, with least squares (LS) mean changes from baseline in the 15-mg, 20-mg, and placebo groups as follows:

• 4 weeks: -41.38 and -43.17 vs -32.96 (P=0.044 and P=0.012 for the placebo comparisons)
• 12 weeks: -57.54 and -60.82 vs -45.33 (P=0.003 and P=0.0001)

Reductions of VMS severity (a 1-3 scale where higher values indicate more severity) were only significant with the 20-mg dose:

• 4 weeks: -0.73 vs -0.56 with placebo (P=0.031)
• 12 weeks: -1.12 vs -0.77 with placebo (P<0.0001)

Responder analyses showed that at 12 weeks, 81.3% of patients in the 15-mg group and 81.7% of those in the 20-mg group had at least a 50% reduction in VMS frequency, as compared with 61.3% of placebo recipients (P=0.001 and P<0.001). Similarly, reductions in VMS frequency of at least 75% from baseline were observed in 56.9%, 49.0%, and 37.3%, respectively (P=0.0007 and P=0.0392).

Secondary outcomes were evaluated through 52 weeks.

For the PROs, Kapoor reported significant improvements at 1 year of treatment on the vasomotor domain of the Menopause-Specific Quality of Life (MENQOL) instrument in both E4 dose groups and in MENQOL total score with the 15-mg dose. Patients on the 20-mg dose also had significant and clinically meaningful improvements on the Clinical Global Impression scale at weeks 4 and 12.

The estrogen deficiency that comes with menopause can increase , which has been linked with increased bone loss.

As for bone health with E4, Black reported that blood biomarkers of bone turnover were lower at week 12 with both doses, including type I collagen cross-linked C-telopeptides (CTX-1), a bone resorption marker; procollagen 1 N terminal propeptide (P1NP), a bone formation marker; and calcium. CTX-1 and P1NP both decreased significantly compared to placebo at 52 weeks as well in both E4 groups.

"CTX-1 and P1NP seem to be predictive of improvement in bone mineral density and a decrease in fracture risk," said Black, adding that "a reduction in calcium levels is actually a good thing from a bone perspective."

No differences between groups were observed with regard to vitamin D levels.

Study limitations included a lack of head-to-head comparisons of E4 to other estrogens or hormone therapies and that for the bone analysis, researchers used blood biomarkers rather than direct assessments.