Current trial
His current randomized controlled phase 3 trial included postmenopausal women ages 40-65 from 151 sites in 14 countries in Europe, Latin America, and North America, and Russia. Among the 640 participants in the trial, 213 women randomly received 15 mg of estetrol, 213 women received 20 mg of estetrol, and 214 women received a placebo every day for 3 months. All women without hysterectomies also received 200 mg of progesterone once daily for two weeks after completing the estetrol treatment to protect the endometrium.
Researchers took blood samples from the participants at baseline and week 12 to assess total cholesterol, LDL, HDL, the total cholesterol/HDL ratio, triglycerides, lipoprotein A, fasting plasma glucose, insulin, and A1c.
Compared with women in the placebo group, women in both the 15 mg and 20 mg groups saw a statistically significant decrease in lipoprotein A and in the ratio of total cholesterol to HDL, and a statistically significant increase in HDL. Only the women in the 15 mg group saw a statistically significant decrease in LDL and increase in triglycerides; an increase in triglycerides in the 20 mg group did not reach statistical significance.
Statistically significant decreases in fasting plasma glucose and A1c also occurred in both treatment groups, but a decrease in insulin levels and in the homeostasis model-assessment-estimated insulin resistance (HOMA-IR) seen in both treatment arms did not reach significance.
“While the mean changes after 12 weeks from baseline overall were small changes to the cholesterol and blood sugar profiles, they are clinically meaningful because it suggests that E4 does not have any adverse effects to these measures,” Dr. Shufelt said in an interview. “An advantage is that this gives us another hormone option for vasomotor symptoms since it is a native estrogen with selective tissue.”
It’s too early, however, to determine whether estetrol offers benefits in terms of its safety profile, compared with currently available therapies, Dr. Shufelt said.
”These findings of E4 are similar to how oral estradiol changes lipids, which finds an increase in high-density lipoprotein cholesterol, and decreases plasma concentrations of total and low-density lipoprotein cholesterol. an increase in HDL-C and triglycerides and decrease in LDL-C,” she said.
Poster findings also promising
For the findings reported in the poster, researchers assessed quality of life and the clinical meaningfulness of vasomotor symptoms’ reduction at baseline and 12 weeks using the Menopause-Specific Quality of Life (MENQOL) questionnaire and the Clinical Global Impression questionnaire, respectively. They also assessed women’s self-reported genitourinary symptoms, including vaginal dryness, pain during urination, vaginal pain and bleeding related to sex, and vaginal or vulvar irritation or itching. Most of these findings primarily confirmed previous positive effects from E4 in other trials.
Women in both the 15 mg and 20 mg estetrol groups reported a statistically significant improvement at 12 weeks, compared with placebo, in their total MENQOL score and in the vasomotor, psychosocial, and sexual functioning domain scores (P < .05). Those in the 20 mg group also had a statistically significant improvement in their physical domain score (P < .05).
Although numerical improvements in genitourinary symptoms occurred at 12 weeks across all three groups, the only statistically significant difference from baseline occurred in patients taking 15 mg of estetrol, who experienced a decrease in vaginal dryness and vaginal pain during sex (P = .0142 and P = .003, respectively).
The Clinical Global Impression questionnaire asked women at 4 and 12 weeks to rate on a seven-item Likert scale their response to this question: “Rate the total improvement, whether or not in your judgment it is due entirely to drug treatment. Compared to your condition at admission to the study, how much has it changed?” Responses of “very much improved” and “much improved” counted as a clinically meaningful difference.
Compared with 27.9% of patients in the placebo group, 52.9% of patients in the 15 mg group and 59.8% of patients in the 20 mg group rated the weekly frequency of moderate to severe vasomotor symptoms as “much improved” or “very much improved” at 4 weeks (P < .0001). At 12 weeks, those numbers rose to 47% in the placebo group, 73.3% in the 15 mg group and 77.8% in the 20 mg group (P < .0001).
The trial’s primary limitation at this point is having only a 12-week follow-up, Dr. Shufelt said, though a few other questions remain.
“Because the two phase 3 RCTs included hysterectomized and nonhysterectomized women, it was unclear how many women in the study had E4 alone versus E4 with progesterone, as that might play a role in both cholesterol and carbohydrate metabolism,” Dr. Shufelt said. “While baseline data was not presented, it would also be important to know baseline values for the women and confirm that none were on lipid-lowering medications.”
The research was funded by Estetra SRL, an affiliate of Mithra Pharmaceuticals. Dr. Utian is a member of the Mithra and Elektra Scientific Advisory Boards. Dr. Shufelt has no disclosures.