麻豆传媒

PHILADELPHIA -- A novel, plant-based oral estrogen improved metabolic profiles while also quelling menopause-related vasomotor symptoms, secondary outcomes from the phase III E4 Comfort I trial indicated.

After 12 weeks of treatment, postmenopausal women who received the native estrogen estetrol (E4) had a significant decrease in total cholesterol to HDL ratio (-0.167 and -0.247 from baseline for the 15-mg and 20-mg doses, respectively, vs -0.019 with placebo), reported Wulf Utian, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland at the annual meeting of the Menopause Society.

Both doses of E4 significantly reduced lipoprotein A, led to small increases in HDL, and improved blood sugar levels, while the 15-mg dose also led to a drop in LDL and an increase in triglycerides, Utian said during a presentation of the findings here.

"The current results add to the likely potential benefits and safety of E4, in this instance in reduction of risk of cardiovascular disease and possible reduced risk of diabetes," said Utian. "It has been well known for years that estrogens have an impact on lipid metabolism and cardiovascular disease. Different estrogens have different properties, as do the mode of delivery of these steroid hormones."

Topline efficacy data from the two , released back in 2022, demonstrated up to an 80% and 56% reduction in hot flash frequency and severity, respectively, versus placebo at week 12.

"E4 is the first new native estrogen to be introduced into women's health in well over six decades and has a unique mode of action," Utian told 麻豆传媒, adding that prior studies on this novel drug have demonstrated benefits on vasomotor symptoms, genitourinary syndrome, and hemostatic factors.

E4 acts as the key estrogen compound in the FDA-approved contraceptive estetrol/drospirenone (Nextstellis), approved in 2021. Developer Mithra is now currently developing the estrogen -- sourced from plants -- as a next-generation hormone therapy product.

Utian added that while this is an orally administered drug, it is "remarkably comparable to other estrogens administered non-orally -- for example, transdermal skin patches."

"Indeed, I have begun to describe oral E4 as 'the first oral transdermal estrogen,'" he said. "It really has the safety parameters of a transdermal and has the convenience of an oral."

That being said, he noted that clinicians should keep in mind that "E4 is a potent estrogen and given alone will have an impact on the endometrium. Any potential future use in women with an intact uterus will require counterbalancing progesterone/progestin."

Chrisandra Shufelt, MD, MS, of the Mayo Clinic in Jacksonville, Florida, said that if approved, "this gives us another estrogen option for vasomotor symptoms, since it is a native estrogen with selective tissue [activity]. It is also described as a plant-synthesized fetal estrogen pharmaceutical as opposed to synthetic, which for some women is important."

Shufelt, who was not involved with the study, told 麻豆传媒 that although the the average lipid profile changes were somewhat small, they’re still "clinically meaningful," because it suggests that E4 doesn't have a negative impact.

E4 Comfort I enrolled 640 postmenopausal women ages 40 to 65 from 14 countries, including North America, randomizing them 1:1:1 to the 15-mg E4 dose, the 20-mg dose, or placebo. All women with an intact uterus received progesterone 200 mg once-daily for 14 days after completion of E4 treatment.

Shufelt pointed out that as hysterectomized and non-hysterectomized patients were included, "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."

For the current study, Utian presented secondary analyses evaluating lipid and metabolic markers based on patients' week 12 blood samples.

Compared with baseline, both doses of E4 significantly reduced lipoprotein A versus placebo (-3.270 mg/dL and -4.140 mg/dL vs 0.094 mg/dL, respectively). And there were small but significant increases with both E4 doses when it came to HDL cholesterol (0.037 mmol/L and 0.073 mmol/L vs 0.0001 mmol/L).

With the 15-mg dose, women on treatment also experienced a significant drop in LDL (-0.224 mmol/L vs -0.038 mmol/L with placebo) and an increase in triglycerides (0.227 mmol/L vs -0.036, respectively).

On top of these lipid changes, E4 treatment was also associated with blood sugar improvements. By week 12, both doses significantly reduced fasting plasma glucose and HbA1c compared with placebo. There were also numerical drops in insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), though these didn't reach significance:

• Fasting plasma glucose: -0.071 mmol/L for the 15-mg dose and -0.118 mmol/L for the 20-mg dose vs 0.070 mmol/L for placebo

• HbA1c: -0.135% and -0.159% vs -0.035%

• Insulin: -13.879 pmol/L and -9.857 pmol/L vs -0.952 pmol/L

• HOMA-IR: -0.711 and -0.382 vs -0.030

Mithra said it plans to submit the data for FDA approval later this year.

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