Nextstellis combined oral contraceptive and endocrine markers

The novel investigational contraceptive, which contains both drospirenone (DRSP) and estetrol (E4), resulted in significantly lower increases in sex hormone-binding globulin (SHBG) compared to two other combined oral contraceptives containing the synthetic estrogen ethinyl-estradiol (EE).

“Nextstellis, as a combined oral contraception, is the only formulation with DRSP and E4, and there is no other pill with E4 on the market,” said presenter Andrew London MD, MBA, an assistant professor of ob/gyn at The Johns Hopkins School of Medicine. “There are pills with DRSP as the progestin, but E4 is unique to Nextstellis.”

Because the estrogen in Nextstellis is selective, “it demonstrated a more neutral effect on the liver endocrine parameters than the two reference oral contraceptives that were included in the study: EE combined with either levonorgestrel (LNG/EE) or drospirenone (DRSP/EE),” London told Contemporary OB/GYN. “EE is a very potent estrogen, while E4 is a much weaker estrogen. The smaller rise in SHBG is very exciting and could potentially help with hormone-related libido issues.”

For the phase 2 study, participants were divided into three groups: DRSP 3 mg/E4 15 mg (Nextstellis) (n = 38); LNG 150 mcg/EE 30 mcg (n = 29); and DRSP 3mg/EE 20 mcg (n = 31).

The 24/4-day regimen (24 active pills followed by 4 inactive pills) spanned six consecutive, 28-day treatment cycles.

Changes from baseline in total testosterone (TT), free testosterone (FT), androstenedione, dehydroepiandrosterone sulphate (DHEAS), cortisol binding globulin (CBG), SHBG and thyroxine binding globulin (TBG) were determined at cycle 3 and 6.

A significant increase in SHBG was observed at cycle 3 (240%) and cycle 6 (251%) with DRSP/EE compared to baseline, and those observed with Nextstellis at 52% and 55%, respectively. LNG/EE was not significantly different at cycle 3 or cycle 6.

At cycle 6, the decrease in TT and FT with Nextstellis (31% and 50%, respectively) was not significantly different from those noted with LNG/EE (38% and 50%, respectively) or DRSP/EE (33% and 71%, respectively). At cycle 3, there were no decreases in TT and FT noted in any of the three groups.

But at cycle 6, Nextstellis showed a significantly lower impact on decreasing DHEAS than DRSP/EE: 10% vs. 27%. No differences in DHEAS levels were noted between DRSP/E4 and LNG/EE.

“There were no real surprises to the study,” London said. “The goal was to identify exactly what was found in the endocrine parameters compared to the currently used oral contraceptives in the study. “However, it is way too early to comment on the real-world experience that women will have. Additionally, there is no claim that Nextstellis is less safe or safer than any other oral contraceptive pill on the market. Nonetheless, it is hoped that the minimal endocrine changes will decrease side effects while maintaining contraceptive efficacy. The fact that Nextstellis is a weaker estrogen than EE in all the pills currently on the market is reassuring.”

Any woman with contraceptive needs and who has no contraindication for estrogen may be a candidate for Nextstellis, according to London. “And as with most pills, it is for first-line use,” he said.

London said study results may change the thinking about the legacy estrogens that have always been used in oral contraceptive formulations because the side effect profile of Nextstellis “appears neutral.”

If approved, Nextstellis would be the first contraceptive product containing E4, plus the first new estrogen introduced in the U.S. for contraceptive use in roughly 50 years.

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Disclosure

London has served on the advisory board of Mayne Pharma.