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Novel bioidentical estradiol vaginal capsule shows promise in pilot study

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WASHINGTON — A novel estradiol vaginal gel cap containing low doses of solubilized bioidentical estradiol improved vaginal cytology and pH in healthy postmenopausal women, according to a presentation at the 25th annual meeting of The North American Menopause Society.

About a half-inch in size, TX-004HR (TherapeuticsMD) capsules of 10 mcg and 25 mcg were safe and well tolerated, with less systemic exposure than with equivalent doses of an existing vaginal estradiol tablet, suggesting another local option for treating menopause-related vulvovaginal atrophy, the researchers said.

“The idea is for the vaginal estrogen to work locally, you really don’t want to get systemic absorption,” James H. Pickar, MD, of Columbia University Medical Center, New York, told Endocrine Today. “That’s exactly what happened. We saw blood levels that were roughly half to a third of those seen with the FDA-approved product at similar doses.”

Pickar and colleagues initially conducted two randomized, single-dose, two-way crossover pharmacokinetic trials comparing the bioavailability of TX-004HR with that of an existing vaginal estradiol tablet (Reference).

Each trial involved 36 healthy postmenopausal women (BMI, 19-30 kg/m²) aged 40 to 65 years. Single vaginal doses of TX-004HR or Reference were administered, followed by single vaginal doses of the alternate therapy after a 14-day washout; one trial used 10-mcg doses and the other 15 mcg.

The scientists sampled blood pre- and post-insertion at set intervals for 24 hours and analyzed for concentration-time curve (AUC_0-24), peak concentration (C_max) and time to peak concentration (t_max) for estradiol and estrone.

Safety and efficacy of TX-004HR was then tested in a pilot study that included 50 healthy postmenopausal women (BMI ≤34 kg/m²) aged 40 to 75 years with at least one moderate to severe vulvovaginal atrophy symptom, superficial cells ≤5% and a vaginal pH >5. The women were randomly assigned to a single vaginal gel cap containing 10 mcg of solubilized 17beta-estradiol or placebo for 14 days.

AUC_0-24 values were 63% (10 mcg) and 69% (25 mcg) less for estradiol and 50% (10 mcg) and 70% (25 mcg) less for estrone with TX-004HR vs. Reference, after baseline adjustments. Similar decreases were seen in C_max values at 29% (10 mcg) and 46% (25 mcg) less for estradiol and 26% (10 mcg) and 55% (25 mcg) less for estrone with TX-004HR vs. Reference. Systemic exposure was significantly reduced with both doses of TX-004HR compared with equivalent doses of Reference. No adverse events were seen in either trial.

At the end of the 2-week pilot, women had higher mean increases from baseline with TX-004HR compared with placebo for superficial cells (35% vs. 4%; P=.0002) and intermediate cells (13% vs. 4%; P=.0002). The mean decrease from baseline in parabasal cells was greater with TX-004HR than placebo (54% vs. 5%; P=.0001), as was the mean decrease in vaginal pH (0.97 vs. 0.34; P=.0002).

“The next thing you would hope to see over time would be relief from symptoms including pain during intercourse, bleeding with intercourse, vaginal itching and burning — the standard symptoms you would see with vaginal atrophy,” Pickar said.

Women treated with TX-004HR also achieved greater improvements in vaginal epithelial integrity and secretions than with placebo. Improvement in vaginal symptoms was similar between groups, which the researchers attribute to small size and short duration.

In 14 of 50 women (28%), 17 treatment-emergent adverse events were observed, although not all were treatment-related. Eye contusion, nephrolithiasis, blood pressure increase, vaginal discharge, dysplasia or pruritus, vulvovaginal pain or burning, hot flush and cervical dysplasia occurred with TX-004HR. Paresthesia, vaginal hemorrhage or vulvovaginal discomfort occurred with placebo. Most events were mild and none were serious, the researchers said.

TherapeuticsMD is running a phase 3 Rejoice Trial for the investigational therapy in doses of 4 mcg, 10 mcg and 25 mcg.

“Our trial includes 700 women with vulvovaginal atrophy and dyspareunia,” Sebastian Mirkin, MD, chief medical officer of TherapeuticsMD, told Endocrine Today. “We are evaluating the effect of this compound over 12 weeks, fulfilling the regulatory guidelines for this particular indication. We expect to have it completed in late 2015.” – by Allegra Tiver

For more information:

Pickar JH. Abstract S-6. Presented at: The North American Menopause Society Annual Meeting; Oct. 15-18, 2014; Washington, D.C.

Disclosure: Pickar reports consultant, advisory board or review panel positions with Ausio Pharmaceuticals, Besins Healthcare, Depomed, Pfizer, Shionogi and TherapeuticsMD.