'Bioidentical' Oral Alternative to Compound Hormones on Horizon

April 10, 2017

An oral soft-gel capsule containing standardized doses of natural estrogen (17-β estradiol) and natural progesterone has been shown in new research to be safe and effective for menopausal symptoms and is expected to be filed for approval in the United States in the second half of this year and in the European Union later on.

Doctors involved in the development of TX-001HR (TherapeuticsMD) say that, if approved, the product will enable women who have been using compounded hormone therapy to use a regulated alternative.

Results of a 12-week efficacy study and a year's data on endometrial safety with TX-001HR were reported last week at ENDO 2017: The Endocrine Society Annual Meeting.

Current combination oral hormone-replacement therapies (HRTs) contain synthetic hormones, Ginger Constantine, MD, of EndoRheum Consultants, Malvern, Pennsylvania, explained to Medscape Medical News, "and following the Women's Health Initiative (WHI) trial, a lot of people blamed the synthetic hormones for the results and turned toward compounded hormone products."

But the latter "are not FDA approved," noted Dr Constantine, who presented a poster detailing the endometrial safety findings of TX-001HR at ENDO 2017.

"What is unique about this product is it will be the only combination…that has natural estradiol and natural progesterone and in which we know the appropriate doses. It's designed for those women who wanted the natural products and who are being forced to take something" that's not ideal, she stressed.  

Numerous professional societies, including the Endocrine Society, the North American Menopause Society, the American College of Obstetricians and Gynecologists (ACOG) and the British Menopause Society have spoken out against the use of custom-compounded hormones to treat menopausal symptoms, saying they are potentially dangerous.

But despite these warnings, use of compounded hormone products by perimenopausal women has skyrocketed, with an estimated 1 to 2.5 million women in the United States alone using such unapproved preparations, representing up to 39 million prescriptions annually.

Asked for her thoughts on TX-001HR at ENDO 2017, Michelle Warren, MD, of the Center for Menopause, Hormonal Disorders, and Women's Health at Columbia University, New York — who was not involved in the development of this product — told Medscape Medical News that she believes there is a real need for this kind of therapy.

"Patients are very concerned about what they are taking and whether it's biologically acceptable, so I think [TX-001HR] is going to be very helpful, and it seems to work very well," she said.

A Real Need for an Oral Preparation of Natural Hormones

Dr Warren explained that there is already a regulated pharmaceutical option for women who want to take natural estrogen, in the form of a 17-β estradiol transdermal gel, but "we don't have a transdermal progesterone [in the United States]," although there are preparations of natural progesterone available in some countries, as vaginal pessaries.

And progesterone is often the sticking point, she said: "What I find with my patients is that they often don't take the progesterone, because they don't feel well or they forget, and that's dangerous."

"So I think this is going to be very helpful, to have an oral preparation," she commented, noting that if TX-001HR is approved she would like to see it made available in perhaps two or three different fixed-dose options.

TX-001HR is currently being developed as four fixed-dose combinations of 17-β estradiol and progesterone: 1.0 mg/100mg; 0.5 mg/100 mg; 0.5 mg/50 mg and 0.25 mg/50 mg, and these were all tested against placebo in the two trials on safety and efficacy reported at the meeting.

Roger Lobo, MD, of the department of obstetrics and gynecology at Columbia University Medical Center, New York, presented the efficacy data during an oral presentation.

The study enrolled 1845 women aged 40 to 65 years with an intact uterus, and those who met the criteria for vasomotor symptoms (more than seven hot flushes a day or >50/week) were randomized to the 12-week efficacy study.

The remainder were randomized and followed for 12 months to assess endometrial safety.

The women qualifying for the hot-flush study continued the study for 12 months after they had completed the assessments for hot flushes, Dr Lobo explained.

There were 726 women who were randomized for the hot-flush study and 89% completed the 12 weeks.

Change from baseline in frequency and severity of hot flushes at weeks 4 and 12 vs placebo were the four co–primary efficacy end points.

All four doses of TX-001HR provided statistically and clinically significant reduction in the weekly frequency of moderate to severe vasomotor symptoms from baseline at week 12, compared with placebo (P < .05 for all four doses).

And the 1.0-mg/100-mg and 0.5-mg/100-mg doses significantly improved the severity of vasomotor symptoms at weeks 4 and 12 compared with placebo (and 0.5 mg/50 mg was significant at weeks 7 and 9 through 12).

There was also improvement in the quality of life (overall MENQOL score) and vasomotor MENQOL domain scores from baseline to week 12 with all four doses, compared with placebo.

Adverse events were mostly mild or moderate in severity and those reported by 5% or more of the population included headache, nasopharyngitis, breast tenderness, upper respiratory tract infection, nausea, and back and abdominal pain. Serious adverse events were low and only seven were considered related to treatment.

TX-001HR Is "Safe on the Endometrium"

For endometrial safety, there was no signal of harm at all, reported Dr Constantine in a poster at the meeting.

"The purpose of this is to finally have studied different doses of the natural products in combination to find out what doses we need to protect the endometrium," she explained to Medscape Medical News.

All women had endometrial biopsies at baseline and 1 year; three pathologists were required to review each slide, and two of the three had to agree on the result.

The endometrial hyperplasia rate was 0%, and no malignancies were detected with any TX-001HR dose.

"The bottom line is that it was safe on the endometrium," Dr Constantine said.

Wrapping up his talk, Dr Lobo said: TX-001HR, "if approved," would be a new oral hormone-therapy option for postmenopausal women with moderate to severe vasomotor symptoms who have an intact uterus.

"It may be a new option for the estimated millions of women currently using less regulated and unapproved compounded bioidentical hormone therapy," he concluded.

 Dr Constantine consults for multiple pharmaceutical companies, including but not limited to TherapeuticsMD and has stock options with TherapeuticsMD. Dr Warren reports research grants from Pfizer. Dr Lobo reports research grants from TherapeuticsMD and consulting for TherapeuticsMD, AMAG, JDS Therapeutics, Pfizer, Allergan, Teva, and Mithra.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

ENDO 2017. April 2 and3, 2017; Orlando, Florida. Abstract LB SUN 07, Abstract OR 16-4

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