Kate Johnson

October 24, 2016

SALT LAKE CITY — When uterine fibroids were treated with the selective progesterone-receptor modulator ulipristal acetate, rates of amenorrhea, defined as no menstrual bleeding for 35 consecutive days, increased, according to results from the first American trial of the drug.

Ulipristal acetate was more effective than placebo in terms of "rate of amenorrhea, time to amenorrhea, and quality of life," said James Simon, MD, clinical professor of obstetrics and gynecology at the George Washington University School of Medicine in Washington, DC.

Results from the VENUS-1 trial were presented here at the American Society for Reproductive Medicine 2016 Scientific Congress.

These findings are "consistent with European data," said Jacques Donnez MD, PhD, professor emeritus at the Catholic University of Louvain in Brussels, Belgium, and director of the Society for Research Into Infertility, who headed the European trials of the drug.

Ulipristal acetate is approved and marketed for the treatment of uterine fibroids in Europe (Esmya, Allergan), but not in the United States.

The European studies and VENUS-1 "prove we can significantly reduce bleeding with this medication," Dr Donnez told Medscape Medical News.

Overall, rates of amenorrhea in VENUS-1 were markedly lower than those seen in the four European PEARL trials, but Dr Donnez and Dr Simon agree that the comparison is not really fair.

"It's very difficult to compare a US-based population with a European one," Dr Simon explained. "The American women were much heavier and had, by and large, much worse fibroids, both in terms of size and number."

There were also differences in study design, he told Medscape Medical News.

"The data are reassuring and we should not focus too much on amenorrhea rates; that's not clinically relevant," Dr Donnez explained. "What's important is control of bleeding to improve quality of life."

The randomized, placebo-controlled, double-blind VENUS-1 trial involved 157 women 18 to 50 years of age with at least one fibroid and excessive prolonged bleeding.

Mean menstrual blood loss was around 200 mL per cycle, mean fibroid volumes were around 59 to 83 cc, and uterine volumes were just over 300 cc.

For 12 weeks, 53 women were randomized to daily treatment with ulipristal acetate 5 mg, 48 were randomized to ulipristal acetate 10 mg, and 56 were randomized to placebo.

The primary end point — amenorrhea for the previous 35 consecutive days of treatment — was achieved by more patients in the ulipristal acetate 5 mg and 10 mg groups than in the placebo group (47.0% vs 58.0% vs 1.8%; P <.0001).

A secondary end point — amenorrhea from day 11 to the end of treatment — was also achieved by more patients in the 5 mg and 10 mg groups than in the placebo group (53.4% vs 58.3% vs 0.0%; P < .001).

There was a "highly statistically significant difference, even after adjustment for multiple comparisons," Dr Simon reported.

Time to amenorrhea was approximately 11 days in the 5 mg and 10 mg groups. The hazard ratio (HR) for the achievement of amenorrhea at any time was, compared with placebo, 35.5 in the 5 mg group (P < .0001) and 49.1 in the 10 mg group (P < .0001).

For quality of life, rated on the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire revised activity subscale, there was "a very small placebo effect but a much greater effect for both active doses," with scores of 82 out of a possible 100 in the 5 mg group and 89 in the 10 mg group, said Dr Simon.

In terms of adverse effects, ulipristal acetate was "extremely well tolerated," he reported. "There were no deaths or treatment-related serious adverse events or discontinuations, no malignant changes, and endometrial changes appeared to be reversible with discontinuation."

Of the six patients in the active treatment groups with hypertension, "five had pre-existing hypertension," Dr Simon noted. And of the five patients in the active treatment groups with elevated levels of creatine phosphokinase, four had elevated levels at baseline and "one had a transient increase that resolved spontaneously."

In the European PEARL I (N Engl J Med. 2012;366:409-420) and PEARL II (N Engl J Med. 2012;366:421-432) studies, rates of controlled bleeding, rather than amenorrhea, were above 90%. In VENUS, rates of amenorrhea were much lower, at 50% to 60%.

This difference is likely related to race, said Ally Murji, MD, from Mount Sinai Hospital in Toronto. "In VENUS, 69% of participants were black, whereas in PEARL, more than 85% were white," he explained.

Dr Murji was involved in a prospective nonrandomized cohort study of ulipristal acetate (Fertil Steril. 2016;106:1165-1169), in which more than 40% of the participants self-identified as black. The researchers were therefore able to compare outcomes "between ethnicities," he explained.

They found that rates of amenorrhea were lower in black patients than in white patients (41% vs 66%). "This is consistent with the findings presented in VENUS-1," Dr Murji told Medscape Medical News.

"We need larger studies to make such subgroup judgments. Head-to-head comparisons would be the best," said Dr Simon.

VENUS-1 was sponsored by Allergan. Dr Simon has been a consultant for Allergan, AbbVie, Agile Therapeutics, Bayer, New England Research Institute, Novo Nordisk, Palatin Technologies, and Symbio Research; has received grants from Amgen, Eisai, Merck, Noven Pharmaceuticals, Novo Nordisk, and Shionogi; and is a member of the speaker's bureau for Sermonix Pharmceuticals. Dr Murji has disclosed no relevant financial relationships.

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress: Abstract O-268. Presented October 19, 2016.

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