Ulipristal is better than placebo for controlling abnormal bleeding associated with uterine leiomyomas, or fibroids, according to the findings of a randomized trial published in the February issue of Obstetrics & Gynecology.
“The findings from this and other studies suggest that ulipristal may be useful for the medical management of abnormal uterine bleeding associated with uterine leiomyomas, especially for patients desiring uterine- and fertility-sparing treatment,” write James Simon, MD, from Women’s Health & Research Consultants in Washington, DC, and colleagues.
In a podcast provided by the journal, Obstetrics & Gynecology editor-in-chief Nancy Chescheir, MD, said the results may be a “huge plus” for patients.
“It will force us [as gynecologists] to take perhaps different approaches to premenopausal patients with symptomatic fibroids. This is going to shake that up pretty clearly,” said Chescheir, a clinical professor of obstetrics and gynecology and a maternal fetal medicine specialist at the University of North Carolina at Chapel Hill School of Medicine.
However, European Union regulators have expressed concern about ulipristal, which is already approved there. In December, the European Medicines Agency announced an investigation into possible liver injury associated with the drug, and on February 9, the group said that women taking the drug should be monitored regularly with liver function tests.
Up to 70% of white women and more than 80% of black women in the United States develop fibroids. Between 25% and 50% of these women experience clinical symptoms, such as excessive or prolonged bleeding, which can interfere with social and physical activities.
Standard treatment for severe bleeding is surgical hysterectomy. But surgery has drawbacks, such as time off from work for recovery. Moreover, it is not an option for younger women who wish to preserve their fertility.
Ulipristal acetate is an oral selective progesterone receptor modulator. Studies in Europe have suggested that the drug is better than placebo for decreasing the size of fibroids, as well as controlling abnormal bleeding. However, these studies were performed mostly in white women with a normal body weight, who have a lower risk for fibroids than black women or women who are overweight.
To evaluate ulipristal in a diverse population more representative of the US population, Simon and colleagues conducted a double-blind placebo-controlled phase 3 clinical trial at 25 centers across the United States. The team enrolled 157 premenopausal women between March 2015 and March 2015. Participants were aged 18 to 50 years with abnormal uterine bleeding, one or more symptomatic fibroids, and a uterine size of 20 weeks’ gestation or less. Participants were nearly 70% black and mostly obese, with a mean body mass index of 32 kg/m2.
Researchers randomly assigned participants to receive 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks, followed by a 12-week drug-free period. Participants reported bleeding using daily e-diaries, and self-reported quality-of-life variables on a standardized questionnaire.
Results showed that 47.2% (25/53; 97.5% confidence interval, 31.6% – 63.2%) of women receiving 5 mg ulipristal achieved the primary endpoint of no bleeding for 35 consecutive days, as did 58.3% (28/48; 97.5% confidence interval, 41.2% – 74.1%) of women receiving 10 mg ulipristal. In contrast, only 1.8% (1/56; 97.5% confidence interval, 0.0% – 10.9%) of the placebo group did so (both P < .001).
In most women who reached the primary endpoint, bleeding was controlled within the first 10 days of starting ulipristal (log-rank P < .001 for both doses vs placebo).
Likewise, both doses were associated with a better quality of life than placebo (P < .001).
Although results were not significant, fibroid size decreased for both doses of ulipristal compared with an increase with placebo (5 mg, 9.6% decrease [P = .218]; 10 mg, 16.3% decrease, [P = .086]; placebo, 7.2% increase).
Common treatment-emergent adverse events included hypertension, elevated blood creatinine phosphokinase, and hot flushes. In addition, ultrasound showed that both dosage groups as well as placebo had similar proportions of progesterone receptor modulator–associated endometrial changes, which decreased after stopping therapy.
In the podcast, Chescheir noted several strengths of the trial. “One of the really important things was that this was an American study, as opposed to a study in Europe, and it more clearly matched US population and people affected by fibroids.”
Although not the main focus of the study, she also noted that the decreased size of fibroids with ulipristal treatment was “pretty impressive,” and that on average, fibroids did not appear to grow back to their pretreatment size after treatment discontinuation.
However, several unknowns about ulipristal remain. Its long-term efficacy and whether patients will have to continue taking it through menopause are unclear. In addition, it is not clear whether the drug interferes with fertility or what is the most effective dose. Another big question is whether ulipristal can be used to decrease the size of submucosal fibroids and improve pregnancy outcomes.
Despite these remaining issues, consulting editor of Obstetrics & Gynecology John Fischer, MD, remained enthusiastic. Participating in the same podcast and noting that the drug is still not yet approved by the US Food and Drug Administration for treating fibroids, he said, “I’m sure that within the next few years we’re going to see this drug coming on the market as a potential treatment option for fibroids.” Fischer is a professor of obstetrics, gynecology and women’s health at the University of Minnesota in Minneapolis.
The study was sponsored by Allergan, plc. Several coauthors are current full-time employees of Allergan plc. One or more coauthors reports consulting, serving on speakers’ bureaus, grants, and/or owing stock for one or more of the following: AbbVie Inc, Allergan Plc, AMAG Pharmaceuticals Inc, Ascend Therapeutics, Azure Biotech Inc, Millendo Therapeutics Inc, Nuelle Inc, Radius Health Inc, Regeneron Pharmaceuticals Inc, Roivant Sciences Inc, Sanofi SA, Sebela Pharmaceuticals Inc, Sermonix Pharmaceuticals Inc, Shionogi Inc, Symbiotec Pharmalab, TherapeuticsMD, Valeant Pharmaceuticals, Novo Nordisk, Agile Therapeutics, Bayer Healthcare LLC, New England Research Institute Inc, ObsEva SA, Palatin Technologies, Symbio Research Inc, Biospecifics, Myovant, and/or Repros.
Obstet Gynecol. 2018;131:431-439. Abstract
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