Ulipristal Tied to Improved Quality of Life With Fibroids

Veronica Hackethal, MD

April 23, 2019

Ulipristal acetate may improve quality of life and symptom severity in women with uterine fibroids, according to a study published online on April 5 in Obstetrics & Gynecology.

"Improvements in health-related quality of life, taken together with the significant improvements in amenorrhea, suggest that ulipristal is a promising, noninvasive treatment option for women suffering from symptomatic uterine leiomyomas," write Andrea Lukes, MD, of Carolina Women's Research and Wellness Center, Durham, North Carolina, and colleagues.

The researchers pooled results from two phase 3 randomized placebo-controlled trials, VENUS I and VENUS II. The trials were conducted as part of the US Food and Drug Administration (FDA) approval process. The data show significant improvements in fibroid-related bleeding and symptoms with ulipristal versus placebo. Compared with European studies, VENUS I and II had cohorts more typical of the American population, including more women of African descent and more obese women.

Briefly, the trials randomly assigned premenopausal women with symptomatic fibroids to 5-mg (n = 215) or 10-mg (n = 205) oral ulipristal daily or placebo (n = 169) for one 12-week course of treatment (VENUS I) or two 12-week courses of treatment (VENUS II).

Researchers compared change in health-related quality of life and symptom severity from baseline to the end of treatment using the validated Uterine Fibroid Symptom Health-Related Quality of Life questionnaire, which is widely used to assess fibroid-related quality of life.

The current analysis included 589 patients from both studies (mean age, 41.1 years; 67.4% black; mean body mass index, 32.1 kg/m2).

Results showed significant improvements from baseline in symptom severity and health-related quality of life with both doses of ulipristal versus placebo (all P < .001).

A significantly higher percentage of women taking ulipristal 5 mg (73.5%) and ulipristal 10 mg (80.6%) showed meaningful improvement (increase of 30 points or more) in social and physical activities compared with placebo (34.9%).

In other words, those treated with the lower dose of the drug were five times more likely to report improvements than women taking placebo (odds ratio [OR], 5.0). Those taking the higher dose of the drug were nearly eight times more likely to do so (OR, 7.9).

Yet the results come with some controversy.

Ulipristal is an oral medication that selectively modulates progesterone receptors on the lining of the uterus, resulting in antiproliferative effects on uterine tissue without affecting estrogen production by the ovaries.

The drug is currently approved by the FDA for emergency contraception in the United States. It is also approved in Europe and Canada for the treatment of uterine fibroids.

Yet postmarketing reports have described several cases of liver failure, including four that required liver transplant. That prompted European authorities to warn about potential liver toxicity. The European Medicines Agency has also recommended patients take only one course of treatment and have monthly liver function tests while taking ulipristal.

In August 2018, concerns about liver toxicity also prompted the FDA to reject a new drug application for ulipristal for the treatment of uterine fibroids. Currently, the future of ulipristal in the United States appears uncertain. Allergan, which makes the drug, has stayed quiet about its plans going forward, although the company has said it will meet with the FDA to discuss the drug.

Some studies have also found endometrial thickening with prolonged exposure to ulipristal. Though evidence suggests endometrial changes associated with treatment appear to be benign and reversible, these findings have raised concern for endometrial cancer.

Yet the fact remains that better treatments for fibroids are badly needed. Fibroids are the leading reason for hysterectomy in the United States, with over half of these surgeries done to treat fibroids. Many women, especially younger women who would still like to have children, prefer minimally invasive treatments or no surgery at all.

Effective medications do exist for treating heavy bleeding and anemia associated with fibroids. But women have few nonsurgical options for the treatment of large fibroids that cause bulk symptoms like frequent urination or abdominal pressure and pain, notes Joanna Hatfield, MD, Oregon Health & Science University, Portland, in an accompanying editorial.

"Ulipristal and other selective [progesterone receptor] modulators have tremendous promise for management of symptomatic leiomyomas, offering a noninvasive way to manage bleeding and bulk symptoms," Hatfield writes.

Untreated, symptomatic fibroids carry risks, she continues. But so does hysterectomy, including infection, thromboembolic events, and injury to the genitourinary system.

Also, she notes that liver injury associated with ulipristal has been reported in five among 760,000 women who have taken the drug. That, along with no reports of liver toxicity in clinical trials, indicates ulipristal-associated liver injury is an "extremely rare event, suggesting an idiosyncratic drug-induced liver injury that likely affects only rare, at-risk individuals," she writes.

"Although causality is difficult to determine with rare events, it is important to put risks and benefits in perspective with other treatments," she continues. "Although ulipristal acetate is neither a panacea nor a Pandora's box, it lies somewhere in the middle, just as nearly all options that present themselves in a woman's life."

While awaiting the development of alternative treatments, women who take ulipristal should be counseled on the "very specific but low" risk of liver injury, she concludes.

The authors also note that the study only evaluated up to two courses of treatment, and long-term effects of ulipristal on quality of life remain unknown.

The study was sponsored by Allergan, which participated in the design, execution, analysis, reporting, and funding of VENUS I and II. Several authors are employees of Allergan. One or more authors has reported consulting, advisory board membership, research grants, speaking, advising, or contributing to educational programs for one or more of the following: Allergan, AbbVie, Myovant, Merck, Bayer, GlaxoSmithKline, Ferring, Inovio, Sequoia, AHM, AMAG Pharmaceuticals, Bayer, Celula, Connect Healthcare, Cory/Paeth, Counsyl, Grey Healthcare Group, Health Advances, Interpublic Group, IntraMed, Meeting Logistics, Merck, Natera, NeoSeq, PharmaWrite, Previvo Genetics, Progenity, Qiagen, Roche Diagnostics, Sera Prognostics, and/or Vermillion. Hatfield has reported no relevant financial relationships.

Obstet Gynecol. 2019;133:855-856, 857-866. Abstract, Editorial

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