Ulipristal Acetate for Uterine Fibroids

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH , Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: In a randomized, placebo-controlled study, daily oral treatment with ulipristal acetate for 13 weeks effectively controlled excessive menstrual bleeding due to uterine fibroids and reduced the size of the myomas. In a second companion RCT by the same group, daily oral ulipristal acetate was shown to be as effective as leuprolide acetate, and better tolerated.

Sources: Donnez J, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421-432. Donnez J, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409-420.

The results of the PEARL I and PEARL II studies were published recently in the same issue of the New England Journal of Medicine. Both were well-designed, randomized, controlled, double-blinded studies that assessed the safety and efficacy of ulipristal acetate (UPA) for the treatment of symptomatic uterine fibroids.

In the PEARL I study, women with symptomatic fibroids resulting in excessive uterine bleeding (defined as a score of > 100 on the pictorial blood-loss assessment chart [PBAC]) and anemia (hemoglobin level of ≤ 10.2 g per dL) were randomized to receive treatment with oral UPA (5 mg per day [96 women] or 10 mg per day [98 women]) or to receive placebo (48 women) for up to 13 weeks. All patients received iron supplementation. The co-primary efficacy endpoints were control of uterine bleeding (PBAC score of < 75) and reduction of fibroid volume at week 13 (after 13 weeks, the subjects could elect to undergo surgery). By 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of UPA and 92% of those receiving 10 mg, compared to only 19% of those receiving placebo (P < 0.001 both doses). The rates of amenorrhea were 73%, 82%, and 6%, respectively. Of note, amenorrhea occurred within 10 days in the majority of patients receiving UPA. The median changes in total fibroid volume were -21%, -12%, and +3% (significantly smaller with both active treatment groups, P < 0.01).

The PEARL II study was a double-blind non-inferiority trial that randomized 307 patients with symptomatic fibroids and excessive uterine bleeding to receive 3 months of daily therapy with oral UPA (at the same doses of either 5 mg or 10 mg) or once-monthly intramuscular injections of leuprolide acetate (LA) at a dose of 3.75 mg. The primary outcome in this study was the proportion of patients with controlled bleeding (defined as a PBAC score of < 75) at study end, with a prespecified non-inferiority margin of -20%. After 13 weeks of treatment, uterine bleeding was controlled in 90% of subjects receiving 5 mg, in 98% of those receiving 10 mg of UPA, and in 89% of those receiving leuprolide acetate. These differences compared to LA (1.2% [95% CI, -9.3 to 11.8] for 5 mg and 8.8 % [95% CI, 0.4 to 18.3] for 10 mg of UPA) were both within the non-inferiority margin. The median times to amenorrhea were 7 and 5 days for subjects receiving 5 mg and 10 mg of UPA, compared to 21 days for those receiving LA. Moderate-to-severe hot flashes were reported significantly less frequently (11% [5 mg] and 10% [10 mg] in subjects who received UPA than in those who received leuprolide acetate [40%, P < 0.001]).

Across both studies, headache and breast tenderness were the most commonly reported adverse events, but there was no difference between the UPA and placebo groups. Hot flushes occurred significantly more often (65% vs 26% and 24%) in women treated with leuprolide acetate than those treated with either dose of UPA.

Results of these two studies demonstrate that UPA is a well-tolerated and effective oral treatment regimen for heavy menstrual bleeding due to fibroids that is clinically equivalent to leuprolide acetate but better tolerated.

Commentary

More than 25 years ago, investigators began studying gynecologic applications for mifepristone, the selective progesterone receptor modulator (SPRM) also known as RU-486. In 1993, Samuel Yen's group in San Diego reported that treatment with 50 mg of RU-486 induced amenorrhea and resulted in a 50% reduction in fibroid volume over 12 weeks of treatment.1 Unfortunately, despite promising initial results, the politics of abortion largely stymied interest and limited funds by pharmaceutical companies to develop SPRMs as treatments for benign gynecologic problems such as fibroids and endometriosis.

Although mifepristone has been available in the United States since 2000, its use has been restricted to first trimester abortion. Some providers have expanded the off-label use to include second trimester abortion, but the high cost and limited availability of the drug has made other off-label uses in gynecology essentially impossible. Since mifepristone is now almost synonymous with medical abortion, it is naïve to believe it would ever find a place on pharmacy shelves in many parts of the country even if a supportive labeling for a gynecologic indication was approved.

Enter ulipristal acetate. Developed by the National Institutes of Health, this SPRM has been extensively tested in a number of gynecologic applications and as a contraceptive. It has not been studied or tested as an abortifacient. Ulipristal recently received FDA approval as a single-dose oral pill for emergency contraception (EC), after initial approval for the same indication by European regulatory authorities.2 Not only is UPA more effective than levonorgestrel (LNG) EC, it has an expanded window of use, up to 5 days after unprotected intercourse. Although the availability of a more effective EC is great news for American women, this indication unfortunately helps to link UPA with medical abortion in the minds of those opposed to family planning. Even though all of the available evidence support that both LNG and UPA act as emergency contraceptives by delaying or preventing follicle rupture, science seems to take a back seat to religious faith in the pursuit of truth regarding mechanism of action.3,4

Unencumbered by this anti-science culture, our European colleagues have moved ahead and will soon have approval for UPA for the treatment of fibroids. The results of these two studies demonstrate conclusively that UPA is a safe, effective oral treatment that shrinks fibroids and reduces bleeding. It works as well as a GnRH antagonist, but without the unpleasant side effect of hot flushes. Furthermore, it appears that UPA could be a long-term medical treatment that is not limited by bone loss, vaginal dryness, or other menopausal symptoms. One concern with long-term treatment is the presence of so-called progesterone receptor antagonist-associated benign endometrial changes.5 These do not appear to be associated with hyperplasia or endometrial cancer, but we will need to follow this story if long-term use becomes routine.

References

  1. Murphy AA, et al. Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 1993;76:513-517.
  2. Glasier AF, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: A randomised non-inferiority trial and meta-analysis. Lancet 2010;375:555-562.
  3. Croxatto HB, et al. Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation. Contraception 2004;70:442-450.
  4. Gemzell-Danielsson K, Meng CX. Emergency contraception: Potential role of ulipristal acetate. Int J Womens Health 2010;2:53-61.
  5. Brache V, et al. Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns, and endometrium in normal women. Contraception 2011 Dec 14. [Epub ahead of print].