EXECUTIVE SUMMARY

Elagolix, a gonadotropin-releasing hormone (GnRH) antagonist used to treat endometriosis pain, is being studied for treatment of uterine fibroids and heavy menstrual bleeding in women.

• The drug, marketed as Orilissa, was approved by the FDA in July 2018 for the treatment of moderate to severe endometriosis pain.

• Uterine fibroids account for one-third to half of all hysterectomies. They also are associated with substantial morbidity and healthcare costs for reproductive-age women. Pharmaceutical treatment approaches to heavy menstrual bleeding due to fibroids include GnRH analogs such as leuprolide acetate, as well as nonspecific hormonal treatments such as birth control pills.


Elagolix, a gonadotropin-releasing hormone (GnRH) antagonist currently used in the treatment of endometriosis pain, is now being studied for treatment of uterine fibroids and heavy menstrual bleeding in women.1 The drug, marketed as Orilissa, was approved by the FDA in July 2018 for the treatment of moderate to severe endometriosis pain.

Researchers enrolled 790 women, ages 18-51 years who experienced heavy bleeding due to fibroids, into two identical, double-blind, randomized, placebo-controlled, six-month Phase III trials. Participants were randomly assigned to three study arms. The first group received elagolix, which reduces the production of estrogen and progesterone. Scientists believed it would shrink fibroid size and reduce bleeding. The second group received elagolix and a low dose of estrogen and progestin, with the aim of reducing hot flashes and bone loss, two side effects of elagolix. The remaining group received identical placebo pills. All study participants underwent ultrasound to confirm uterine fibroids and heavy menstrual bleeding (defined as more than 80 mL of blood loss per cycle) for at least two cycles. One trial was conducted at 76 sites in the United States from December 2015 through December 2018. The second trial was performed at 77 sites in the U.S. and Canada from February 2016 through January 2019.

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Researchers reported that 80.4% of the women treated with elagolix alone experienced a 50% or more reduction in menstrual bleeding, compared to 9.6% of the women in the placebo group. Seventy-two percent of women treated with elagolix and supplemental estrogen/progestin therapy reported a reduction of 50% or more. While women who were treated with elagolix alone showed more bone mineral loss compared with the women treated with placebo, there was no difference between the loss of bone mineral in the group treated with elagolix and the supplemental hormones as compared to those in the placebo group.1

Uterine fibroids account for one-third to one-half of all hysterectomies. Fibroids are associated with substantial morbidity and healthcare costs for reproductive-age women.2

Which nonsurgical treatment options are available for heavy menstrual bleeding due to fibroids? Uterine artery embolization and high-intensity focused ultrasound are two options, notes William Schlaff, MD, chair of the department of obstetrics and gynecology at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia. Schlaff led the two current trials of elagolix. Pharmaceutical approaches include GnRH analogs such as leuprolide acetate, as well as nonspecific hormonal treatments such as birth control pills. Medications and procedures may or may not be FDA-approved for use in treating fibroids, states Schlaff.

Tranexamic acid has been used as first-line treatment for heavy menstrual bleeding, and is frequently used for women with small fibroids despite limited evidence.3 Use of mefenamic acid, a nonsteroidal anti-inflammatory drug commonly used for dysmenorrhea, has registered modest reduction in heavy menstrual bleeding in women without fibroids, although it is less effective than tranexamic acid.3 No clinical trials have been conducted on its effect on fibroids.4

Ulipristal, a selective progesterone receptor modulator, is approved and marketed in Europe as Esmya for the preoperative and intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age. However, the FDA rejected approval of the drug in 2018 for such use in the United States because of concerns of liver injury. The European Medicines Agency issued new measures to protect women, including liver tests before, during, and after stopping treatment.5

Scientists also are examining relugolix, an oral GnRH antagonist, for use in fibroid treatment. In women with uterine leiomyomas, once-daily treatment with the drug demonstrated noninferiority to monthly leuprorelin in decreasing heavy menstrual bleeding.6 The drug, under development by Myovant Sciences, is involved in two international advanced clinical trials.

REFERENCES

  1. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 2020;382:328-340.
  2. Stewart EA, Laughlin-Tommaso SK, Catherino WH, et al. Uterine fibroids. Nat Rev Dis Primers 2016;2:16,043.
  3. Goldstein SR, Lumsden MA. Abnormal uterine bleeding in perimenopause. Climacteric 2017;20:5414-5420.
  4. Lethaby A, Augood C, Duckitt K, et al. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2007;CD000400.
  5. European Medicines Agency. Esmya: New measures to minimise risk of rare but serious liver injury, July 26, 2018. Available at: https://bit.ly/3bqWnNr.
  6. Osuga Y, Enya K, Kudou K, et al. Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: A randomized controlled trial. Obstet Gynecol 2019;133:423-433.