Elagolix May Be Effective for Reducing Pain From Endometriosis

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Hypoestrogenic adverse effects including reduced bone mineral density, increased lipid levels, and an increased incidence of hot flushes were reported in both elagolix dose groups.
Hypoestrogenic adverse effects including reduced bone mineral density, increased lipid levels, and an increased incidence of hot flushes were reported in both elagolix dose groups.

Both low and high doses of elagolix improved dysmenorrhea and nonmenstrual pelvic pain in endometriosis, according to research published in The New England Journal of Medicine.1

Hugh S. Taylor, MD, from the Yale School of Medicine in New Haven, Connecticut, and colleagues conducted 2 double-blind, randomized, 6-month, phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II] ClinicalTrials.gov identifiers: NCT01620528 and NCT01931670) to evaluate how 2 dosages of elagolix (low-dose group: 150 mg once daily; high-dose group: 200 mg twice daily) vs placebo would affect dysmenorrhea and nonmenstrual pelvic pain in women with endometriosis.

In the first trial, 872 women were randomly assigned to receive high- or low-dose elagolix and 653 (74.9%) completed the trial; in the second trial, 817 women were randomly assigned to receive high- or low-dose dose elagolix and 632 (77.4%) completed the trial. Reductions in pain were measured via the participants' pain scores and whether their use of rescue analgesics was decreased or stable.

At 3 months, significantly more women receiving both doses of elagolix had reductions in dysmenorrhea and nonmenstrual pelvic pain compared with women in the placebo group:

Elaris EM-I: Clinical response to dysmenorrhea:

  • 46.4% of women in the low-dose elagolix group
  • 75.8% of women in the high-dose elagolix group
  • 19.6% in the placebo group (P <.001 for all)

Elaris EM-I: Clinical response to nonmenstrual pelvic pain:

  • 50.4% of women in the low-dose elagolix group
  • 54.5% of women in the high-dose elagolix group
  • 36.5% in the placebo group (P =.003 for all)

Elaris EM-II: Clinical response to dysmenorrhea:

  • 43.4% of women in the low-dose elagolix group
  • 72.4% of women in the high-dose elagolix group
  • 22.7% in the placebo group (P <.001 for all)

Elaris EM-II: Clinical response to nonmenstrual pelvic pain:

  • 49.8% of women in the low-dose elagolix group
  • 57.8% of women in the high-dose elagolix group
  • 36.5% in the placebo group (P <.001 for all)

These clinical responses were sustained at 6 months.

Pain Scores

At 6 months in the Elaris EM-I trial, scores on the Numeric Rating Scale were -1.74±0.12 for women in the low-dose elagolix group, -2.39±0.12 for women in the high-dose group, and -1.09±0.10 in the placebo group.

At 6 months in the Elaris EM-II trial, scores on the Numeric Rating Scale were -1.90±0.12 for women in the low-dose elagolix group, -2.55±0.12 for women in the high-dose group, and -1.33±0.10 in the placebo group.

Decreased or Stable Use of Rescue Analgesic Agents

At 6 months, the percentages of women with decreased or stable use of rescue analgesic agents were:

  • Elaris EM-I for dysmenorrhea: 42.1% in the low-dose group, 75.3% in the high-dose group, and 23.1% in the placebo group
  • Elaris EM-I for nonmenstrual pelvic pain: 45.7% in the low-dose group, 62.1% in the high-dose group, and 34.9% in the placebo group
  • Elaris EM-II for dysmenorrhea: 46.2% in the low-dose group, 76.9% in the high-dose group, and 25.4% in the placebo group
  • Elaris EM-II for nonmenstrual pelvic pain: 51.6% in the low-dose group, 62.2% in the high-dose group, and 40.6% in the placebo group

Adverse Effects

Hypoestrogenic adverse effects including reduced bone mineral density, increased lipid levels, and an increased incidence of hot flushes were reported in both elagolix dose groups. The researchers noted that the “[adverse effects were] similar to those of injectable GnRH [gonadotropin-releasing hormone] agonists, but the magnitude of the effects may differ.”

At 6 months, the mean percentage changes from baseline in bone mineral density were:

  • Elaris EM-I, lumbar spine: -0.32% in the low-dose group (P <.01), -2.61% in the high-dose group (P <.001), 0.47% in the placebo group
  • Elaris EM-I, total hip: -0.32% in the low-dose group (P <.01), -1.52% in the high-dose group (P <.001), 0.22% in the placebo group
  • Elaris EM-I, femoral neck: -0.39% in the low-dose group (not significant), -1.89% in the high-dose group (P <.001), 0.02% in the placebo group
  • Elaris EM-II, lumbar spine: -0.72% in the low-dose group (P <.001), -2.49% in the high-dose group (P <.001), 0.56% in the placebo group
  • Elaris EM-II, total hip: -0.47% in the low-dose group (P <.001), -1.58% in the high-dose group (P <.001), 0.58% in the placebo group
  • Elaris EM-II, femoral neck: -0.35% in the low-dose group (P <.05), -1.42% in the high-dose group (P <.001), 0.31% in the placebo group

“In ongoing analyses, we are assessing whether these decrements are reversible after the discontinuation of elagolix, as has been reported with leuprolide acetate,” the researchers wrote.2 “After 6 months of treatment, fewer than 5% of the women in the elagolix groups had a z score of -1.5 or less for bone mineral density at the lumbar spine.”

There were no adverse endometrial findings.

Summary and Clinical Applicability

High and low dosages of elagolix (150 mg once daily and 200 mg twice daily, respectively) were effective in reducing dysmenorrhea and nonmenstrual pelvic pain in endometriosis. The high dose of elagolix was associated with hypoestrogenic adverse effects, including hot flushes and changes in bone mineral density and lipid levels.

Limitations and Disclosures

  • The 2 trials were limited by entry criteria and length of the intervention period (for example, the effect of elagolix was not assessed in women with a z score of less than -1.5 for bone mineral density or in women with large endometriomas)
  • Staging of endometriosis was incomplete and not used in the analysis because surgical diagnoses had occurred within the previous 10 years
  • These 2 trials were limited to 6 months of treatment, but long-term or repeated courses of elagolix are likely necessary for medical management

These trials were funded by AbbVie.

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References

  1. Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist [published online May 19, 2017]. NEJM. doi:10.1056/NEJMoa1700089
  2. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol. 2002; 99:709-719.
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