Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.  

Exciting Phase 3 trials of Elagolix for Endometriosis-Associated Pain

Key Points

Highlight:

• Elagolix improved dysmenorrhea and non-menstrual pelvic pain during a 6 months double-blind, randomized, placebo-controlled phase 3 clinical trial study.

Importance:

• Elagolix can reduce endometriosis-associated pain

What's done here:

• A total 653 women with endometriosis completed this study.
• They were randomized to receive either 150 mg elagolix once daily (low dose group), 200 mg elagolix twice daily (high dose group), or a placebo.
• The primary end points were the proportion of women with the clinical response with respect to menstrual and non-menstrual pelvic pain.

Data:

• With respect to menstrual pain, in the first group women received low and high dose elagolix had 46.4% and 75.8% clinical response, as compared to placebo at 19.6%. In the second group, these were 43.4% and 72.4%, as compared to 22.7%, respectively.
• With respect to non-menstrual pelvic pain, the percentages were not as high, 50.4% in low dose, 54.5% in high dose and 36.4% in placebo for the first study; and 49.8%, 57.8% and 36.5%, respectively for the second study.
• All comparisons were statistically significant and these responses were collected at 3 months and were sustained at 6 months.
  
  Limitations:
• Drug side effects – mild to moderate hot flashes, higher levels of serum lipids, reduce bone mineral density
• Study limitation – Incomplete endometriosis staging data, longer follow-up of greater than 6 months may be more informative as long-term or repeated elagolix likely needed for management
• No conclusion on the effect of elagolix in pregnancy

Lay Summary

Taylor et al. presented an exciting recent study in The New England Journal of Medicine. This article reported the results from a multicentre, double-blind, randomized, placebo-controlled phase 3 trials of elagolix for the treatment of endometriosis-associated pain. As women with endometriosis can relate, these painful symptoms include dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, which can significantly affect the quality of life.

Current therapies include nonsteroidal anti-inflammatory drugs (NSAIDs), progestin-containing oral contraceptives, and gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate. The latter two are associated with side effects, and surgical approaches are also available, but often can recur within 12 months. Hence, new medicines for endometriosis are needed. Elagolix is a GnRH antagonist that is orally given and works by competitively inhibiting GnRH receptors in the pituitary gland, thus reducing circulating gonadotropins and estradiol. The suppression of estradiol is a key factor in the management of endometriosis.

This study consists of two trials, Elaris Endometriosis I (EM-I) and Elaris Endometriosis II (EM-2), whereby 653 and 632 women completed the trials, respectively. Recruited women were randomized into groups received either 150 mg elagolix once daily (low dose group), 200 mg elagolix twice daily (high dose group), or a placebo. The primary end points measurements were the proportion of women with the clinical response with respect to menstrual and non-menstrual pelvic pain. These responses were measured at 3 months and 6 months during the trials.

At the 3 months responses, the results showed that women in EM-I who received low and high dose elagolix had 46.4% and 75.8% clinical response with respect to dysmenorrhea, as compared to placebo at 19.6%. In EM-II, these were 43.4% and 72.4%, as compared to 22.7%, respectively. About non-menstrual pelvic pain, the percentages were not as high, 50.4% in low dose, 54.5% in high dose and 36.4% in placebo for EM-I study; and 49.8%, 57.8% and 36.5%, respectively for EM-II. All comparisons were statistically significant and were sustained at 6 months. Moreover, at both 3 and 6 months, women in the high-dose groups were taking a lower amount of rescue analgesic agents, including NSAIDs or opioids.

In regards to safety, 10% or fewer women discontinued their participation because of adverse events. The most frequently reported were hot flushes, headache, and nausea. The incidence of mild and moderate hot flashes was significantly higher with either low or high dose of elagolix in comparison with placebo. Other concerns include decreases in bone mineral density at 6 months and an increase in lipid measurements including cholesterol and triglycerides.

In conclusion, these trials show the highly promising use of elagolix for managing endometriosis-associated pain. Future studies may be needed to assess longer term use and also the potential effect on pregnancy.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/28525302