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Elagolix, a gonadotropin-releasing hormone antagonist, was effective in improving pain relief with menstruation and pelvic pain among women with endometriosis compared with use of placebo, according to the results of two phase III clinical trials.

Both trials tested a higher dose (200 mg twice daily) and a lower dose (150 mg once daily) of elagolix and found that a significantly higher proportion of women in the intervention groups had a clinically meaningful reduction in dysmenorrhea and non-menstrual pelvic pain versus controls, reported Hugh S. Taylor, MD, chair of Obstetrics, Gynecology, and Reproductive Sciences at Yale University, and colleagues.

However, adverse events included hot flushes, decreases in bone mineral density, and higher levels of serum lipids, all of which were significantly higher in the intervention groups, the authors wrote online in the

The study was presented simultaneously at the 13th World Congress on Endometriosis in Vancouver.

for endometriosis pain include nonsteroidal anti-inflammatory drugs (NSAIDs) and progestin-containing oral contraceptives, the authors explained. Injectable depot forms of gonadotropin-releasing hormone (GnRH) agonists are considered second-line therapies.

However, although the authors argued that injectable GnRH agonists are "effective" and "reduce estrogen levels to postmenopausal levels," since side effects include progressive bone loss and severe vasomotor symptoms, the agents for 6 months without hormone-replacement therapy.

Taylor et al noted that phase II trials of oral, non-peptide elagolix in controlling dysmenorrhea and non-menstrual pelvic pain, with "partial estrogen suppression" . However, a of elagolix at 200 mg twice daily "led to nearly full estrogen suppression."

The team conducted two multicenter, double-blind, randomized, 6-month, phase III trials -- called Elaris Endometriosis I and II (EM-I and EM-II, respectively). Premenopausal women from ages 18 to 49 who received a surgical diagnosis of endometriosis in the previous 10 years were eligible to participate.

Prior to the 6-month treatment period, women discontinued use of hormone-replacement therapy, if applicable, and switched from use of usual analgesic agents to "rescue medication" of 500 mg of naproxen, an opioid according to country or both. Patients were then treated for 6 months and followed for up to 12 months.

Overall, 653 women in Elaris EM-I and 632 in Elaris EM-II completed treatment. Women were a mean age of 31 to 33, over 85% were white, mean body mass index was 27 to 28, and all had a surgical diagnosis of endometriosis for over 40 months.

A significantly higher portion of both high-dose and low-dose elagolix groups had a clinically meaningful reduction in dysmenorrhea and decreased or stable use of rescue analgesic agents for pain at 3 months of treatment:

• 75.8% (EM-I high-dose), 46.4% (EM-I low-dose),EM-I: 19.6% (EM-I placebo, P<0.001 for all)
• 72.4% (EM-II high-dose), 43.4% (EM-II low-dose), 22.7% (EM-II placebo, P<0.001 for all)

Similar results were seen in the proportion of women with a clinically meaningful reduction in non-menstrual pelvic pain and decreased or stable use of analgesics at 3 months:

• 54.5% (EM-I high-dose), 50.4% (EM-I low-dose), EM-I: 36.5% (EM-I placebo, P<0.001 for all)
• 57.8% (EM-II high-dose), 49.8% (EM-II low-dose), 36.5% (EM-II placebo, P<0.001 for high-dose, P=0.003 for low-dose)

Secondary endpoints included reduction in pain from baseline to 3 months as measured with the Numeric Rating Scale, as well as significant reductions from baseline to 6 months in pain scores for dysmenorrhea and non-menstrual pelvic pain. These reductions were "apparent at 1 month and sustained at 6 months," the authors said.

Regarding safety, a significantly greater portion of women in the intervention groups reported "mild or moderate" hot flushes. Most women in the intervention groups also had significantly greater mean decreases in bone mineral density at the lumbar spine, femoral neck, and total hip from baseline to 6 months. Lipid measurements, such as total cholesterol, LDL and HDL cholesterol, and triglycerides, significantly increased from baseline to 6 months for most women in the intervention group.

There was one death (a suicide) in the lower-dose elagolix group in the EM-II trial. Overall, 10% or less of the women discontinued participation due to adverse events. There were 23 pregnancies in both trials, including eight in the intervention groups. Of those, there were three live births, one spontaneous abortion, two pregnancy terminations, and two losses to follow-up.

The authors noted that "elagolix did not completely suppress ovulation at either of the two doses," despite the women being instructed to use non-hormonal contraception during the trial. But the team cautioned that no conclusions on the effect of the drug on pregnancy could be made, due to the small number of pregnancies.

Limitations to the data include the entry criteria (excluding women with a z-score of less than -1.5 for bone mineral density or women with large endometriomas) and the length of the intervention period.

The researchers noted that because these trials were limited to 6 months of treatment, "longer-term or repeated courses" of the drug will likely be needed for medical management. The authors also recommended "additional evaluation of the overall safety profile" of the drug over multiple courses of treatment.

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