The two companies are also assessing elagolix’s effect in women with uterine fibroids.
How elagolix works
Elagolix is a molecule that dampens the effect of gonadotropin-releasing hormone (GnRH) — a molecule produced in the body that stimulates the synthesis and secretion of ovarian hormones.
Elagolix blocks hormone receptors that GnRH binds to, subsequently inhibiting GnRH’s ability to produce other hormones, including estrogen that is linked to the development of endometriosis.
In this way, elagolix stops the abnormal growth of endometrial cells in women with endometriosis, decreasing inflammation and relieving pain.
Elagolix in clinical trials for endometriosis
Researchers have concluded two similar, double-blind, randomized, six-month Phase 3 clinical trials: the Elaris EM-I study (NCT01620528) and the Elaris EM-II study (NCT01931670). Together, the studies evaluated the effects of two doses of elagolix — 150 mg once daily and 200 mg twice daily — as compared to placebo in almost 1,700 women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain.
Both the studies assessed changes in daily non-menstrual pelvic pain and daily menstrual cramps before treatment, and again at three and six months after the treatment began. Both doses of elagolix in both studies reduced, with statistical significance, non-menstrual pelvic pain and menstrual cramps associated with endometriosis at three and six months. The higher dose showed a significant reduction in pain associated with intercourse at month three. However, both doses were associated with side effects such as hot flushes and a decrease in bone mineral density. These effects were consistent with the partial hormone suppression associated with the treatment’s mechanism of action.
Based on positive results from these two pivotal Phase 3 studies, the U.S. Food and Drug Administration (FDA) granted priority review for the new drug application, filed by AbbVie in September 2017 requesting elagolix be approved as a treatment for endometriosis.
The six-month pivotal Phase 3 studies then rolled into two replicate Phase 3 extension studies: Elaris EM-III (an extension study of Elaris EM-I, NCT01760954) and Elaris EM-IV (an extension study of Elaris EM-II, NCT02143713). Both extension studies evaluated the long-term safety and efficacy of elagolix for an additional six months, with doses of 150 mg once daily and 200 mg twice daily.
Results from both extension studies showed that elagolix reduced non-menstrual pelvic pain and menstrual cramps associated with endometriosis throughout 12 months of treatment. The higher dose again showed a better reduction in pain associated with intercourse after 12 months. No new safety concerns were seen with long-term use of elagolix.
Elagolix in clinical trials for uterine fibroids
Other clinical trials evaluated elagolix as a treatment for heavy bleeding due to uterine fibroids, or scarring.
A randomized, double-blind, placebo-controlled Phase 2b clinical trial (NCT01817530) evaluated the safety and efficacy of elagolix alone and in combination with hormonal add-back therapy (estradiol/norethindrone acetate), compared to placebo, in 567 women with heavy menstrual bleeding associated with uterine fibroids. The study was conducted at 100 sites in the U.S., Canada, Puerto Rico, Chile, and the U.K.
Results showed that elagolix effectively and rapidly reduced heavy menstrual bleeding, with and without add-back therapy, compared to placebo. Elagolix was also seen to be well-tolerated, with continuous treatment associated with decreased symptom severity and improved quality of life. The side effects observed were hot flush, headache, and insomnia. Add-back therapy reduced the occurrence of hot flush and the decrease in bone mineral density.
A Phase 3 program is ongoing and includes two pivotal, six-month studies (NCT02654054 and NCT02691494), followed by a six-month extension study (NCT02925494). The studies are assessing the safety and efficacy of 300 mg twice daily doses of elagolix both alone and in combination with add-back therapy (estradiol/norethindrone acetate). Each of the studies enrolled about 400 women with heavy menstrual bleeding due to uterine fibroids across the U.S., Canada, and Puerto Rico.
The Phase 3 studies will compare the percentage of women with a reduction in uterine blood flow, as measured by alkaline hematin levels before treatment and six months after treatment began.
Other details about elagolix
Estrogen is one of the hormones produced by the ovaries. Besides stimulating endometrial cell growth, estrogen is fundamental to bone growth. GnRH antagonists lead to bone density loss because they reduce estrogen levels. Since elagolix has less impact on estrogen levels than other GnRH antagonists, it is thought to possibly have a lesser effect on bone growth.
Elagolix can lead to infertility due to the menstrual cycle changes it causes. Other common adverse events associated with its use include hot flushes, headaches, nausea, and fatigue. While most adverse events are seen to be similar across groups regardless of elagolix dose, some, such as hot flushes and bone mineral density loss, are dose-dependent.
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