It was approved by the U.S. Food and Drug Administration on July 23, 2018, for the treatment of moderate to severe pain caused by endometriosis. It was approved under priority review, a designation reserved for medications that have the potential to significantly improve treatment outcomes for a certain disease.
Endometriosis affects approximately 1 in 10 women. It can cause significant pain and reduce quality of life. Orilissa is also being evaluated to treat uterine fibroids.
How Orilissa works
Orilissa is a molecule that dampens the effect of gonadotropin-releasing hormone (GnRH), a hormone produced in the brain that stimulates the production and secretion of ovarian hormones.
Orilissa works by blocking hormone receptors on the pituitary gland (a part of the brain responsible for producing a majority of the body’s hormones) to which GnRH binds. In this way, GnRH’s action is stopped, and the production of ovarian hormones inhibited.
Estrogen is the main hormone that incites the abnormal growth of endometrial cells in women with endometriosis. By decreasing levels of estrogen, Orilissa is able to reduce inflammation and relieve endometriosis-associated pain.
Orilissa in clinical trials for endometriosis
Orilissa’s approval was supported by data from two large, randomized, double-blind Phase 3 clinical trials: the Elaris EM-I study (NCT01620528) and the Elaris EM-II study (NCT01931670). Together, these studies evaluated the effects of two doses of Orilissa, 150 mg once daily and 200 mg twice daily, compared with placebo, in almost 1,700 women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain.
Both studies assessed changes in daily nonmenstrual pelvic pain and menstrual cramps before treatment, and at three and six months after treatment. Both doses of Orilissa significantly reduced nonmenstrual pelvic pain and menstrual cramps associated with endometriosis at three and six months. 200 mg doses of Orilissa were also able to significantly reduce pain associated with sexual intercourse in the third month after the start of treatment.
Both doses caused side effects such as hot flushes and a decrease in bone thickness, known as bone mineral density. However, these effects are consistent with the partial hormone suppression associated with the treatment’s mechanism of action.
The six-month pivotal Phase 3 trials then rolled into two replicate Phase 3 extension studies: Elaris EM-III (NCT01760954), an extension of Elaris EM-I, and Elaris EM-IV (NCT02143713), an extension of Elaris EM-II. Both extension studies evaluated the long-term safety and effectiveness of Orilissa for an additional six months, with doses of 150 mg once daily and 200 mg twice daily.
Results from both extension studies showed that Orilissa reduced nonmenstrual 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.
Orilissa in clinical trials for uterine fibroids
Other clinical trials evaluated Orilissa as a treatment for heavy bleeding due to uterine fibroids, or scarring.
A randomized, double-blind, placebo-controlled Phase 2b trial (NCT01817530) evaluated the safety and effectiveness of Orilissa alone and in combination with hormonal therapy (estradiol/norethindrone acetate, also known as hormonal add-back therapy), compared with 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.
The results showed that Orilissa effectively and rapidly reduced heavy menstrual bleeding, with and without add-back therapy, compared with placebo. Orilissa was well-tolerated, and patients experienced decreases in symptom severity as well as an improved quality of life. Some noted side effects were hot flushes, headaches, and insomnia. Orilissa taken with hormonal add-back therapy was able to reduce hot flushes and decreases 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 effectiveness of twice-daily 300 mg doses of Orilissa, both alone and in combination with add-back therapy. 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, measured by levels of a substance known as alkaline hematin before treatment and six months after treatment begins.
Besides stimulating endometrial cell growth, estrogen is fundamental to bone growth. GnRH antagonists such as Orilissa can lead to bone thinning, or loss of bone density, because it reduces estrogen levels. For this reason, Orilissa should be avoided in those known to have osteoporosis, a condition that causes bone thinning.
Other common side effects associated with the use of Orilissa include hot flushes, headaches, nausea, and fatigue. While most adverse events occur regardless of the dose of Orilissa, some, such as hot flushes and bone mineral density loss, are dose-dependent.
Orilissa may also cause changes in the pattern of menstrual bleeding, possibly affecting a woman’s ability to recognize pregnancy. Additionally, estrogen-based contraceptive pills may reduce the effectiveness of Orilissa.
Orilissa should not be used by women who are pregnant, \have liver problems, or are using medications that function as organic anion transporting polypeptides (OATP)1B1 inhibitors.
Orilissa is available in either once-daily 150 mg or 200 mg doses that can be taken with or without food.
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