Regulatory Decision Summary for Orilissa

The efficacy and safety of Orilissa (elagolix) in the treatment of moderate to severe pain associated with endometriosis was demonstrated in two double-blind, randomized, placebo-controlled, multicentre Phase 3 studies. The studies enrolled premenopausal women 18 to 49 years of age who had a clinical diagnosis of endometriosis, confirmed by laparoscopy/laparotomy within the previous 10 years. In all, the two studies randomized 1686 patients to placebo or one of two doses of Orilissa (150 mg once daily or 200 mg twice daily, for a total of 952 Orilissa-treated patients).

The reduction in pain associated with endometriosis was assessed over 6 months of treatment, using electronic daily diaries, validated questionnaires for pain and quality of life assessment, and monitoring of analgesic use. The study co-primary efficacy endpoints were the proportion of responders for menstrual pain, or dysmenorrhea (DYS), and non-menstrual pelvic pain (NMPP) after 3 months of Orilissa treatment, compared to placebo-treated patients. The patients were considered responders if they experienced a defined, clinically meaningful reduction in DYS and/or NMPP, without increased analgesic use. The effect of Orilissa on endometriosis lesions was not directly measured.

At Month 3, a greater proportion of women treated with either dose of Orilissa were responders for DYS and NMPP compared to placebo, with a dose response evident, and persistence of efficacy was demonstrated through Month 6. More than 75% of women who completed the two studies were elected to continue in two blinded extension studies for an additional 6 months, during which patients who had received placebo were switched to one of the Orilissa doses, and durability of the improvement in DYS and NMPP was observed over a total of 12 months.

The main safety concerns associated with Orilissa therapy are chiefly due to its hypoestrogenic effects, and include hot flushes, night sweats, mood changes, headaches, and changes in menstrual flow, as well as increases in serum lipids. Of particular concern is a time- and dose-dependent loss of bone mineral density. This risk has been addressed by limiting Orilissa treatment to 12 months for the 150 mg daily dose, and 6 months for the 200 mg twice daily dose. Since hepatic metabolism is the major route of elimination of elagolix, treatment is limited to a dose of 150 mg daily for 6 months for women with moderate hepatic impairment, and Orilissa is contraindicated in women with severe hepatic impairment. Use of Orilissa is also not advised in women at increased risk for osteoporosis.

Mood changes, depression and suicidal ideation have been reported in women taking Orilissa, therefore the Product Monograph (PM) contains warnings to monitor for depressive symptoms. Dose-dependent elevations of hepatic transaminases (i.e. ALT) have also occurred during Orilissa treatment; therefore, warnings are included in the PM to monitor patients for signs of liver injury and to promptly investigate elevations in liver function tests.

Orilissa is not a contraceptive and its safety during pregnancy has not been established, therefore women treated with Orilissa must use an effective contraceptive method not containing estrogen, which might compromise the efficacy of Orilissa. The PM also advises that Orilissa frequently causes alterations in menstrual bleeding patterns (including amenorrhea) and recommends prompt pregnancy testing if pregnancy is suspected, with prompt discontinuation of Orilissa therapy until pregnancy is excluded.