Linzagolix With and Without Hormonal Add-Back Therapy for the Treatment of Symptomatic Uterine Fibroids: Two Randomized, Placebo-Controlled, Phase 3 Trials

Uterine fibroids occur in 50% to 60% of women and are symptomatic in 30% of patients by causing abnormal uterine bleeding and pelvic pressure. Treatment of uterine fibroids involves surgical and radiological interventions, as well as progestogens and other medical therapies. A new drug class (oral, nonpeptide, GnRH receptor antagonists) has shown the ability to reduce heavy menstrual bleeding but also reduces ovarian production of estradiol and is only approved for uterine fibroids in combination with hormonal add-back therapy to prevent hypoestrogenic effects. Linzagolix is an oral GnRH receptor antagonist that has a partial-suppression dose of 100 mg once daily and may reduce the requirement for hormonal add-back therapy, which is contraindicated in the setting of many risk comorbidities. Two phase 3 randomized, placebo-controlled trials (PRIMROSE 1 and PRIMROSE 2) were conducted to investigate the efficacy and safety of daily linzagolix (100 mg or 200 mg), both with and without hormonal add-back therapy for the treatment of signs associated with uterine fibroids. PRIMROSE 1 enrolled women at 94 sites in the United States between May 2017 and October 2020, whereas PRIMROSE 2 enrolled women at 95 sites in Europe and the United States from June 2017 to May 2020. Both trials had a 24-week off-treatment follow-up period after 52 weeks of treatment. Adult women with ultrasound-confirmed fibroids and heavy menstrual bleeding without a history of uterine surgery or undiagnosed uterine bleeding were included. Women were randomized in a 1:1:1:1:1 ratio to receive one of the following: (1) placebo, (2) 100 mg linzagolix daily, (3) 100 mg linzagolix daily with daily hormonal add-back therapy, (4) 200 mg linzagolix daily, or (5) 200 mg linzagolix daily with daily hormonal add-back therapy. The primary outcome was reduction in menstrual blood loss from baseline in the 28 days before week 24. Response rates for the proportion of women with reduced heavy menstrual bleeding at 24 weeks were calculated for each treatment group versus placebo. Patients underwent bone mineral density assessments of the lumbar spine, femoral neck, and total hip to evaluate for hypoestrogenic bone mineral density loss. A total of 511 patients were included in PRIMROSE 1 and 68% of women completed treatment, whereas 501 were included in PRIMROSE 2 and 85% completed treatment. The proportion of women with reduced menstrual bleeding was higher in all linzagolix treatment groups compared with placebo (all P's < 0.003). Median serum estradiol was suppressed to less than 20 pg/mL in the 200 mg linzagolix group, whereas concentrations in the other linzagolix groups were maintained at 30-50 pg/mL. Dose-dependent decreases in lumbar spine bone mineral density were observed, with a 4% decrease associated with 200 mg linzagolix and 2% decrease with 100 mg linzagolix, both of which were ameliorated by add-back therapy. Continued decreases were observed at 52 weeks. The results of these 2 large phase 3 randomized, placebo-controlled trials demonstrate that linzagolix was safe and effective in reducing heavy menstrual bleeding with or without add-back therapy; however, it did result in a sustained decrease in bone mineral density, especially when administered without hormonal add-back therapy.