Linzagolix rapidly reduces heavy menstrual bleeding in women with uterine fibroids: an analysis of the PRIMROSE 1 and 2 trials

OBJECTIVE: To study the timing of the effect of linzagolix, an oral gonadotropin-releasing hormone receptor antagonist, on significant reduction in heavy menstrual bleeding (HMB) in women with uterine fibroids. DESIGN: The study used pooled data from PRIMROSE 1 and PRIMROSE 2, two double-blind, similar placebo-controlled trials of linzagolix in the United States and Europe, respectively. Eligible participants were randomized equally across four treatment arms (linzagolix 100 mg and 200 mg, with and without concomitant hormonal add-back therapy ABT consisting of 1-mg estradiol and 0.5-mg norethisterone acetate) and one placebo arm. The cumulative incidence of achieving clinically significant HMB reduction and maintaining it to week 24 was compared between the linzagolix arms and the placebo arm using the Kaplan-Meier plots adjusted for confounding by race and study (PRIMROSE 1 vs. PRIMROSE 2). SUBJECTS: The PRIMROSE trials randomized 1,012 women aged ≥18 years with ultrasound-confirmed uterine fibroids and HMB. INTERVENTION: Linzagolix (100 mg and 200 mg, with and without hormonal ABT) vs. placebo. MAIN OUTCOME MEASURES: The main outcome of this analysis was the time to achievement of clinically significant HMB reduction and its maintenance up to week 24. RESULTS: The onset of action in achieving and maintaining clinically significant HMB reduction was significantly more rapid for the linzagolix treatment arms than for the placebo arm, with a median time of <4 weeks for most linzagolix doses (except 100 mg alone). The fastest onset was seen with linzagolix 200 mg with or without ABT doses, with a median time of only 3 days. The cumulative incidence of achieving clinically significant HMB reduction by week 4 and maintaining it to week 24 was also significantly higher for the linzagolix treatment arms than for the placebo arm. Specifically, across four linzagolix treatment arms, 23.2%-68.1% achieved clinically significant HMB reduction by week 4 and maintained it to week 24 vs. 7.8% for the placebo arm. CONCLUSION: Linzagolix was associated with a quick effect on reducing clinically significant HMB compared with placebo. Linzagolix, thus, offers a novel noninvasive treatment approach for the rapid management of HMB symptoms in patients with uterine fibroids.