Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy

Abstract

BACKGROUNDUterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormonereceptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODSWe conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTSA total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONSOnce-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIB-ERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium

“…Since African American women are at higher risk for both developing symptomatic uterine fibroids and vitamin D deficiency, several studies have focused on the role of vitamin D in fibroids and have noted that vitamin D deficiency could be an important risk factor for uterine fibroids [37][38][39][40][41][42]. A recent report showed that combination therapy of Relugolix and vitamin D improves outcomes for women with uterine fibroid symptoms, which could lead to fewer hysterectomies for women with clinically significant fibroids [43]. Many of these studies showed that expression of VDR is lower in fibroids.…”

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life

“…LS-BMD at 12 months: Elagolix 300 mg BID: placebo-controlled clinical trials compared relugolix 40 mg once daily administered with add-back therapy (1.0 mg estradiol/0.5 mg norethindrone) at the start of treatment (immediate add-back) or initiated after 12 weeks of monotherapy (delayed add-back) in premenopausal women with heavy menstrual bleeding and uterine fibroids. 69 During the first 12 weeks of treatment, total hip and lumbar spine BMD decreased by 1% and 2%, respectively, in the delayed add-back therapy group, and minimal decreases in lumbar spine BMD were observed in the immediate add-back therapy group. Initiation of estradiol and norethindrone acetate halted further BMD loss in the delayed add-back therapy group but did not reverse prior BMD decreases.…”

“…Add-back therapy has proved effective for mitigating hypoestrogenic effects associated with GnRH antagonists, including changes in BMD (Table 3). 64,65,67,69 At month 6 in 2 identical, phase 3, randomized, placebo-controlled clinical trials of elagolix in women with heavy menstrual bleeding and uterine fibroids, differences in BMD reduction at most measured sites were statistically significant for elagolix 300 mg twice daily alone compared with placebo ( p < 0.05), whereas changes from baseline in mean BMD in patients receiving elagolix 300 mg twice daily plus add-back therapy (1.0 mg estradiol/0.5 mg norethindrone acetate) were similar to the placebo group. 65 Patients enrolled in these phase 3 trials had the option of continuing treatment with elagolix or elagolix plus add-back therapy in a 6-month extension study.…”

“…One publication each was identified for the GnRH antagonists ASP1707, linzagolix, and relugolix (Table 3). [69][70][71] A phase 2, dose-ranging clinical trial assessed the efficacy and safety of ASP1707 3 to 15 mg once daily compared with placebo and monthly leuprolide acetate 3.75 mg in premenopausal women with endometriosis (N = 540). 70 Decreases in BMD at week 24 were observed in all active-treatment groups; however, the magnitude of decrease in total hip and spine BMD was significantly greater with leuprolide versus ASP1707 (-1.2% to -2.3% vs. -3.9%; p < 0.001).…”

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy

“…Both lesions can grow to notably large sizes; in such cases, surgery is strongly recommended to patients. Recent clinical phase 3 trials reported that relugolix combination therapy with 1 mg of estradiol and 0.5 mg of norethindrone acetate significantly improved abnormal bleeding with minor adverse vasomotor events, including hot flushes and headaches [ 23 , 23 ]. In our case, we did not prescribe the relugolix combination therapy, but used a traditional Japanese Kampo medicine, kamishoyosan, to ameliorate the adverse vasomotor effect induced by continuous relugolix administration for 2 months.…”