Combination therapy with relugolix, an investigational oral gonadotropin-releasing hormone antagonist, estradiol, and norethindrone acetate effectively preserved bone mineral density (BMD) in two replicate phase 3 studies enrolling women with heavy menstrual bleeding associated with uterine fibroids.
The BMD findings, released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists, build upon previously reported positive primary endpoint data from the LIBERTY 1 and LIBERTY 2 studies. ACOG canceled the meeting and released abstracts for press coverage.
The developer of the drug, Myovant Sciences, plans to submit a new drug application to the Food and Drug Administration for approval of the single-tablet combination therapy for women with uterine fibroids, according to Albert Liao, the company’s director of corporate communications.
The two multinational LIBERTY studies randomized women who had a monthly menstrual blood loss volume of at least 80 mL in two consecutive cycles (or 160 mL in one cycle) in a 1:1:1 ratio to one of three groups: relugolix combination therapy for 24 weeks (once-daily relugolix 40 mg plus estradiol 1.0 mg plus norethindrone acetate 0.5 mg); relugolix alone (40 mg once daily) for 12 weeks followed by relugolix combination therapy for 12 weeks; or placebo for 24 weeks.
In October 2019 at the American Society for Reproductive Medicine Scientific Congress, investigators reported that 73% of women receiving combination therapy in the LIBERTY 1 trial achieved a menstrual blood loss of less than 80 mL and a 50% or greater reduction from baseline over the last 35 days of treatment, compared with 19% in the placebo group. The mean percent reduction in menstrual blood loss from baseline at week 24 was 84% for combination therapy and 23% for placebo.
Earlier in 2019, Myovant Sciences announced that, in the LIBERTY 2 study, 71% of women receiving combination therapy met the primary endpoints, compared with 15% in the placebo group. The reduction in menstrual blood loss in this study’s combination therapy arm was also 84%, according to a company press release from June 2019.
Each of the two clinical trials enrolled upwards of 380 women.
The new abstract released for press coverage by ACOG and published inreports that women receiving relugolix combination therapy in the LIBERTY 1 and LIBERTY 2 studies had a mean change in lumbar spine BMD of –0.36% and –0.13%, respectively, from baseline to 24 weeks. Percent change in lumbar spine BMD in the delayed combination therapy groups (12 initial weeks of relugolix monotherapy) was –1.82% and –2.12%. In the placebo groups, the change was 0.05% and 0.32%.
, who is the lead author of the abstract and was scheduled to present the findings at the ACOG meeting, said in an interview that the slight decreases in lumbar spine BMD with combination therapy were noted largely at week 12 and are “clinically insignificant in my opinion.” BMD by dual-energy x-ray absorptiometry was assessed at weeks 12 and 24.
“There was no further increase [after week 12] and [in some patients] there was even a return to baseline,” said Dr. McClung, of the Oregon Osteoporosis Center in Portland.
The safety and efficacy of longer-term treatment with relugolix combination therapy has been investigated thus far through an open-label extension study that brought the treatment period to 52 weeks. The 1-year data has been positive and will be presented or published soon, said Mr. Liao. In addition, a “second, 52-week randomized withdrawal study has been designed to provide 2-year safety and efficacy data … and to evaluate the need for maintenance therapy.”
It’s important, Dr. McClung said, “for clinicians to be confident that BMD loss is prevented or minimized with longer-term relugolix combination therapy since treatment for uterine fibroids is not a short-term proposition. Given the stability of BMD values between weeks 12 and 24 in the LIBERTY studies, I’d anticipate that we will see stable values with longer-term treatment.”
Dr. McClung disclosed that he has served as a consultant/advisory board member and speaker for Amgen and a consultant/advisory board member for Myovant. Several of his coauthors disclosed employment and ownerships interests in Myovant.
SOURCE: McClung MR et al. Obstet Gynecol. 2020 May.