Pfizer/Myovant's Oral GnRH Receptor Antagonist Relugolix Combination Therapy Shows Significant Improvement in Heavy Menstrual Bleeding and Pain in Uterine Fibroids

February 18, 2021 News /BioValleyBIOON/ ---PfizerPfizer and Myovant Sciences recently announced that the results of two Phase 3 studies (LIBERTY 1 and LIBERTY 2) evaluating once-daily relugolix combination tablets (relugolix 40 mg, estradiol 1.0 mg, and norethisterone acetate 0.5 mg) for the treatment of uterine fibroids in women were published in the New England Journal of Medicine (NEJM). As previously reported, both studies met the primary endpoint of response rate for heavy menstrual bleeding, as well as six of the seven key secondary endpoints. The relugolix combination tablet also maintained bone mineral density comparable to placebo, reflecting a favorable safety profile with good tolerability over 24 weeks.

The two most common symptoms of uterine fibroids are heavy menstrual bleeding (HMB) and pain. The relugolix combination tablet, administered orally once daily, is currently under review by regulatory authorities in the United States and Europe for the treatment of moderate to severe symptoms associated with uterine fibroids in women. In the United States, the Prescription Drug User Fee Act (PDUFA) target action date is June 1, 2021. If approved, the relugolix combination tablet will provide a once-daily, one-pill treatment option for women with uterine fibroids.

The Phase III LIBERTY program for uterine fibroids comprised two multinational, pivotal, repeatable Phase III clinical studies (LIBERTY 1 and LIBERTY 2), which enrolled women with uterine fibroids and heavy menstrual bleeding to evaluate 24 weeks of treatment with relugolix combination tablets. Patients who completed both studies and met eligibility criteria had the opportunity to enroll in an active-treatment extension study. In this extension study, all patients received relugolix combination tablets for 28 weeks, resulting in a total treatment duration of 52 weeks, with the aim of assessing the safety and efficacy of long-term treatment. Following the completion of this 52-week total treatment period, eligible patients could opt to participate in a second 52-week randomized withdrawal study, designed to provide 2-year safety and efficacy data for relugolix combination tablets and to assess the necessity of maintenance therapy. Across all studies, treatment response was defined as a reduction in menstrual blood loss of ≥80 mL relative to baseline and a ≥50% decrease from baseline during the last 35 days of treatment, as measured by the alkaline hematin method.

Uterine Fibroids (Image Source: clinicaladvisor.com)

The results showed that both the LIBERTY 1 and LIBERTY 2 studies met their primary endpoints (p<0.0001): (1) At Week 24 of treatment, 73.4% and 71.2% of patients receiving the relugolix combination tablet achieved the response criteria, compared with 18.9% and 14.7%, respectively, in the placebo groups (both p<0.001); (2) On average, across the two studies, patients treated with the relugolix combination tablet experienced an 84.3% mean reduction in menstrual blood loss from baseline (p<0.0001).

In the two studies, 6 of the 7 key secondary endpoints measured at Week 24 achieved statistical significance, including: mean reduction in menstrual blood loss, amenorrhea, pain reduction in women with baseline pain, improvement in Bleeding and Pelvic Discomfort Scale scores, and reduction in uterine volume (all p < 0.001 vs. placebo); presence at baseline examinationAnemiaimprovement in anemia in women (p < 0.05 vs. placebo for both). Furthermore, among approximately 50% of women who had moderate to severe pain at baseline, the proportion of women treated with relugolix combination tablets who reported mild or no pain during the last 35 days of treatment was significantly higher than that in the placebo group (two studies: 43% vs. 10%, 47% vs. 17%; p < 0.001 for both). In neither of these two studies was the seventh key secondary endpoint of reduction in fibroid volume achieved.

The data also showed that at the end of treatment in the two studies, changes in bone mineral density (BMD) were comparable between the relugolix and placebo groups. As assessed by dual-energy X-ray absorptiometry (DXA), the distribution of BMD changes (including outliers) was similar between the relugolix and placebo groups over the 24-week treatment period. The overall incidence of adverse events was also comparable between the relugolix and placebo groups (62% vs. 66%, and 60% vs. 59%, respectively), including hot flashes (11% vs. 8%, and 6% vs. 4%, respectively). No pregnancies occurred in the relugolix groups in either of the two studies.

The open-label study also met its primary endpoint: after one year of treatment, the response rate in the relugolix group was 87.7%, demonstrating the durability of responses observed in LIBERTY 1 and LIBERTY 2. Furthermore, female patients experienced a mean reduction of 89.9% in menstrual blood loss from baseline. DXA assessments were conducted every three months, and changes in bone mineral density during the one-year treatment period were consistent with those observed in the LIBERTY 1 and LIBERTY 2 studies. Among female patients treated with relugolix for one year, adverse events reported in more than 10% of participants included only hot flushes at rates higher than placebo after six months.

Chemical Structure and Mechanism of Action of Relugolix (Structure image source: medchemexpress.com)

In December 2020, Pfizer and Myovant Sciences reached a $4.2 billion collaboration agreement to develop and commercialize relugolix for oncology and women’s health indications in the United States and Canada. Pfizer will also obtain rights to commercialize relugolix outside the United States and Canada (excluding certain Asian countries) forTumorExclusive option rights in the academic field.

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits testicular testosterone production, a hormone that can stimulate the growth of prostate cancer cells. Additionally, relugolix reduces ovarian estradiol production by blocking GnRH receptors in the pituitary gland; estradiol is known to stimulate the growth of uterine fibroids and endometriosis.

Relugolix was developed by Takeda. In June 2016, Myovant Sciences (a company established by Roivant and Takeda) obtained exclusive global rights to the drug, excluding Japan and other Asian countries. In Japan, relugolix was approved in January 2019 and marketed under the brand name Relumina for the improvement of the following symptoms associated with uterine fibroids: menorrhagia, lower abdominal pain, low back pain, and anemia.

Prostate Cancer / Uterine Fibroids / Endometriosis (Images sourced from: istockphoto.com, clinicaladvisor.com, insider.com)

Currently, Myovant is developing once-daily oral relugolix tablets (120 mg) for the treatment of advanced prostate cancer. On December 18, 2020, Orgovyx (relugolix, 120 mg tablets) received U.S.FDAApproved for the treatment of adult patients with advanced prostate cancer.

It is worth mentioning that Orgovyx is the United StatesFDAThe first and only oral GnRH receptor antagonist approved for the treatment of advanced prostate cancer. The drug was approved through the Priority Review program. In the Phase 3 HERO study, relugolix demonstrated a response rate of up to 96.7%, significantly superior to leuprolide acetate (88.8%), while reducing the risk of major adverse cardiovascular events (MACE) by 54%.

In addition, Myovant is also developing a once-daily oral combination tablet of relugolix (relugolix 40 mg, estradiol 1.0 mg, and norethisterone acetate 0.5 mg) for the treatment of uterine fibroids and endometriosis in women. Currently, the relugolix combination tablet for the treatment of uterine fibroids in women is under review by the U.S. FDA, with a target action date of June 1, 2021. The relugolix combination tablet for the treatment of endometrial cancer is expected to be submitted to the U.S.FDASubmit New Drug Application

(Bioon.com)

Original Source: Myovant Sciences and Pfizer Announce Publication in The New England Journal of Medicine of Phase 3 LIBERTY Studies of Once-Daily Relugolix Combination Therapy in Women with Uterine Fibroids