Linzagolix effective in women with uterine fibroids

Linzagolix reduced uterine and fibroid volumes and improved pain and hemoglobin levels in women with uterine fibroids, according to multiple analyses of two phase 3 clinical trials.

The findings were presented at the American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting.

“There are currently no long-term medical therapies for uterine fibroids,” William H. Catherino, MD, PhD, a reproductive endocrinologist, professor and chair in the department of gynecologic surgery and obstetrics at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, said during a presentation. “They are associated frequently with chronic heavy menstrual bleeding.”

Catherino and colleagues evaluated linzagolix (ObsEva) in the randomized, double-blind, placebo-controlled phase 3 PRIMROSE 1 and PRIMROSE 2 trials, which enrolled 1,037 patients with uterine fibroids from the United States and Europe. The patients were randomly assigned in a 1:1:1:1:1 ratio to receive placebo; 100 mg linzagolix; 100 mg linzagolix with hormonal add-back therapy; 200 mg linzagolix; and 200 mg linzagolix with hormonal add-back therapy.

The researchers measured uterine and fibroid volumes with transvaginal or abdominal ultrasound as well as hemoglobin and ferritin levels at baseline and weeks 12, 24, 36 and 52. Patients self-reported pain at baseline and weeks 12, 24, 36, 52 and 64 using a numerical rate scale score of zero to 10; scores of zero to three were considered mild pain, scores of four to six were considered moderate pain and scores of seven to 10 were considered severe pain. The study’s safety endpoints were treatment-emergent adverse events and bone mineral density loss. The primary analysis was conducted at week 24; patients received treatment through week 52, and follow-up assessments were conducted until week 76.

Patients treated with 200 mg linzagolix without add-back therapy experienced “marked reductions” in uterine (about 40%) and uterine fibroid (about 48%) volumes (P < .001), according to Jacques Donnez, MD, PhD, the director of the Infertility Research Unit and professor at the Catholic University of Louvain in Belgium, and colleagues. This was the only dose to consistently demonstrate “substantial and significant reductions” in both uterine and fibroid volumes, they added. There were no significant reductions in women who received placebo.

At week 24, pain scores decreased by 2.2 (95% CI, –1.7 to –2.6) for patients in the 100-mg arm, 2.5 (95% CI, –2.1 to –3) in the 100-mg with hormonal add-back therapy arm, 3.3 (95% CI, –2.9 to –3.7) in the 200-mg arm, and 3 (95% CI, –2.6 to –3.4) in the 200-mg with hormonal add-back therapy arm vs. 0.9 (95% CI, –0.5 to –1.3) in the placebo arm. The proportion of patients with decreases of 1 or more pain categories was 61.8% in the 100-mg arm, 62.1% in the 100-mg with hormonal add-back therapy arm, 77.5% in the 200-mg arm, and 68.2 in the 200-mg with hormonal add-back therapy arm (P < .001 for all).

In an analysis of women with anemia, the researchers reported that hemoglobin and ferritin levels improved with both the high and low doses of linzagolix with and without hormonal add-back therapy.

Rates of discontinuation due to treatment-emergent adverse events were similar in the treatment arms (8.6%) and placebo arm (8.1%). The most common treatment-emergent adverse events were hot flush, headache, nausea and anemia, although anemia was present in 65% of patients at baseline, according to the researchers. They also wrote that hot flushes were dose-dependent and reduced with hormonal add-back therapy. The researchers told Healio Primary Care that “the incidence of depression and other mood disorder adverse events was low and revealed no consistent drug-related pattern.”

At week 24, lumbar spine bone mineral density decreased from baseline by 2.158% for patients in the 100-mg arm, 1.017% for patients in the 100-mg with hormonal add-back therapy arm, 3.833% for patients in the 200-mg or 200-mg with hormonal add-back therapy arm, and 1.102% for patients in the 200-mg with hormonal add-back therapy arm. At week 52, lumbar spine bone mineral density decreased from baseline by 2.312% for patients in the placebo arm, 2.91% for patients in the 100-mg arm, 0.96% for patients in the 100-mg with hormonal add-back therapy arm, 3.134% for patients in the 200-mg or 200-mg with hormonal add-back therapy arm, and 1.75% for patients in the 200-mg with hormonal add-back therapy arm.

“Rapid uterine and fibroid volume reduction was observed in the 200-mg group as proved by the result observed at 12 weeks,”  Donnez said during a presentation. “Linzagolix is the only GnRH antagonist with a high-dose, non-add back therapy option with the potential for short-term use for rapid and significant reduction of uterine and fibroid volume.”

References:

• Al-Hendy A, et al. Impact of linzagolix on pain in patients with fibroid-related heavy menstrual bleeding: Results of two phase 3 trials. Presented at: American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting; April 30-May 4, 2021 (virtual meeting).
• Catherino WH, et al. Impact of linzagolix treatment on anemia in women with uterine fibroid related heavy menstrual bleeding: Results of two phase 3 clinical trials. Presented at: American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting; April 30-May 4, 2021 (virtual meeting).
• Donnez J, et al. Effects of the oral GNRH antagonist linzagolix on uterine and fibroid volume in two phase 3 trials. Presented at: American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting; April 30-May 4, 2021 (virtual meeting).
• Taylor H, et al. Safety of linzagolix in the treatment of women with uterine fibroids: Results from two phase 3 clinical trials. Presented at: American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting; April 30-May 4, 2021 (virtual meeting).