Linzagolix reduces HMB in women with uterine fibroids

The use of linzagolix, a new oral gonadotropin-releasing hormone (GnRH) antagonist, with or without add-back therapy (ABT) significantly reduces heavy menstrual bleeding (HMB) in women with uterine fibroids, according to the PRIMROSE 2* trial presented at ESHRE 2020.

“[Linzagolix] is the only GnRH antagonist being developed with two dose options for both treatment of endometriosis associated pain and HMB in women with uterine fibroids,” said lead author Dr Hugh Taylor from Yale School of Medicine in New Haven, Connecticut, US.

This phase III, multicentre, double-blind, placebo-controlled trial evaluated 501 women (mean age 42.9 years, mean BMI 27.02 kg/m²) who had a baseline menstrual blood loss of 218 mL due to uterine fibroids. Participants were randomly assigned to receive placebo (n=102), linzagolix 100 mg alone  (n=97) or with ABT (n=101), or linzagolix 200 mg alone (n=103) or with ABT (n=98) daily for 24 weeks. ABT consisted of oestradiol 1 mg and norethindrone acetate 0.5 mg. Patients were followed up until 24 weeks. [ESHRE 2020, abstract O-027]

At 24 weeks, a higher percentage of women treated with linzagolix 100 mg with or without ABT had significantly reduced menstrual blood loss compared with placebo (77.2 percent and 56.7 percent vs 29.4 percent; p<0.001 for both).

Similarly, those on linzagolix 200 mg with or without ABT demonstrated a significantly reduced menstrual blood loss than those on placebo at 24 weeks (93.9 percent and 77.7 percent vs 29.4 percent; p<0.001 for both). “[Of note,] the linzagolix 200 mg with ABT resulted in a remarkable 94 percent decreased in HMB,” said Taylor.

A significantly higher percentage of women on either dose of linzagolix with or without ABT also achieved a higher rate of amenorrhoea vs placebo (63.4 percent and 34.0 percent; p<0.001 for 100 mg and 80.6 percent and 70.9 percent; p<0.001 for 200 mg vs 11.8 percent).

Among subjects with anaemia (defined as haemoglobin [Hb] <12 g/dL at baseline), a significant increase in Hb levels was observed in the linzagolix 100 mg with or without ABT group (difference vs placebo, 1.6 g/dL; p<0.001 and 0.9 g/dL; p=0.002) and linzagolix 200 mg with or without ABT group (1.9 and 1.7 g/dL; p<0.001 for both) than the placebo group.

A significant decrease in uterine volume was observed in all linzagolix groups (median change from baseline, p=0.004 and p=0.003 for linzagolix 100 mg and both p<0.001 for linzagolix 200 mg with or without ABT, respectively), whereas a significant decrease in fibroid volume was only noted in the linzagolix 200 mg without ABT group (median change from baseline, p<0.001).

Linzagolix recipients achieved a significant improvement in pain (0–10 NRS** score; p≤0.002) and quality of life (UFS-QoL*** total score; p≤0.003) at 12 and 24 weeks compared with the placebo recipients.

As ABT reduces bone mineral density (BMD) loss, all linzagolix treatment groups were associated with a 1–2 percent BMD loss, mainly in the lumbar spine, except with the linzagolix 200 mg without ABT treatment group. “Of note, in this study, we did not give supplemental calcium or vitamin D [to either treatment groups],” said Taylor, who added that the “effects on BMD of calcium or vitamin D supplementation with linzagolix in uterine fibroids are not known”.

Treatment-emergent adverse event was noted in 50.5 percent of participants in both the linzagolix 100 mg without ABT arm and the linzagolix 200 mg with ABT arm, ”which was expected … [and this] gives the most profound reduction in oestradiol levels,” Taylor noted.

“In conclusion, [either] linzagolix 100 or 200 mg with or without ABT significantly decreased HMB, 57 percent responded with linzagolix 100 mg without ABT, … which has the potential for long-term treatment, … and 94 percent responded with linzagolix 200 mg with ABT,” Taylor noted.

“Data from a similar ongoing US trial should provide information on linzagolix in a broader population,” he added.

*PRIMROSE 2: Efficacy and safety of OBE2109 in subjects with heavy menstrual bleeding associated with uterine fibroids

**NRS: Numerical Rating Scale

***UFS-QoL: Uterine fibroid symptom and quality of life