Linzagolix reduces endometriosis-associated pain, but long-term safety remains uncertain

This Gebu review evaluates the place of linzagolix, an oral gonadotropin-releasing hormone antagonist, in treating endometriosis-associated pain. The drug produces dose-dependent reductions in estrogen and progesterone levels. The main studies reviewed are EDELWEISS 3 and its extension, EDELWEISS 6.

Efficacy

The randomized, double-blind EDELWEISS 3 study analyzed 484 participants with surgically confirmed endometriosis and moderate-to-severe pain. It compared placebo, linzagolix 75 mg and linzagolix 200 mg with low-dose estrogen and progesterone add-back therapy, administered once daily.

At 3 months, dysmenorrhea response occurred in 72.9% of participants receiving 200 mg with add-back versus 23.5% receiving placebo; non-cyclic pelvic pain response occurred in 47.3% versus 30.9%. Response required clinically meaningful pain reduction and stable or reduced analgesic use. With 75 mg, dysmenorrhea response was 44.0%, but the difference in non-cyclic pelvic pain was not statistically significant. At 6 months, both regimens improved both pain outcomes compared with placebo.

Safety and limitations

At 6 months, adverse events were reported in 46.9% of participants in both the placebo and 75 mg groups, and 56.8% receiving 200 mg with add-back. According to the review’s detailed section, 98% of events were mild or moderate. At 12 months, the mean reduction in bone mineral density in the linzagolix groups was at most 1.1% from baseline.

There are no direct comparisons with other hormonal therapies. Attrition, potential unblinding and subjective endpoints limit interpretation. Efficacy and safety beyond 1 year and effects on fertility have not been studied. Oral contraceptives or progestogen-only preparations remain first-line treatment.