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Linzagolix markedly decreases dysmenorrhea and non-menstrual pelvic pain in moderate-to-severe endometriosis, with sustained benefits for up to 6 months.
In a phase 3 clinical trial, linzagolix (an oral gonadotropin-releasing hormone [GnRH] antagonist) offered effective relief for moderate-to-severe endometriosis-associated pain. The study, known as EDELWEISS 3, evaluated two dosing strategies—75 mg daily without hormonal support and 200 mg daily with add-back therapy (ABT)—against placebo, highlighting prominent improvements in symptoms, particularly dysmenorrhea and non-menstrual pelvic pain.
EDELWEISS 3 was a randomized controlled trial executed across multiple centers. A total of 486 women battling moderate-to-severe endometriosis-related pain were enrolled and randomized in a 1:1:1 ratio to receive placebo, 75 mg linzagolix, or 200 mg linzagolix combined with ABT (1 mg estradiol and 0.5 mg norethindrone acetate). Treatment was given orally once daily for up to 6 months. Participants recorded their pain levels using a daily verbal rating scale in electronic diaries.
Key findings at 3 months
The 200 mg linzagolix + ABT group met the primary efficiency goal at 3 months, achieving reductions in both non-menstrual pelvic pain and dysmenorrhea. Responder rates for dysmenorrhea reached 72.9% compared to 23.5% in the placebo group, while for non-menstrual pelvic pain, 47.3% of patients responded versus 30.9% in the placebo group.
The 75 mg daily dose illustrated significant improvement in dysmenorrhea compared with placebo (44.0% vs. 23.5%), though reductions in non-menstrual pelvic pain did not reach statistical significance. Both treatment groups also showed meaningful improvements in dyschezia and overall pelvic pain, while changes in dyspareunia were minimal and not statistically significant.
Key findings at 6 months
By 6 months, both the 200 mg with ABT and 75 mg alone regimens continued to yield significant reductions in dysmenorrhea and non-menstrual pelvic pain compared with placebo, reinforcing the sustained efficacy of linzagolix therapy.
Safety and tolerability
Both dosing strategies were well-tolerated. Hypoestrogenic adverse effects like hot flushes and bone density loss were mild, with less than 1% bone loss observed. The addition of ABT helped minimize vasomotor symptoms and preserved bone health in the higher-dose group.
Clinical implications
The findings suggest that 200 mg linzagolix with ABT may be a strong candidate for tackling endometriosis-related pain while minimizing side effects linked to low estrogen. Meanwhile, the 75 mg dose without ABT could represent a suitable long-term therapy for those unable or unwilling to use hormonal add-back therapy, pending further validation. Overall, the study positions linzagolix as a promising new oral therapy that may broaden therapeutic options for women living with endometriosis.
Human Reproduction
Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3)
Jacques Donnez et al.
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