O-027 Efficacy results from a phase 3, randomized, placebo-controlled trial testing two doses of linzagolix in women with endometriosis-associated pain

Abstract

Abstract Study question Does once-daily linzagolix for up to 6 months reduce the pain symptoms in women with endometriosis? Summary answer Once-daily oral use of the GnRH agonist linzagolix alone or in combination with combined hormonal add-back therapy (ABT) for 24 weeks improved endometriosis-associated pain symptoms. What is known already Linzagolix is an oral GnRH antagonist under development to treat endometriosis-associated pain (EAP). In the EDELWEISS 3 study linzagolix 200mg+ABT met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) in a clinically meaningful fashion along with a stable or decreased use of analgesics. Linzagolix 75mg significantly reduced DYS but not NMPP. Secondary endpoints were DYS, NMPP, overall pelvic pain, dyschezia, and dyspareunia at 6 months assessed with a numeric and/or verbal rating scale (NRS and/or VRS), and interference of pain with daily activities assessed with the Endometriosis-Health-Profile-30 (EHP-30) pain domain. Study design, size, duration EDELWEISS 3 was a randomized, double-blind, placebo-controlled Phase 3 study, investigating efficacy and safety of linzagolix 75mg and linzagolix 200mg with ABT (1mg estradiol/0.5mg norethindrone acetate) for up to 24 weeks in women with moderate to severe EAP. To qualify, subject had to demonstrate over 2 menstrual cycles at least moderate DYS and NMPP for ≥2 days each and at least moderate overall pelvic pain for ≥5 days. Participants/materials, setting, methods Eligible women with moderate to severe EAP were equally randomized to once daily oral: placebo, linzagolix 75mg or linzagolix 200mg+ABT. Efficacy assessments included DYS, NMPP, dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain). The co-primary endpoint was a responder analysis at Month 3. We present secondary endpoints at Month 6. Main results and the role of chance Participants (n = 484) had a mean age of 35 years, a BMI of 24kg/m2 with 99% of subjects being White. At Month 6, compared to placebo significant improvements in DYS and NMPP (VRS) were observed in the 200mg+ABT group, with an estimated mean change from baseline (CfB) of -1.83 (95%CI: 1.96, 1.70; difference with placebo p < 0.001) and 0.92 (95%CI: 1.03, 0.82; p = 0.002), respectively. For the 75mg group, the mean CfB was 1.10 (95%CI: 1.23; 0.97; p < 0.001) and 0.84 (95%CI: 0.95; 0.73; p = 0.048), respectively. For overall pelvic pain (NRS), marked improvements were observed with an estimated mean CfB of 3.39 (95%CI: 3.74, 3.03; p < 0.001) for 200mg+ABT and 2.84 (95%CI: 3.20, 2.48; p = 0.024) for 75mg. Similarly, dyschezia (NRS) was significantly improved for both groups with a mean CfB of 1.99 (95%CI: 2.29, 1.70; p = 0.012) for 200mg+ABT and -1.98 (95%CI: 2.28, 1.69; p = 0.015) for 75mg. Both doses offered a marked, statistically significant improvement in the interference of pain with daily activities as measured on the EHP-30 Pain Dimension, with an estimated mean CfB of 35.60 (95%CI: 38.73, 32.48; p < 0.001) and -27.37 (95%CI: 30.50, 24.25; p = 0.001) for the 200mg+ABT and 75mg group, respectively. Both doses did not provide significant improvements in dyspareunia. Limitations, reasons for caution We report data of the EDELWEISS 3 study for up to Month 6. An extension study of this trial will provide more information on the sustained effect and potential symptom recurrence after stopping treatment. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial improvement in endometriosis-associated pain symptoms. The 75mg dose was less effective but demonstrated still marked improvements. There exists an substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT03992846