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Long term treatment of endometriosis associated pain (EAP) with linzagolix: efficacy and safety after 12 months of treatment

2019; Elsevier BV; Volume: 112; Issue: 3 Linguagem: Inglês

10.1016/j.fertnstert.2019.07.935

1556-5653

Robert N. Taylor, Elke Bestel, Jean‐Pierre Gotteland, V. Lecomte, Rachel Dubouloz, Paul Terrill, Andrew Humberstone, Ernest Loumaye,

Medicinal plant effects and applications

To assess safety and maintenance of efficacy of linzagolix after 52 weeks (w) of treatment. Linzagolix is an oral GnRH receptor antagonist that induces a dose-dependent reduction of estradiol and is being developed to treat EAP. EDELWEISS was a Phase 2b, double-blind, placebo (PBO)-controlled trial evaluating once daily linzagolix doses of 50, 75, 100 and 200 mg. At 24 w, subjects could extend active treatment up to 52 w. Participants were women with surgically confirmed endometriosis and moderate to severe EAP. Efficacy was assessed using a daily eDiary as the % of responders (≥ 30% reduction in mean 28-day scores) in overall pelvic pain (OPP), dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP). Dyspareunia and dyschezia scores were also assessed. Bone mineral density (BMD) of the femur, hip and spine were assessed by dual-energy X-ray absorptiometry (DXA). At 12 w, there was a significant increase in the % of responders for OPP, DYS and NMPP for doses of 75 mg and above compared to PBO. These effects were generally maintained or increased at 24 and 52 w. At 12 w, there were significant improvements in dyspareunia (200 mg only) and dyschezia scores which were maintained or increased at 24 and 52 weeks. Mean BMD losses (spine) at 24 weeks were <1% at doses of 50 and 75 mg and increased with increasing dose up to 2.6% for 200 mg. A similar pattern was observed at 52 w. BMD changes in femur and hip were similar but generally smaller. Linzagolix at daily doses of 75 mg and above significantly improved EAP symptoms at 12 w and these effects were maintained or increased at 24 and 52 w. These data support Phase 3 trials in women with EAP using linzagolix 75 mg once daily alone and 200 mg once daily with low-dose add-back hormonal therapy.Table 1PBO‡50 mg75 mg100 mg200/100 mg†N12 w534956515624 w4048394452 w30362230% responders OPP12 w34.549.461.5*56.4*56.3*24 w52.570.866.777.352 w66.769.253.882.4% responders DYS12 w28.543.368.2*68.6*78.9*24 w47.558.382.184.152 w50.069.269.264.7% responders NMPP12 w37.146.258.5*61.5*47.724 w50.072.964.172.752 w66.769.253.876.5Dyspareunia Mean (SD) CFB12 w-0.4 (0.9)-0.6 (0.7)-0.7 (0.8)-0.7 (0.9)-0.8 (1.1)*24 w-0.7 (0.8)-0.7 (0.8)-0.6 (0.8)-1.0 (1.0)52 w-0.5 (1.1)-0.9 (0.8)-0.7 (1.1)-0.9 (0.9)Dyschezia Mean (SD) CFB12 w-0.7 (1.7)-1.4 (1.7)-2.1 (2.5)*-2.0 (1.8)*-1.7 (2.3)*24 w-1.5 (2.1)-2.2 (2.5)-2.0 (2.3)-2.5 (2.6)52 w-2.3 (1.8)-2.1 (2.9)-2.9 (3.1)-2.6 (2.7)BMD spine Mean (95% CI) % CFB24 w0.14 (-0.83, 1.11)-0.80 (-1.57, -0.03)-1.37 (-2.14, -0.59)-2.60 (-3.56, -1.65)52 w0.14 (-1.04, 1.31)-1.14 (-2.21, -0.07)-1.40 (-3.35, 0.55)-2.19 (-3.59, -0.78)‡PBO only to 12 w; †Subjects randomized to 200 mg received 100 mg from 24 to 52 w; *p < 0.05 compared to PBO. Open table in a new tab