In 2015, ObsEva in-licensed Linzagolix from Kissei Pharmaceutical Co., which had completed several Phase 2a clinical trials in Japan.
Linzagolix is a novel, orally administered GnRH receptor antagonist that potentially provides effective management of endometriosis-associated pain while mitigating bone mineral density loss and other adverse effects typically associated with currently approved treatments. Unlike marketed GnRH agonists, Linzagolix has the potential to be administered orally once a day, with symptoms relieved within days, while potentially mitigating the initial worsening of symptoms often associated with GnRH agonist treatments. Linzagolix has the potential to dose-dependently lower estradiol levels hence maintaining such levels within an optimal range to mitigate patient bone mineral density loss. Linzagolix has the potential to allow patients to receive the relief needed to live normal lives again and enhance their quality of life with fewer side effects and complications requiring doctor’s visits or surgery.
The completed Phase 2b EDELWEISS 1, double-blind, placebo (PBO)-controlled trial evaluated once daily linzagolix doses of 50, 75, 100 and 200 mg for 24 weeks. At 24 w, subjects could extend active treatment up to 52 w. The primary endpoint was the proportion of subjects with 30% or more reduction in pelvic pain over 28 days, assessed on a Verbal Rating Scale using an electronic diary. Secondary endpoints included dysmenorrhea, non-menstrual pelvic pain (NMPP), dyspareunia, dyschezia, serum estradiol (E2), difficulty of doing daily activities, Patient Global Impression of Change/Severity (PGIC/S), Endometriosis Health Profile-30 (EHP-30), amenorrhea, BMD with Dual-energy X-ray Absorptiometry (DXA) and adverse events.
At 12 week, 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 week and these effects were maintained or increased at 24 week and 52 week. 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 (E2 1mg/NETA 0.5mg).
The pivotal Phase 3 EDELWEISS 2 (US) and 3 (Europe and US) clinical trials of linzagolix, as compared to placebo have been intiatated in 2019 . EDELWEISS 1 & 2 trials were targeting enrollment of approximately 900 women with endometriosis-associated pelvic pain. The EDELWEISS 3 trial in the EU is progressing as planned, with primary endpoint data expected in 4Q 2021. Screening and enrollment for EDELWEISS 2 in the US has been increasingly challenging, particularly in the context of the persisting difficult environment of the ongoing pandemic and has led to ObsEva’s decision to discontinue the study. No new or significant safety issues have been observed. The ongoing Phase 3 EDELWEISS 3 study will enroll approximately 450 patients with endometriosis associated pain, with a co-primary endpoint of response on both dysmenorrhea (menstrual pain) and non-menstrual pelvic pain. The study includes a 75 mg once daily dose without hormonal ABT, and a 200 mg once daily dose in combination with hormonal ABT (1mg E2 / 0.5mg NETA). Subjects who have completed the initial six-month treatment period will have the option to enter a 6-month treatment extension.