Linzagolix – Endometriosis

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 trial, 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 and 3 clinical trials of Linzagolix, as compared to placebo in endometriosis are underway in the US and Europe. EDELWEISS 1 & 2 trials are targeting enrollment of approximately 900 women with endometriosis-associated pelvic pain.

Preclinical

Phase 1

Phase 2

Phase 3

*** Study completed: Primary and secondary endpoints met

Linzagolix – Uterine Fibroids

In 2015, ObsEva in-licensed Linzagolix for the treatment of endometriosis from Kissei Pharmaceutical Co. 

Linzagolix is a a novel, orally administered GnRH receptor antagonist antagonist that potentially provides effective management of heavy menstrual bleeding (HMB) associated with uterine fibroids (UF) 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.

In a Phase 2a clinical trial, which included a subgroup of patients with both endometriosis and UF, Linzagolix provided significant, dose-dependent decreases in serum LH and estradiol levels in UF patients. This resulted in the reduction of bleeding days within the first month of treatment (>90 percent of patients) and anemia correction within three months (>90 percent of patients) of treatment.

The pivotal Phase 3 PRIMROSE 1 and 2 clinical trials of Linzagolix in women with heavy menstrual bleeding (HMB) associated with uterine fibroids (UF) are currently underway in the US and Europee. PRIMROSE 1 and PRIMROSE 2 trials are targeting enrollment of approximately 1,000 women with heavy menstrual bleeding associated with uterine fibroids.  The efficacy and safety of two doses of linzagolix are being studied, including 100mg without ABT and 200mg with ABT. Patient recruitment was completed for PRIMROSE 1 and PRIMROSE 2 trials in Q1 2019 and Q2 2019 respectively.  Six-month primary endpoint data are expected from the PRIMROSE 2 and PRIMROSE 1 trials in Q4 2019 and H1 2020 respectively.

Preclinical

Phase 1

Phase 2

Phase 3

Clinical Studies

We are currently conducting six international clinical research studies.

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