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


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.

In December 2019, we announced positive Phase 3 trial results from the PRIMROSE 2 trial of linzagolix for the treatment of heavy menstrual bleeding (HMB) due to uterine fibroids. The PRIMROSE 2 trial enrolled 535 women with uterine fibroids. The trial was conducted in Europe and the US, and evaluated the efficacy and safety of once daily oral linzagolix, including 100 mg and 200 mg doses, both with and without hormonal add-back therapy (ABT). The primary efficacy endpoint was the reduction in HMB; responders were defined as patients with menstrual blood loss volume of ≤ 80 mL and a 50 percent or greater reduction from baseline in menstrual blood loss volume at 24 weeks, measured using the alkaline hematin method. Bone mineral density (BMD) was measured centrally via Dual Energy X-ray Absorptiometry (DEXA) scan at baseline and 24 weeks. The responder rate was 93.9% (p < 0.001) for patients receiving 200 mg with ABT and 56.7% for patients receiving 100 mg without ABT (p < 0.001), compared to 29.4% in the placebo group. Both doses achieved significant rates of amenorrhea (p< 0.001), reduction in pain (p < 0.001), and improvement in quality of life (p < 0.001). Additionally, significant improvement (p< 0.001) in Hb levels, a reduction in number of days of bleeding and reduction in uterine volume were observed. A significant reduction in fibroid volume was also observed for the 200 mg dose with ABT (p < 0.001). The overall safety profile was in line with expectations. The most frequently observed adverse events (occurring in > 5% of patients) were headache, hot flushes, and anemia.  Mean percentage change from baseline in BMD was consistent with the previous trial.

We expect to report primary endpoint results following 24 weeks of treatment from the PRIMROSE 1 clinical trial and the 52 weeks of treatment from PRIMROSE 2 in the second quarter of 2020. A Marketing Authorization Application (MAA) to the EMA and a new drug application submission to the FDA are planned by the fourth quarter of 2020 and the first quarter of 2021 respectively

Preclinical

Phase 1

Phase 2

Phase 3

Clinical Studies

We are currently conducting six international clinical research studies.

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Note that the following information contains information on investigational medicinal products. These products have not yet been approved for marketing by the European Medicines Agency or the U.S. Food and Drug Administration and are still under development. Further additional investigations may be needed in order for the marketing authorization to be granted, which grant may depend on a variety of factors and is not guaranteed. Click on “return” if you do not wish to receive such information. By clicking on “continue” you acknowledge that you wish to receive scientific information on our investigational products.

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Disclaimer

Note that the following information contains information on investigational medicinal products. These products have not yet been approved for marketing by the European Medicines Agency or the U.S. Food and Drug Administration and are still under development. Further additional investigations may be needed in order for the marketing authorization to be granted, which grant may depend on a variety of factors and is not guaranteed. Click on “return” if you do not wish to receive such information. By clicking on “continue” you acknowledge that you wish to receive scientific information on our investigational products.

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