In 2015, ObsEva in-licensed Linzagolix for the treatment of endometriosis from Kissei Pharmaceutical Co.
Linzagolix is a novel, orally administered GnRH receptor 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.
Linzagolix is the only GnRH antagonist being developed to provide differentiated options for women suffering from uterine fibroids.
Because not every woman is the same, one size does not fit all
We initiated a Phase 3 program in uterine fibroid in Q2:2017. PRIMROSE 1 and 2 are prospective, randomized, parallel group, double-blind, placebo‑controlled Phase 3 studies investigating the efficacy and safety of two dosing regimens of linzagolix, 100 mg and 200 mg once daily, alone and in combination with hormonal ABT (Estradiol 1mg/ Norethisterone Acetate 0.5mg) for the treatment of heavy menstrual bleeding associated with uterine fibroids. Women participating in the study did not receive Vitamin D or calcium supplementation. PRIMROSE 1 is being conducted in the US and enrolled 574 women; PRIMROSE 2 is being conducted in Europe and the US and enrolled 535 women. Both trials comprised a 12-month treatment period followed by a 6-month post treatment follow-up period. 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 (DXA) scan at baseline 24 and 52 weeks
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 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, reduction in pain, and improvement in quality of life. Additionally, significant improvement 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.
In July 2020, we announced positive Phase 3 trial results from the PRIMROSE 1 trial of linzagolix for the treatment of heavy menstrual bleeding (HMB) due to uterine fibroids Results from PRIMROSE 1 showed that at week 24, women receiving linzagolix experienced a clinically and statistically significant reduction in menstrual blood loss (≤80 mL and a ≥50% reduction from baseline) compared with placebo. Women receiving 200 mg with ABT achieved a 75.5% (P<0.001) response rate and those receiving 100 mg without ABT achieved a 56.4% (P=0.003) response rate. In PRIMROSE 1, the incidence of adverse events was similar between placebo and active treatment. The most frequently observed adverse events, with an incidence >5%, were headache and hot flushes. In addition, mean percentage change in bone mineral density (BMD) from baseline to week 24 was minimal.
The pooled week 24 data from these two Phase 3 studies support a best-in-class profile, with a responder rate of 85% in women receiving linzagolix 200 mg with ABT, and 57% in women receiving linzagolix 100 mg without ABT.
Across both studies, women receiving linzagolix experienced statistically significant improvements across several clinically important secondary endpoints, including reduction in pain, improvement in anemia and quality of life.
In addition, new data from PRIMROSE 2 demonstrate that continued treatment with linzagolix up to week 52 provides sustained efficacy. Response rates of 91.6% and 53.2% were observed in women receiving 200 mg with ABT and 100 mg without ABT, respectively, both of which are similar to the response rates observed at week 24 of the study.
In PRIMROSE 2, the most frequently observed adverse events, with an incidence >5%, were headache, hot flushes, and anemia. In addition, a small incremental change in BMD was observed at week 52 compared to week 24.
In December 2020, we announced additional Phase 3 PRIMROSE 1 and 2 study results confirming sustained efficacy and continued safety of linzagolix in the treatment of uterine fibroids. The Week 52 PRIMROSE 1 results showed that continued treatment with linzagolix led to sustained efficacy for the primary endpoint of reduced heavy menstrual bleeding (defined as menstrual blood loss of at least 50% less than baseline and at or below 80 mL). This was seen across all doses of linzagolix and was in line with the earlier findings in PRIMROSE 2. The pooled Week 52 results from the two studies showed that at Week 52, 56.4% of women on 100 mg of linzagolix met the primary endpoint, and with the higher dose of 200 mg+ABT the responder rate was 89.3%. Key clinically relevant secondary endpoints including pain reduction as well as improvement in anemia and quality of life, were sustained up to the 52-week time point in PRIMROSE 1, as previously observed
In PRIMROSE 2, following three months off-treatment, pain scores remained lower than baseline in all treatment arms, further supporting the durability of the linzagolix treatment effect.
For a significant proportion of women, rapid and substantial shrinkage in uterine and fibroid volume is a primary treatment objective. The 52-week PRIMROSE study results demonstrate that in women initially treated with 200 mg without ABT, uterine and fibroid volume reduction is substantially more marked than with 200 mg+ABT, and introduction of ABT on top of 200 mg after 24 weeks clearly counteracts the GnRH antagonist volume effects. These results support the need for and potential value of a high-dose regimen without ABT; linzagolix is the only GnRH antagonist developed with a high- dose, non-ABT option.
PRIMROSE 1 52-week safety results showed similar incidence of adverse events between placebo and active treatment when treatment is continued beyond week 24. From Week 24 to 52, there was low occurrence of hot flushes, headaches, and anemia, which were the most frequently observed adverse events (incidence of >5%) up to 24 weeks. Adverse events of interest, including mood-related events, decreased libido, and alopecia, were rare and similar to placebo. Regarding BMD, in PRIMROSE 1, incremental decrease in lumbar spine BMD similar to placebo was observed in the 100 mg treatment arm at week 52 compared to week 24, with less change seen in the 200 mg+ABT arm. PRIMROSE 2 DXA results at Week 76 showed evidence of BMD recovery for patients treated with both the 100 mg and 200 mg+ABT doses.
ObsEva submitted in November 2020 a Marketing Authorization Application (MAA) for uterine fibroids to the European Medicines Agency (EMA) and anticipates submitting a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in H1:2021. Additional efficacy and safety data from the clinical trial program will also be submitted for presentation at upcoming scientific conferences.
We are currently conducting three international clinical research studies.Read more
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