Pharmacological treatment of painful endometriosis is primarily based on estrogen-progestin oral contraception or progestin treatment. GnRH agonists are recommended as second line, in combination with a add-back therapy (ABT) to prevent decline in bone mineral density and improve quality of life. Oral GnRH antagonists are also being developed which can regulate estradiol levels in a dose-dependent manner. Thus, linzagolix has shown that it can reduce pain linked to endometriosis and improve quality of life for daily doses of 75 mg or more (phase 2b EDELWEISS 1 study). These data motivated the conduct of a phase 3 EDELWEISS study in which two dosages were studied.
Two dosages studied: 75 mg alone or 200 mg in combination with ABT
This international study was conducted among women with pelvic endometriosis associated with moderate to severe associated pain, confirmed during a 3-month screening period. Then, the recruited women were randomized between three groups (75 mg/day of linzagolix, 200 mg/day of linzagolix + ABT and placebo) and treated for 6 months. The primary endpoint was treatment effectiveness and safety during follow-up. Co-efficacy endpoints were clinically significant reduction in dysmenorrhea and non-menstrual pelvic pain at 3 months.
Satisfactory tolerance, particularly bone
In total, 484 women were included in the study (mean age 35 years, 98.8% of Caucasian origin, diagnosis 4 to 5 years). The average blood estradiol level in the two experimental groups was between 20 and 60 pg/mL throughout the study.
At 3 months, the percentage of responders to treatment in the linzagolix 75 mg group and in the linzagolix 200 mg+ABT group was 44% and 72.9% respectively regarding dysmenorrhea, compared to 23.5% in the placebo group (odds ratio (GOLD) 2.56 [1,46 – 4,49]p = 0.001) and 8.8 [4,86 – 15,91], p = 0.001). Similarly, the rate of responders regarding non-menstrual pelvic pain was 47.3% under linzagolix 200 mg + ABT compared to 30.9% in the placebo group, i.e. an OR of 2.0 ([1,18 – 3,42], p = 0.007). The reduction in this parameter was not significant in the linzagolix 75 mg group. The results at 6 months confirmed those observed at 3 months.
The average number of days of moderate to severe pelvic pain decreased in the experimental groups, from 18.5 monthly days to approximately 12 monthly days from the first month and reaching 4.75 and 7.28 monthly days in the linzagolix groups 75 mg and 200 mg + ABT at the end of 6 months. Likewise, the number of pain-free days at 6 months and the number of bleeding days, including spotting, also evolved more favorably in the active groups than in the placebo group. However, the effect of treatment on dyspareunia was not significant. Finally, women reported a better quality of life with a better ability to carry out daily activities at 3 and 6 months.
In terms of safety at 6 months, the rate of patients experiencing treatment-related adverse events was comparable in the placebo and linzagolix 75 mg groups (46.9%) and was 56.8% in the linzagolix 200 mg group. + ABT. In all three groups, these events were almost exclusively mild to moderate in intensity. The most common events were headaches as well as hot flashes in the experimental groups. Data at 6 months show minimal change in BMD, which averaged less than 1% in all three groups. In the same way, the changes in the Z-score between inclusion and 6e months were comparable in the three groups and for all the measurement sites carried out.
Funding
The study was funded by ObsEva (Switzerland).
