Linzagolix (formerly OBE2109) is an experimental oral treatment being developed by ObsEva to ease symptoms of pain and heavy menstrual bleeding associated with endometriosis and uterine fibroids. The treatment was initially developed by Kissei Pharmaceutical.
How Linzagolix works
During the menstrual cycle, the lining of the uterus, or the endometrium, thickens in preparation for pregnancy. If conception does not occur, the endometrial cells detach from the walls of the uterus and are discharged during menstruation. Estrogen is among the hormones that stimulate this process.
The gonadotropin-releasing hormone (GnRH) plays a key role in regulating estrogen levels, along with the levels of other reproductive hormones. GnRH is produced by the brain and binds to receptors on the pituitary gland. This stimulates the production of two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), which control the levels of reproductive hormones such as estrogen and progesterone. Among other roles in the body, estrogen and progesterone are essential to stimulating the growth and break down of the endometrium.
Endometriosis is marked by the growth of endometrial cells outside the uterus. These cells undergo the same monthly cycles as those inside the uterus but cannot be expelled through menstruation. This causes severe pain and inflames the affected areas.
Linzagolix is a GnRH antagonist. It acts to block the action of GnRH on the pituitary gland by binding to the receptors and preventing GnRH from activating them. This results in less FSH and LH being produced, which in turn lowers estrogen levels.
By reducing estrogen levels, Linzagolix should stop the monthly menstrual cycle and prevent the growth of new endometrial lesions.
But estrogen and progesterone have other roles in the body, and significantly reducing their levels can have such side effects as a loss of bone mineral density. Unlike other GnRH receptor antagonists, Linzagolix is thought to be effective at both low or high doses, meaning it may be tailored to an individual’s needs. This may lessen potentially damaging side effects in patients, and possibly mitigate the need for an add-back therapy. An add-back therapy is a small supplementary dose of either estrogen or progesterone to maintain overall health.
Linzagolix in clinical trials
In a Phase 2a clinical trial that included women with endometriosis and uterine fibroids, treatment with Linzagolix was seen to lead to a decrease in the levels of the menstrual cycle hormones.
Study participants also reported lesser endometriosis-associated pain and fewer bleeding days. The use of Linzagolix also led to a reduction in the use of pain medication to manage endometriosis symptoms. In patients with uterine fibroids, Linzagolix treatment lowered bleeding days within the first month of treatment and anemia was corrected within three months.
A randomized, double-blind, placebo-controlled Phase 2b study (NCT02778399) called EDELWEISS assessed the effectiveness and safety of varying doses of Linzagolix over 24 weeks in 330 women with endometriosis-associated pain.
The final results of EDELWEISS were announced in September 2018. Linzagolix was found to be significantly better at easing endometriosis-associated pain compared to a placebo at all doses. The intermediate dose of 75 mg was the most effective at easing pelvic pain, with 70.8 percent of patients reporting at least a 30 percent reduction. The highest dose of 200 mg was the most effective at easing menstrual cramps.
Unlike many other endometriosis treatments, Linzagolix at 75 mg did not result in a clinically significant reduction in bone mineral density, while still showing efficacy. But the 200 mg dose caused a significant drop in bone mineral density in patients, leading ObsEva to recommend that future trials at this dose include an add-back therapy. The overall safety and tolerability of Linzagolix were similar to placebo, except for a dose-dependent increase in the incidence of hot flushes.
Two Phase 3, randomized, double-blind, and placebo-controlled studies (NCT03070899, NCT03070951) are currently recruiting premenopausal women with heavy menstrual bleeding associated with uterine fibroids at sites worldwide. The trials will investigate the effectiveness and safety of Linzagolix alone and in combination with add-back therapy in managing the menstrual bleeding. (Information is available by clicking on each trials NCT number.)
ObsEva aims to open further Phase 3 trials assessing Linzagolix in early 2019.
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