Treatment with linzagolix can effectively reduce endometriosis-associated pelvic pain and painful periods, and provide long-term symptom relief, according to the latest results of a Phase 2b clinical trial.
After completion of end-of-Phase 2 regulatory discussions, ObsEva, the therapy’s developer, intends to launch a Phase 3 program for linzagolix in early 2019.
Linzagolix, also known as OBE2109, is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist designed to reduce pain and heavy menstrual bleeding related to endometriosis.
By binding to and inhibiting GnRH in the pituitary gland, linzagolix prevents the ovaries from producing estrogen. Unlike other similar compounds currently available, this new treatment candidate can be tailored to the patient’s individual needs, and it can provide fast symptom relief.
The Phase 2b trial (NCT02778399), called EDELWEISS, enrolled 327 women with moderate to severe endometriosis-associated pain across 86 sites in the United States and Europe.
The patients were randomized to orally receive one of four tested doses of linzagolix (50, 75, 100, or 200 mg) or a placebo once daily for 12 weeks. The participants then continued to receive the treatment as initially randomized for up to a total of 24 weeks. After this, those initially on the placebo group started treatment with 100 mg of linzagolix, and half of the subjects in the 75 mg group received tailored doses of linzagolix based on their estradiol levels.
Results from 12 weeks of treatment, announced in June, showed that women treated with the top three doses of linzagolix reached the primary goal of the study, defined as at least a 30% reduction in menstrual and nonmenstrual pelvic pain over a minimum of 28 days.
The best response rate at week 12 was 61.5% in the 75 mg dose group, followed by 56% in the 100 mg or 200 mg groups. In the placebo-treated group, only 34.5% of the patients achieved a similar positive response.
More recent data collected at 24 weeks shows that long-term treatment with linzagolix can provide sustained relief of endometriosis-related symptoms.
Approximately 70.8% of patients treated with 75 mg of linzagolix achieved overall pain reduction of at least 30%. A similar positive response was reported in 66.7% of women treated with 100 mg and 77.3% of those taking the 200 mg dose.
Good response rates were also reported regarding the reduction of nonmenstrual and menstrual pelvic pain. The proportion of patients who experienced nonmenstrual pelvic pain reduction in the 75 mg group increased from 58.5% at week 12 to 72.9% at week 24. Additionally a 2.6% improvement in patient response was reported in the 100 mg group and a 25% improvement in the 200 mg group from week 12 to week 24.
The number of patients who also had a significant reduction of painful periods increased by the 24th week in the group of patients treated with the two higher doses, with 13.5% and 5.2% more treatment responders over week 12.
“We are very pleased with these favorable results that further demonstrate the differentiated therapeutic potential of linzagolix for alleviating the severe, painful and chronic symptoms of endometriosis,” Ernest Loumaye, MD, PhD, co-founder and CEO of ObsEva, said in a press release. “These data strongly validate ObsEva’s development strategy for linzagolix as a potential best in class oral GnRH antagonist.”
Bone mineral density (BMD) is often affected as a result of GnRH inhibition, which can lead to osteoporosis and serious bone fragility.
Analysis of linzagolix’s impact in BMD after 24 weeks of treatment showed that partial estradiol suppression with the 75 mg dose and full estradiol suppression with the 200 mg dose led to BMD reductions between 0.3% and 2%, which is below the 2.2% threshold considered to be clinically significant for BMD loss.
Still, lumbar spine analysis showed a 2.6% BMD reduction in the 200 mg group, suggesting the need for add-on treatment with a low-dose, add-back hormone replacement therapy (ABT) when linzagolix is used for longer than six months.
“Overall, we believe these data strongly support the planned development of a 75 mg once daily dose (without ABT), and a 200 mg once daily dose in combination with low dose ABT,” ObsEva’s spokesperson said. “Offering dual therapeutic options, is the cornerstone of ObsEva’s strategy to address the needs of the large and diverse endometriosis patient population.”
In general, linzagolix was found to be safe and well-tolerated. As expected, a dose-dependent increase in hot flashes was reported, with 19% of women in the 75 mg group and 45.6% in the 200 mg group reporting at least one event by 24 weeks.
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