ObsEva SA, a clinical-stage biopharmaceutical company focused on the development and commercialization of novel therapeutics for serious conditions that compromise a woman’s reproductive health and pregnancy, reported positive 12-week results from the EDELWEISS Phase 2b clinical trial of linzagolix, its oral GnRH receptor antagonist, for the treatment of endometriosis-associated pain.
The company also is identifying the two doses of linzagolix intended to be studied in the upcoming Phase 3 program, one for full estradiol (E2) suppression and one targeting partial suppression.
EDELWEISS is a Phase 2b, randomized, double blind, placebo controlled clinical trial designed to evaluate the safety and efficacy of multiple doses of linzagolix in 327 women with moderate-to-severe endometriosis-associated pain recruited from 64 gynecological clinics across the U.S. and Europe.
Following a lead-in phase of two menstrual cycles to establish baseline pain level, patients were randomized to receive either an oral once daily dose of linzagolix (50mg, 75mg, 100mg or 200mg) or placebo for up 12 weeks.
The primary endpoint of the EDELWEISS clinical trial was a responder analysis, with responses defined as a reduction of at least 30%1 in combined menstrual and non-menstrual pelvic pain, recorded daily and assessed via electronic diary over the last 28 days of treatment on a verbal rating scale (VRS) of 0 (no pain) through 3 (severe pain).
Demographics and baseline characteristics were comparable between groups with a mean baseline overall pain VRS of 1.7, menstrual pain VRS of 2.1, and non-menstrual pain VRS of 1.6.
Primary Endpoint Results:
- The study primary endpoint was achieved for the three top doses, and patients receiving a 75mg dose had the highest responder rate of 61.5% compared to the placebo at 34.5%.
- With respect to the menstrual pain VRS, patients receiving a 200mg dose reported the highest responder rate at 78.9%, compared to a placebo responder rate of 28.5%.
- Responder rates for the non-menstrual pain VRS endpoint were statistically significant for the 75mg dose and the 100mg dose and both doses showed comparable responder rates at 58.5% and 61.5% respectively.
|
Dose |
Placebo |
50mg (n=49) |
75mg (n=114)* |
100mg (n=51) |
200mg (n=56) |
|
Responder Rate |
34.5% |
49.4% |
61.5% |
56.4% |
56.3% |
|
P-Value |
— |
0.155 |
0.003 |
0.039 |
0.034 |
*as per protocol
Secondary Endpoint Results:
|
Dose |
Placebo |
50mg |
75mg |
100mg |
200mg |
|
Responder Rate |
28.5% |
43.3% |
68.2% |
68.6% |
78.9% |
|
P-Value |
— |
0.141 |
<0.001 |
<0.001 |
<0.001 |
|
Dose |
Placebo |
50mg |
75mg |
100mg |
200mg* |
|
Responder Rate |
37.1% |
46.2% |
58.5% |
61.5% |
47.7% |
|
P-Value |
— |
0.380 |
0.017 |
0.022 |
0.297 |
*200mg at week 8: responder rate 57.0% (p=0.022)
In addition, doses of linzagolix from 75mg to 200mg significantly and consistently improved dyschezia and patient well-being as assessed by Endometriosis Health Profile-30 score, Patient Global Impression of Change scale (PGIC), Patient Global Impression of Severity (PGIS), the activity impairment score and the modified Biberoglu & Behrman score. Dyspareunia was also improved for all doses and reached statistical significance at the 200mg dose.
Serum Estradiol median levels at week 12 were 12 pg/ml for the 200mg dose and 48 pg/ml for the 75mg dose, which indicates full suppression at the higher dose and partial suppression at the 75mg dose.
Linzagolix was observed to be safe and well tolerated. In line with the therapeutic class and mechanism of action, a moderate proportion of patients reported at least one hot flush as an adverse event (which is a side effect of suppression of E2 levels). The incidence of hot flush in the most effective 75mg dose cohort was 18.4%, versus the placebo arm of 10.9%. Additionally, the incidence of hot flush in the 200mg dose cohort was 42.1%, which is expected for a full E2 suppression dose.
Currently, patients in the EDELWEISS trial continue to receive linzagolix for an additional 12 weeks. Twenty-four-week data, including the bone mineral density assessment, is expected to be available in the fourth quarter of 2018. ObsEva subsequently intends to seek feedback from regulatory authorities on the design of a Phase 3 clinical trial program by the end of 2018.
(Source: ObsEva SA)
Filed Under: Drug Discovery
