SAN DIEGO, March 25 /PRNewswire-FirstCall/ -- Neurocrine Biosciences, Inc. today announced top-line efficacy and safety results from its fourth Phase II clinical trial using its proprietary, orally-active nonpeptide Gonadotropin-Releasing Hormone (GnRH) receptor antagonist, elagolix, in patients with endometriosis. The 702 study (Lilac PETAL study) randomized 155 patients with a confirmed diagnosis of endometriosis into three treatment arms; elagolix 150 mg once daily, elagolix 250 mg once daily, or placebo. After completion of the initial three months of treatment, placebo recipients were re-randomized to elagolix for an additional three months. The top-line results reflect the three-month placebo-controlled portion of the study.
"It is clear from this study and all of our previous studies that elagolix is a safe and effective treatment for endometriosis sufferers," said Kevin Gorman, President and Chief Executive Officer of Neurocrine Biosciences. "This Phase II study provides the information we need to continue to move this program forward. While limitations were discovered in some of the new exploratory efficacy measures, elagolix again showed strong efficacy in the historical validated endometriosis measures, with an excellent safety profile."
The Lilac PETAL study assessed endometriosis pain through a variety of measures, several of which were never before utilized in an endometriosis trial. These exploratory endpoints included three daily assessments using an electronic diary: a numeric rating scale (NRS) for pain (scale 0-10); a dysmenorrhea pain assessment (scale 0-3); and a non-menstrual pelvic pain assessment (scale 0-3). The NRS is the pain assessment scale suggested by the National Institutes of Health (NIH) and the American Society of Reproductive Medicine. The dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) assessments were suggested by the Food and Drug Administration (FDA). The trial also utilized two validated efficacy endpoints consisting of the Patient Global Impression of Change (PGIC), an assessment of the changes in endometriosis-related pain; and the Endometriosis Health Profile 5 (EHP-5), a disease specific quality of life scale.
The top-line data confirm that elagolix provides endometriosis sufferers with clinical improvement of symptoms, coupled with an excellent safety and tolerability profile. However, certain aspects of the exploratory endpoints, used as an alternative to the validated Composite Pelvic Signs and Symptoms Scale (CPSSS), require additional dialogue with our expert advisors and regulatory authorities.
Efficacy Endpoints: Mean Change From Baseline to Week 12 Placebo 150 mg 250 mg Numeric Rating Scale (mean daily pain, 0-10) -0.90 -1.19 -1.25 Numeric Rating Scale (peak pain, 0-10) -1.33 -2.45* -2.75** Non-Menstrual Pelvic Pain (mean daily pain, 0-3) -0.24 -0.27 -0.25 Dysmenorrhea (mean daily pain, 0-3) -0.27 -0.68** -0.76** Endometriosis Health Profile (pain dimension, 0-100) -11 -23* -20*** Efficacy Endpoints: Status at Week 12 Patient Global Impression of Change (mean score, 1-7) 3.2 2.2** 2.3** Patient Global Impression of Change (% subjects score < /=2) 33% 67%** 62%** *p<0.05, **p<0.01, ***p=0.068
As shown with all previous elagolix trials, symptoms of dysmenorrhea improved significantly in both elagolix treatment groups compared to placebo (elagolix 150 mg, p<0.01; elagolix 250 mg, p<0.001). Additionally, the percentage of dysmenorrhea pain-free days was markedly higher in the elagolix treatment groups when compared to placebo (elagolix 150 mg, p=0.0012; elagolix 250 mg, p=0.0002).
The impact of elagolix treatment on "worst pain" is evident when examining the monthly peak NRS. Statistically significant improvement was documented for elagolix 150 mg (p< 0.05) and elagolix 250 mg (p<0.005) compared to placebo.
The PGIC utilizes a standard 7-point Likert scale spanning "Very Much Worsened" to "Very Much Improved" ("No Change"=4) to assess the change in endometriosis-related pain. Clinically meaningful and statistically significant improvement was documented at all time points for either dose of elagolix compared to placebo, even when using the conservative definition of "Much Improved" or "Very Much Improved" (p<0.05 at Weeks 4 and 8, p<0.01 at Week 12).
Subjects treated with elagolix also reported improvement compared to placebo on the EHP-5 core domain of endometriosis pain, a validated endometriosis-specific scale which documents the impact of treatment on a variety of health outcome domains. Statistical significance (p< 0.05) for the core pain domain was demonstrated at Weeks 8 and 12 for elagolix 150 mg and at Week 8 for elagolix 250 mg (Week 12 value, p=0.068).
Two of the exploratory scales (daily NRS and non-menstrual pelvic pain, each averaged monthly) were relatively insensitive to treatment effects. Although the daily pain scores improved numerically over the course of treatment on the primary endpoint NRS, the change from baseline was not statistically significant compared to placebo. The non-menstrual pelvic pain score of 0.9 was low at baseline and decreased across all treatment groups by approximately -0.25 points. The results from both of these two exploratory scales are in direct contrast to the statistically significant results of the validated PGIC and EHP-5 pain dimension.
To better understand this observation, we examined treatment effects in subjects with moderate or greater pain (CPSSS non-menstrual pelvic pain score at baseline >/=2); which accounted for two-thirds of the subjects (n=95). For these subjects, both elagolix treatment arms were superior to placebo on a composite of the FDA-suggested daily scales (total score DYS + NMPP): elagolix 150 mg, p=0.0305 and elagolix 250 mg, p=0.0440. This observation suggests that changes in the exploratory FDA composite scale is clinically relevant in women with dysmenorrhea and non-menstrual pelvic pain (if moderate or severe at baseline) and confirms the effect of elagolix as shown with the validated endpoints. It also suggests that the NMPP component of the FDA exploratory scale may not be useful in assessing patients with mild endometriosis symptoms.
"This is the first time that we have assessed the exploratory endpoints suggested by the FDA and the NIH," said Dr. Chris O'Brien, Chief Medical Officer of Neurocrine Biosciences. "The decoupling of these exploratory daily scales from the established monthly validated scales will prompt us to seek input from regulatory authorities and our expert clinical consultants. Most importantly, this trial replicated our previous results with women recognizing significant improvement in endometriosis symptoms across multiple time points and elagolix doses."
Safety Profile
Elagolix was generally safe and well tolerated; the frequency of treatment-related adverse events was 8% in the placebo group and 14 and 15% in the two elagolix treatment groups. There were no serious adverse events during the treatment period. The two most common adverse events were headache and nausea, which were typically mild and transient. Consistent with previous clinical studies, elagolix showed a dose dependent decrease in mean estradiol levels and minimal impact on bone mineral density and related serum n-telopeptide levels during the initial three months of treatment.
Conference Call and Webcast Information
The Company will host a live conference call and webcast to provide additional details of this study tomorrow morning, Thursday March 26, 2009 at 8:00 a.m. Eastern Time (5:00 a.m. Pacific Time). Participants can access the live conference call by dialing 1-800-862-9098 (US) or 785-424-1051 (International) using the conference ID: 7GNRH1. The call can also be accessed via the webcast through the Company's website at http://www.neurocrine.com/.
If you are unable to attend the Webcast and would like further information on this announcement please contact the Investor Relations Department at Neurocrine Biosciences at (858) 617-7600. A replay of the Conference Call will be available approximately one hour after the conclusion of the call by dialing 1-800-723-0528 (US) or 402-220-2654 (International) using the conference ID: 7GNRH1. The call will be archived for two weeks.
Neurocrine Biosciences, Inc. is a biopharmaceutical company focused on neurological and endocrine diseases and disorders. Our product candidates address some of the largest pharmaceutical markets in the world including endometriosis, anxiety, depression, pain, diabetes, benign prostatic hyperplasia (BPH), irritable bowel syndrome (IBS) and other neurological and endocrine related diseases and disorders. Neurocrine Biosciences, Inc. news releases are available through the Company's website via the internet at http://www.neurocrine.com/
In addition to historical facts, this press release may contain forward-looking statements that involve a number of risks and uncertainties. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks and uncertainties associated with Neurocrine's business and finances in general, as well as risks and uncertainties associated with the Company's GnRH program and Company overall. Specifically, the risks and uncertainties the Company faces with respect to the Company's GnRH program include, but are not limited to, risk that the Company's elagolix Phase II clinical trials will fail to demonstrate that elagolix is safe and effective; risk that elagolix will not proceed to later stage clinical trials; risk associated with the Company's dependence on corporate collaborators for development, commercial manufacturing and marketing and sales activities. With respect to its pipeline overall, the Company faces risk that it will be unable to raise additional funding required to complete development of all of its product candidates; risk relating to the Company's dependence on contract manufacturers for clinical drug supply; risks associated with the Company's dependence on corporate collaborators for commercial manufacturing and marketing and sales activities; uncertainties relating to patent protection and intellectual property rights of third parties; risks and uncertainties relating to competitive products and technological changes that may limit demand for the Company's products; and the other risks described in the Company's report on Form 10-K for the year ended December 31, 2008. Neurocrine undertakes no obligation to update the statements contained in this press release after the date hereof.
