Elagolix - Gonadotropin-Releasing Hormone (GnRH) Antagonist

Endometriosis

Endometriosis is associated with a multitude of symptoms, some of the most common of which include pain related both to menstruation (dysmenorrhea) and sexual intercourse (dyspareunia) as well as chronic pelvic pain throughout the menstrual cycle, infertility, and menorrhagia, among many others. The wide range of symptoms associated with endometriosis serves to complicate and delay diagnosis due to the significant overlap of symptoms with the disease profiles of other conditions. The World Endometriosis Research Foundation estimates that there are approximately 100 million women worldwide who suffer from endometriosis. Datamonitor (2007) estimates that there are approximately 7.5 million women in the United States who suffer from the symptoms of endometriosis. With annual healthcare costs and endometriosis-related productivity losses of approximately $4,000 per patient, the annual direct and indirect costs of endometriosis are estimated to exceed $20 billion in the United States alone (Simoens et al Human Reproduction Update 2007, 13, 395). We believe that the availability of an oral treatment, lacking the side effect profile of the currently available peptide GnRH agonists, may be a desirable alternative to current pharmaceutical therapies and ultimately encourage a higher treatment rate.

Addressable Population

• 7.5 million women in the US alone are believed to suffer from clinically significant endometriosis (Datamonitor)
• When diagnosed, 75% of endometriosis sufferers have symptoms defined as ‘moderate or severe’ (IMS Health, NDTI)
• 10-20% of all oral contraceptive prescriptions are written off-label for endometriosis (IMS Health, Neurocrine market research)
• OBGYNs prescribe NSAIDs and opioids “off-label” to approximately 25% of their endometriosis patients

Neurocrine Approach - Nonpeptide GnRH Antagonists

Gonadotropin-releasing hormone, or GnRH, is a peptide that stimulates the secretion of the pituitary hormones that are responsible for sex steroid production and normal reproductive function. Researchers have found that chronic administration of GnRH agonists, after initial stimulation, reversibly shuts down this transmitter pathway and is clinically useful in treating hormone-dependent diseases such as endometriosis and uterine fibroids. Several companies have developed peptide GnRH agonists on this principle, such as Lupron® and Zoladex®. However, since they are peptides, they must be injected via a depot formulation rather than the preferred oral route of administration. In addition, GnRH agonists can take up to several weeks to exert their desired effect once the initial stimulation has occurred, a factor not seen with the use of GnRH antagonists. More importantly, until the desired effects are maximal, GnRH agonists have shown a tendency to exacerbate the condition via a hormonal flare. The ultimate profound suppression effect observed with GnRH agonists is similar to that seen after menopause and can be associated with hot flashes and the loss of bone mineral density.

Orally active, nonpeptide GnRH antagonists potentially offer several advantages over injectable GnRH peptide drugs, including rapid onset of hormone suppression without a hormonal flare. Also, injection site reactions commonly observed in peptide depots are avoided and dosing can be rapidly discontinued if necessary – a clinical management option not available with long-acting depot injections. Importantly, by using GnRH antagonists, it may be possible to alter the level of pituitary GnRH suppression thereby titrating circulating estrogen levels. Using this approach, an oral GnRH antagonist may provide patients relief from the painful symptoms of endometriosis while avoiding the need for the active management of bone loss.

Clinical Results

To date, 17 Phase I and II clinical trials of our lead, orally active nonpeptide GnRH antagonist, elagolix, for endometriosis have been completed.  One additional study remains ongoing.  These studies demonstrated that elagolix was safe and well tolerated.  A dose-dependent suppression of estradiol with once a day dosing was observed with doses between 50mg and 400mg /day.  The reduction in estradiol has been correlated with a reduction in pain and other symptoms of endometriosis and is a useful biomarker for safety and efficacy.  Based on the results of these Phase I trials, we completed two separate exploratory three-month Phase IIa trials, during 2006, in endometriosis patients to assess efficacy and tolerability of elagolix.  Efficacy in these Phase II studies was assessed by the Composite Pelvic Sign and Symptoms Score (CPSSS) and Visual Analog Scale (VAS) industry-standard and validated measures utilized for evaluating pain reduction in endometriosis patients.  In addition to the standard clinical and laboratory assessments of safety, a biomarker for bone resorption (n-telopeptide) was also measured to assess potential impact on bone mineral density.

During 2007, we completed a bridging study comparing elagolix drug formulations (tablets and solutions) we had used in clinical trials to date to new formulations of tablets. The successful completion of this study that allowed us to select what we anticipate will be our final commercial tablet formulation of elagolix .

During 2008, we completed the dosing and 6-month follow-up of a Phase IIb study (603 study) in which 252 patients, with a laparoscopic diagnosis of endometriosis, were treated over the initial 6-month period. This multi-center, randomized, double-blind, double-dummy study consisted of three treatment groups,  elagolix  150mg once a day,  elagolix  75mg twice daily, and an active control, DMPA-SC. The primary purpose of this study was to assess the impact of six months of treatment of elagolix on bone mineral density as measured by a dual energy x-ray absorptiometry (DXA) scan at the conclusion of treatment and at 6 and 12 months post treatment. This study also assessed, as secondary endpoints, the impact of treatment on endometriosis symptoms as measured by Composite Pelvic Signs and Symptoms Scale (CPSSS), a monthly recall scale that measures dysmenorrhea, non-menstrual pelvic pain, dyspareunia, pelvic tenderness and induration (all elements of endometriosis pain). Top-line results showed that elagolix  met the primary endpoint by having minimal impact on bone mineral density at the conclusion of treatment. This study also showed that elagolix had both a statistical and clinically meaningful reduction in endometriosis symptoms as measured by CPSSS with an 86% responder rate in the 150mg once daily elagolix arm of the study.

This study confirmed our decision to move forward with once daily dosing as elagolix displayed approximately the same efficacy whether given once or twice daily and demonstrated a superior safety profile for bone mineral density when given once daily. Patient follow up both 6 and 12 months post treatment showed elagolix  did not result in a significant reduction in bone mineral density as measured by DXA, with a mean time of return to ovulation of 24 days for  elagolix  subjects.

We conducted two additional Phase IIb trials of elagolix to fully explore its dose range, to evaluate modified endpoints as proposed by the U.S. Food and Drug Administration (FDA), for dysmenorrhea, non-menstrual pelvic pain and dyspareunia as measured on a daily basis (rather than the CPSSS monthly recall) and to evaluate elagolix in a comparator trial with a monthly injection of leuprorelin (Prostap® SR). Both of these trials utilized our selected commercial formulation tablet for six months of treatment. These two trials were designed to assess  elagolix  against placebo (and Prostap® SR) for an initial three months, with the non-elagolix  treatment arms re-randomized after three months into treatment groups of either 150mg or 250mg of  elagolix  once daily for an additional three months.

The first additional Phase IIb trial (Lilac PETAL study or 702 study) consisted of three arms, elagolix 150mg once daily, elagolix 250mg once daily, and placebo. We randomized 155 subjects with a laparoscopic diagnosis of endometriosis in this trial. The placebo controlled portion of the 702 study concluded in early 2009, and showed that elagolix provides endometriosis sufferers with clinical improvement of symptoms, coupled with an excellent safety and tolerability profile. As shown with all previous  elagolix  trials, symptoms of dysmenorrhea as measured by the FDA proposed daily scale improved significantly in both  elagolix  treatment groups compared to placebo ( elagolix  150 mg, p<0.01;  elagolix  250 mg, p<0.001). However, the FDA-proposed non-menstrual pelvic pain daily scale was relatively insensitive to treatment effects. The non-menstrual pelvic pain score of 0.83 was low at baseline and decreased across all treatment groups by approximately 0.25 points.

During the 702 study, 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 and consistent with our previous studies. Additionally, the 150mg dose of elagolix did not have any significant impact on bone mineral density, consistent with the results of the 603 study.

During 2009, the second additional Phase IIb trial (Tulip PETAL study or 703 study) completed the three-month placebo controlled portion in Central Eastern Europe which consisted of four arms,  elagolix  150mg once daily,  elagolix  250mg once daily, Prostap ®  SR 3.75mg (leuprorelin), and placebo. We enrolled 174 subjects, with a laparoscopic diagnosis of endometriosis, in this trial. The placebo controlled portion of the 703 study confirms that  elagolix  and leuprorelin are associated with reductions in dysmenorrhea and non-menstrual pelvic pain daily scores when compared to placebo. As shown with all previous  elagolix  trials, symptoms of dysmenorrhea improved significantly in both  elagolix  treatment groups and with leuprorelin compared to placebo (p<0.0001). Additionally, the percentage of dysmenorrhea pain-free days was markedly higher in the elagolix treatment groups when compared to placebo (elagolix 150mg, elagolix  250mg, and leuprorelin, p<0.0001). However, the FDA proposed non-menstrual pelvic pain daily scale numeric changes and dynamic range were small.

The most common adverse events reported in the 703 trial as occurring more often with elagolix than with placebo were nausea and headache ( < 12%), consistent with previous clinical studies of  elagolix . These events were generally mild or moderate, transient and not associated with study discontinuation. There were no treatment-related serious adverse events.

In August 2009, we held a Type C meeting with the FDA to discuss the non-menstrual pelvic pain scale as proposed by the FDA and used in the 702 and 703 studies. Based on this meeting, we modified the wording of the non-menstrual pain and dysmenorrhea daily scale and launched a new clinical trial, the Daisy PETAL Study (901 Study) in the United States. This double-blind placebo-controlled clinical trial is designed to provide an assessment of the modified scale over a two-month treatment period of 150mg elagolix, followed by twenty weeks of open-label treatment. This trial will randomize approximately 120 subjects at 36 centers. Preliminary review of blinded data from the screening period indicates that the non-menstrual pain scale has a wide dynamic range and therefore should be more appropriate for pivotal trials than the scale used in the 702 and 703 studies. We will use the top-line data, expected in May 2010, from the Daisy PETAL Study to inform our Phase III protocol design which we intend to submit as a Special Protocol Assessment to the FDA.

We expect to have an end of Phase II meeting with the FDA in mid-2010, the purpose of which would be to agree with the FDA on the design of the pivotal Phase III program for elagolix in endometriosis. Subject to agreement with the FDA on the trial design, we expect elagolix  to be ready for Phase III clinical trials in late 2010. We do not intend on initiating the elagolix Phase III studies until we have partnered the elagolix program.
 

Other Applications

Our Phase I and II data for elagolix in women support its potential use not only in endometriosis, but also in a range of other women’s health indications.  A wealth of clinical data in the literature supports the utility of maintaining low, but not post menopausal estrogen levels for several strategies to assist in the management of uterine fibroids.  Additionally, adenomyosis (abnormal endometrial growth within the muscle of the uterus) responds to estrogen deprivation in a fashion analogous to endometriosis.  Menorrhagia (excessive uterine bleeding) and primary dysmenorrhea commonly result from underlying endometriosis, uterine fibroids or adenomyosis and, as such, may be amenable to treatment with a nonpeptide GnRH antagonist.  Current peptide antagonists are commercially available for prevention of premature luteinizing hormone (LH) surge as part of Assisted Reproductive Therapy.  Oral GnRH antagonists could reduce the burden of injections for women undergoing these procedures.  Additional women’s health indications such as premenstrual dysphoric disease (PMDD), polycystic ovarian syndrome (PCOS), breast cancer prevention, precocious puberty, or even contraception may also be appropriate indications for an oral nonpeptide antagonist.

In the men’s health category, benign prostatic hypertrophy (BPH), defined by enlargement of the prostate gland, is an indication currently in Phase III development using an injectable for peptide GnRH antagonist.  Significant advantages may be provided by oral nonpeptide GnRH antagonist as moderate to severe BPH affects an estimated 21 million men in the United States (Mattson Jack 2006).  Additionally, more than 40% of all men over the age of 60 suffer from the symptoms of BPH.  Worldwide sales of current treatments for BPH exceeded $3 billion in 2006.