Profile: Neurocrine Biosciences Inc (NBIX.O)

Neurocrine Biosciences, Inc., incorporated in January 1992, is engaged in developing, discovering and commercializing drugs for the treatment of neurological and endocrine-related diseases and disorders. During the year ended December 31, 2008, the Company had eight programs in various stages of research and development, including five programs in clinical development. The products of the Company in the clinical development include Elagolix, CRF1 Antagonist (561679), CRF2 Peptide Agonist (urocortin 2) and CRF1 Antagonist (586529). The research programs of the Company include Vesicular Monoamine Transporter 2 Inhibitor (VMAT2), Glucose Dependent Insulin Secretagogues and GnRH Antagonists. The other products of the Company include Indiplon five milligram and 10 milligram capsules, and Indiplon 15 milligram tablets.

Programs under Clinical Development

Gonadotropin-releasing hormone (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, uterine fibroids and benign prostatic hyperplasia (BPH). Orally active, nonpeptide GnRH antagonists potentially offer several advantages over injectable GnRH peptide drugs, including onset of hormone suppression without a hormonal flare.

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 range of symptoms associated with endometriosis serves to complicate and delay diagnosis due to the overlap of symptoms with the disease profiles of other conditions. The Phase I clinical trials of the orally active nonpeptide GnRH antagonist, elagolix, for endometriosis have been completed. During the yeare ended December 31, 2007, the Company completed the bridging study comparing elagolix drug formulations (tablets and solutions) used in clinical trials to date to new formulations of tablets. In 2008, the Company completed the dosing and 6-month follow up of a Phase IIb study in which 252 patients, with a laparoscopic diagnosis of endometriosis, were treated over a six-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 Company is also conducting two additional Phase II b studies of elagolix to explore its dose range, to evaluate modified endpoints proposed by the United States Food and Drug Administration (FDA), and to evaluate elagolix in a comparator trial with a monthly injection of leuprolide (Prostap SR). These two trials are designed to assess elagolix against placebo (and Prostap SR) for an initial three months and after completing three months of treatment the non- elagolix treatment arms are re-randomized into either 150mg or 250mg of elagolix once daily for an additional three months.

In 2008, the first additional Phase IIb trial was fully enrolled and consists of four arms, elagolix 150milligram once daily, elagolix 250 milligram once daily, Prostap SR 3.75 milligram, and placebo. The second additional Phase IIb trial is enrolling in Central Eastern Europe and consists of four arms, elagolix 150milligram once daily, elagolix 250 milligram once daily, Prostap SR 3.75 milligram and placebo.

BPH is defined by the enlargement of the prostate gland. In BPH, as the prostate grows larger and presses against the urethra, normal flow of urine is hindered. Researchers have determined that dihydrotestosterone (DHT), a derivative of testosterone, contributes to prostate enlargement. During the year ended December 31, 2004, the Company conducted the Phase I single dose study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the GnRH antagonist in healthy males.

Depression is one of a group of neuropsychiatric disorders that is characterized by extreme feelings of despair, loss of body weight, decreased aggressiveness and sexual behavior, and loss of sleep. Anxiety is among the commonly observed group of central nervous system disorders, which includes phobias or irrational fears, panic attacks, and other syndromes.

The first clinical trial offer evidence of proof of concept of CRF antagonists in addressing depression (and anxiety as a co-examined variable) was a Phase II a open label trial conducted by the Company in 1999 pursuant to collaborations with Janssen Pharmaceutica (Janssen) in the field of CRF antagonists. In July 2001, the Company announced the second CRF antagonist collaboration, a global collaboration with GlaxoSmithKline (GSK), to develop and commercialize CRF antagonists for psychiatric, neurological and gastrointestinal diseases. During 2004, GSK advanced one of the CRF1 drug candidates arising out of the collaboration into Phase I clinical trials. GSK has completed a Phase II clinical trial with CRF1 receptor antagonist compound, 876008, for social anxiety disorder (SocAD). In this double-blind, randomized, placebo controlled, multiple dose study to evaluate the safety and efficacy of the CRF1 receptor antagonist compound in patients with SocAD, no statistical differences were observed in the efficacy endpoints between 876008 and placebo at 12 weeks.

GSK has advanced a second lead CRF1 receptor antagonist compound, 561679, into a Phase II depression study during 2008. This multicenter randomized, double-blind, placebo-controlled trial is designed to assess the safety and efficacy of 561679 in approximately 150 subjects with major depressive disorder. GSK has also completed the Phase I single dose escalating clinical trial with 586529, an additional CRF1 receptor antagonist compound.

Research has also suggested that CRF plays a role in the control or modulation of the gastrointestinal system. Studies have demonstrated that central administration of CRF acts to inhibit emptying of the stomach while stimulating bowel activity, and suggest that overproduction of CRF in the brain may be a main contributor to stress-related gastrointestinal disorders. GSK has completed a Phase II clinical trial assessing the CRF1 receptor antagonist compound 876008 in IBS. In this double-blind, randomized, placebo controlled study to evaluate the safety and efficacy of 876008 in patients with IBS, no statistically significant differences were observed in the key efficacy endpoints between 876008 and placebo.

Congestive heart failure (CHF) is a condition where the heart cannot pump enough blood to supply all of the body’s organs. It is a result of narrowing of the arteries combined with high blood pressure, which results in increased respiration, as well as edema from water retention. In the case of acute symptomology, CHF patients will experience a rapid deterioration and require urgent treatment in the hospital.

Urocortin 2 is an endogenous peptide ligand of the CRF2 receptor present in the cardiovascular system, notably the heart and cerebral arterial system. Urocortin 2 plays a role in the control of the hormonal, cardiovascular, gastrointestinal, and behavioral responses to stress, and has an array of effects on the cardiovascular system and metabolism. Based on preclinical efficacy and safety data, together with its known role in human physiology, we believe that urocortin 2 may have positive hemodynamic effects on cardiac output and blood pressure which may benefit patients with acute CHF.

During the year ended December 31, 2005, the Company completed a Phase II placebo controlled dose-escalation study to evaluate the safety, pharmacokinetics and pharmacodynamics of two dose levels of urocortin 2 in patients with stable CHF. Results of this study demonstrated a dose-related increase in cardiac output of up to 50% with only a modest increase (6%) in heart rate. The Company completed an additional Phase II study evaluating urocortin 2 over four-hour infusions in patients with stable CHF in the first half of 2006. The treatments were generally well tolerated without serious adverse events, abnormalities in electrocardiograms or significant changes in renal function. Positive hemodynamic effects were noted in virtually all patients with increases in cardiac output ranging from 6% to 54%. During 2008, the Company completed the necessary preclinical work to allow for periods of infusion of urocortin 2 up to 14 days.

Research Programs

The research and development program of the Company is focused on addressing the diseases and disorders of the central nervous system and endocrine system, which include therapeutic categories ranging from diabetes to stress-related disorders and neurodegenerative diseases. VMAT2 is a protein concentrated in the human brain that is essential for the transmission of nerve impulses between neurons. VMAT2 is primarily responsible for re-packaging and transporting monamines (dopamine, norepinephrine, serotonin, and histamine) among nerve cells. Specifically, dopamine enables neurotransmission among nerve cells that are involved in voluntary and involuntary motor control. Type II diabetes disease is characterized by reduced ability to secrete and respond to insulin. Drugs, which can improve the secretion of insulin in response to rising blood glucose levels can improve blood glucose. Anticonvulsants are utilized in the treatment of epileptic seizures by suppressing the rapid firing of neurons that initiate a seizure. Anticonvulsants also have a mood stabilizing effect that has proved beneficial in bipolar disease.

Programs subject to regulatory review

Indiplon is a non-benzodiazepine gamma-amino butyric acid-A (GABAA) receptor agonist for the treatment of insomnia, which acts through the same mechanism as the non-benzodiazepine therapeutics. The Company has obtained the rights to Indiplon through a global sublicense agreement that was entered into with DOV Pharmaceutical, Inc. (DOV) in June 1998. Based on the results of preclinical studies and Phase I, Phase II and Phase III clinical trials on Indiplon, as well as a non-clinical data package related to Indiplon manufacturing, formulation and commercial product development, the Company assembled and filed new drug applications (NDAs) with the United States Food and Drug Administration (FDA) for both Indiplon capsules and Indiplon tablets.

The Company competes with TAP Pharmaceuticals, Pfizer, Merck, Boehringer Ingelheim Pharmaceuticals, Hoffman-La Roche, Bristol-Myers Squibb, GSK, Wyeth, Forest Laboratories, Sanofi-Aventis, King Pharmaceuticals, Inc., Sepracor, Inc., Takeda Pharmaceutical Company, Eli Lilly, Janssen and AstraZeneca.