SAN DIEGO, April 5 /PRNewswire-FirstCall/ -- Neurocrine Biosciences, Inc. today announced the publication of studies on the mechanism of action of indiplon that confirm its high affinity and selectivity for the subtype of the GABA receptor that is responsible for the principal effect of "non-benzodiazepine" sleep agents. Results demonstrate that indiplon has an enhanced combination of affinity and selectivity for alpha 1 containing GABA-A receptors compared to the currently marketed non-benzodiazepine sleep agents zolpidem (Ambien(R)), zaleplon (Sonata(R)) and zopiclone (Imovane(R), which is the racemic form of s-zopiclone [Lunesta(R)]). These results further support and partially elucidate the consistent efficacy and safety of indiplon that has been demonstrated throughout multiple clinical studies and support the conclusion that indiplon is a novel GABA-A receptor potentiator for the treatment of insomnia. Furthermore, the selectivity profile of indiplon revealed in this study suggests a low propensity for unwanted side effects. The results are published in the April 2006 edition of the Journal of Pharmacology and Experimental Therapeutics.
This peer-reviewed paper builds on earlier publications that showed indiplon to have high affinity for the benzodiazepine site on the GABA-A receptor and selectivity for receptors containing the alpha 1 subunit (the subunit principally responsible for the hypnotic effects of "non-benzodiazepine" drugs). The newly published findings used GABA-A receptor responses to directly compare indiplon with currently marketed "non-benzodiazepine" sleep agents. The key findings include the following:
* When tested for the ability to potentiate native GABA-A receptor responses in neurons, where a mixture of GABA-A receptor subtypes was present, indiplon had the highest affinity of the drugs tested, requiring concentrations that were 8, 13 and 170 times lower than zolpidem, zopiclone and zaleplon, respectively, to elicit the same receptor response; * When individual GABA-A receptor subtypes that varied in their alpha subunit composition were systematically expressed, indiplon showed the highest affinity and greatest selectivity for alpha 1 containing receptors (the primary target of "non-benzodiazepine" sleep agents). Compared to alpha 1 containing receptors, indiplon was 9, 24, and 30 fold less active at alpha 2, alpha 3 and alpha 5 containing receptors, respectively. Zopiclone and zaleplon showed little or no subtype selectivity, and zolpidem showed moderate selectivity for alpha 1 versus alpha 2 and 3 containing receptors, and good selectivity for alpha 1 versus alpha 5 containing receptors, in agreement with the published literature; * At receptors containing the GABA-A alpha 1 subunit, indiplon again had the highest affinity, requiring concentrations that were 27, 62 and 190 times lower than zolpidem, zopiclone and zaleplon, respectively, to elicit the same receptor response.
"These pharmacological studies confirm our earlier published data that indiplon has the best combination of affinity and selectivity of the 'non-benzodiazepine' sleep agents reported to date to potentiate GABA-A receptors", said Alan C Foster, PhD, Neurocrine Fellow at Neurocrine Biosciences. "Furthermore, the data demonstrate that indiplon is highly active at the subtype of GABA-A receptors that is believed to be responsible for hypnotic effects, with less affinity for receptor subtypes that may produce unwanted side effects".
"The comprehensive pharmacological profiling of non-benzodiazepine sleep agents reported in this paper reveals indiplon to have a unique selectivity profile for GABA-A receptor subtypes. This, combined with an optimized duration of action is likely to underlie the excellent efficacy and safety demonstrated by indiplon in multiple clinical studies of insomnia patients," added Dr. Foster.
Neurocrine Biosciences, Inc. is a product-based biopharmaceutical company focused on neurological and endocrine diseases and disorders. The product candidates address some of the largest pharmaceutical markets in the world including insomnia, anxiety, depression, diabetes, irritable bowel syndrome, eating disorders, pain, and autoimmunity. 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, risk and uncertainties associated with the Company's indiplon program and planned commercialization activities, including but not limited to; risk that regulatory authorities find our indiplon NDAs incomplete or insufficient or otherwise unapprovable or that approvals may be delayed; risk associated with our reliance on our strategic alliance partner for manufacturing and commercialization of indiplon; risk that following approval of indiplon commercialization may be delayed for any of a number of reasons including market conditions and product supply; risk that the indiplon labeling granted by regulatory authorities may limit the commercial success of indiplon; and risk relating to market acceptance of indiplon following marketing approval; in addition to the other risks described in the Company's report on Form 10-K for the year ended 2005. Neurocrine undertakes no obligation to update the statements contained in this press release after the date hereof.
FACT SHEET: ---- ----- Background Glossary on GABA-A Receptors and Subtype Selective Drugs
Indiplon and other "non-benzodiazepine" sleep agents achieve their effects by potentiating the actions of the primary inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). These drugs bind to a specific site on the GABA-A receptor, the receptor on neurons that mediates GABA's inhibitory effects. This site is termed the "benzodiazepine site", since it was first identified using the classic benzodiazepine drugs, but it can also be accessed by compounds with different chemical structures, the so-called "non-benzodiazepines".
The GABA-A receptor is made up of 5 protein subunits that assemble in neuronal membranes as a pentamer around a central pore that is selectively permeable to chloride ions. Upon GABA binding, the central pore opens and chloride ions can flow through the pore and into the neuron, producing an inhibition of neuronal activity. Neurons have a choice of 16 different genes that encode GABA-A receptor subunits and these are grouped into families based on their structural similarities: alpha(1-6), beta(1-3), gamma(1-3), delta, epsilon, pi and theta. A typical GABA-A receptor pentamer is composed of two alpha, two beta and one gamma subunits. The delta, epsilon, pi and theta subunits have some reported selective functions but are not yet fully understood. Theoretically, there are thousands of possible subunit combinations, but a limited number of subtype combinations have been found in native systems with alpha1,beta2,gamma2, alpha2,beta3,gamma2, and alpha3,beta3,gamma2 being the most abundant. The assembly of alpha, beta, gamma subunits is required to produce functional GABA-A receptors that exhibit all the pharmacological properties of native GABA-A receptors.
The benzodiazepine binding site occurs at the interface between alpha and gamma2 subunits, and sedative hypnotic drugs that bind here increase the affinity of GABA for its own recognition site (that lies between the alpha and beta subunits). This allosteric interaction between concurrent occupation of the benzodiazepine and GABA recognition site results in an increased chloride conductance thus enhancing the GABA-A receptor response. Consequently, the action of indiplon and other "non-benzodiazepine" sedative hypnotics is to potentiate the inhibitory action of GABA through this allosteric interaction within the GABA-A receptor.
The pharmacological spectrum of benzodiazepine site ligands, ranging from the therapeutic benefits of hypnosis, anxiolysis, anticonvulsant, and muscle relaxation to the potentially unwanted aspects of impaired motor co-ordination, attention and memory, tolerance and dependence and potentiation of the effects of alcohol, are believed to result from interactions with multiple GABA-A receptor subtypes. In particular, GABA-A receptors that differ in their alpha subunit variant appear to mediate particular pharmacological actions of benzodiazepine site ligands. This has been deduced from both molecular genetic and classical pharmacological studies and can be summarized as follows:
GABA-A receptor subtype containing: alpha1: sedation, anticonvulsant alpha2: anxiolysis, muscle relaxation, alcohol interaction alpha3: anxiolysis, muscle relaxation, motor impairment alpha5: memory, tolerance
The classical benzodiazepine drugs show no selectivity between these GABA-A receptor subtypes and can exhibit the entire spectrum of pharmacological effects, depending on the dose. Some non-benzodiazepines show selectivity, particularly towards alpha1-containing GABA-A receptors, and these produce a predominant hypnotic pharmacological profile. Consequently, it has been proposed that greater selectivity and affinity for alpha1- containing GABA-A receptors versus other alpha subunit containing GABA-A subtypes will translate into greater sedative hypnotic efficacy with fewer side effects.
Neurocrine Biosciences, Inc.CONTACT: Elizabeth Foster or Claudia Woodworth, both Investor Relations ofNeurocrine Biosciences, Inc., +1-858-617-7600
Web site: http://www.neurocrine.com/
