Data Presented at the American Psychiatric Association Meeting Reveals Mechanism of Action and Unique Binding Site
SAN FRANCISCO, May 21, 2003 - Results from early-stage trials demonstrate that TAK-375, under development by Takeda Pharmaceuticals North America (TPNA) for chronic and transient insomnia, is a highly selective ML-1 receptor agonist. The ML-1 receptor is a key mediator of natural sleep and may be an important new target for sleep agents.
In pre-clinical studies presented today at the American Psychiatric Association (APA) annual meeting in San Francisco, TAK-375 showed high selectivity for the ML-1 receptor with greater affinity, selectivity, and potency than melatonin, which is produced by the pineal gland and known to regulate sleep and wake cycles. Additionally, TAK-375 showed no affinity for any of a large number of other potential binding sites in the brain, including receptors for other neurotransmitters, peptides and cytokines, as well as ion channels and various enzymes.
"We are encouraged by these early data and the selectivity of TAK-375 for the ML-1 receptor," said Charlene M. Stubbs, Ph.D., vice president of Clinical Research, TPNA, Lincolnshire, Ill. "Phase III trials are now underway to further examine the potential of TAK-375."
TAK-375 Demonstrates High Affinity, Specificity for ML-1 Receptor
TAK-375 and its major active metabolite, M-II, showed notable differences in binding to the ML-1 receptor compared to endogenous melatonin. The following chart outlines findings from the study.
|ML-1 receptor||10-fold higher affinity than endogenous melatonin|
|ML-2 receptor||100-fold lower affinity than endogenous melatonin|
|ML-1a receptor CHO cells expressing human||4-fold higher potency than endogenous melatonin|
"In these pre-clinical studies, the pharmacological profile of TAK-375 suggests it may offer a new and unique way to treat insomnia and circadian rhythm sleep disorders," said Keisuke Hirai, Ph.D., Research Head, Takeda Chemical Industries, Ltd., who presented these data at the meeting.
Other studies that measured the binding of TAK-375 and its major active metabolite to several potential binding sites also showed that it is highly selective for the ML-1 receptor with no affinity for any of several receptors or neurotransmitters including GABA and opiate, peptides, or cytokines.
Safety, Pharmacokinetics and Pharmacodynamics of TAK-375
Researchers also examined the safety, pharmacokinetics and pharmacodynamics of a single oral dose of TAK-375 in 60 healthy adults. In this randomized, double-blind study, subjects received a single dose of placebo or TAK-375 at 1 of 5 dose levels (4, 8, 16, 32 or 64 mg). The frequency of adverse events was similar between placebo and any of the TAK-375 study arms. In addition, TAK-375 exhibited rapid absorption, good dose proportionality, and dose-independent half-lives ranging from 0.834 and 1.903 hours. TAK-375 was extensively metabolized and half-lives of metabolites appeared comparable across all dosing groups.
"We are excited about moving forward with the development of TAK-375, due to its high selectivity for the ML-1 receptor, pharmacokinetic profile and low incidence of adverse events," said Dr. Stubbs. "Takeda is committed to the further study of TAK-375 to continue substantiating these early observations."
Function of Melatonin Receptors
Melatonin, a hormone released by the pineal gland in the brain in response to cycles of light and darkness, is believed to initiate sleep and wake periods by broadly targeting ML-1 receptors. ML-1 receptors are located in the suprachiasmatic nucleus (SCN), a part of the hypothalamus that is known as the body`s "master clock" because it regulates circadian rhythm (e.g., sleep-wake cycles). ML-2 receptors are diffused throughout the body and thought to have other effects beyond promoting sleep. When activated, ML-1 receptors encourage sleep onset. There are several ML receptors, though studies show the ML-1 receptor is a primary mediator of the natural sleep cycle.
About Takeda Pharmaceuticals North America, Inc.
Based in Lincolnshire, Ill., Takeda Pharmaceuticals North America, Inc. is a wholly owned subsidiary of Takeda Chemical Industries, Ltd. in Osaka, Japan. Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the industry's leaders worldwide, Takeda is committed to strive toward better health for individuals and progress in medicine by developing superior pharmaceutical products.
Takeda Pharmaceuticals North America
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