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Apr 1, 2009 (Vol. 29, No. 7)

Getting a Handle on Metabolic Disorders

Targets and Methods Vary, but the End-Goal Is the Same—More Effective Therapeutics

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    The Pound Mouse is genetically obese, it exhibits symptoms of metabolic syndrome, and it fills a much- needed niche for studies involving prediabetic stages of obesity, according to Charles River Laboratories.

    IBC’s “Targeting Metabolic Disorders” meeting, held late last month in Boston, was particularly timely given the new regulatory hurdles and higher standards for efficacy required for the next generation of metabolic drug products. Most of the presenters were confident that their research efforts would ultimately lead to the development of better metabolic therapeutics.

    Representing Metabolex, Maria Wilson, Ph.D., senior scientist, and Charles McWherter, Ph.D., senior vp of research and preclinical development, discussed the company’s ongoing research. Dr. Wilson specifically reviewed her work with the GPR119 agonist MBX-2982, a drug candidate in Phase I development.

    GPR119, a Gas-coupled GPCR, is expressed in b-cells in the pancreatic islets and endocrine cells in the gastrointestinal tract. Activation of GPR119 can improve glycemia by two mechanisms. In the b-cells, activation of the receptor signals the increased release of insulin in response to glucose. Activation of the receptor in the gastrointestinal endocrine cells increases levels of the incretin hormone GLP1.

    “Rodent models have shown that acute treatment with MBX-2982 results in enhanced clearance of a glucose load. In fat-fed, female ZDF rats, a diabetic animal model, MBX-2982 delayed the onset of disease compared to untreated rat controls, which showed hyperglycemic symptoms within seven days,” Dr. Wilson said. 

    Pharmacokinetic studies to date indicate that a single dose of MBX-2982 results in lower blood glucose levels by increasing insulin secretion and releasing incretin hormones such as GLP-1, potentially preserving beta cell health in the treatment of type 2 diabetes, she added.

    The firm has two other drug candidates in clinical development. MBX-102, its lead candidate for type 2 diabetes, currently in Phase II trials, is being developed in collaboration with Johnson & Johnson. The drug acts as an insulin sensitizer but without the side effects of other marketed drugs in this class such as weight gain and edema, according to Dr. McWherter.

    MBX-8025 is a therapeutic agent that just completed a Phase II proof-of-concept trial for treating mixed dyslipidemia.  Results from this trial indicated that MBX-8025 addresses all the key defects associated with the atherogenic mixed dyslipidemia that commonly afflicts millions of diabetics and is thought to be linked to the cardiovascular consequences of the disease, Dr. McWherter stated. Its benefits included the lowering of triglycercides and LDL cholesterol, the raising of HDL cholesterol, and the reduction of the atherogenic small dense LDL particles and C-reactive protein. 

    “Dyslipidemia in diabetics is one of the most important unserved needs because the diabetic’s ultimate demise is most often due to cardiovascular events,” Dr. McWherter added. He described the mechanism of MBX-8025 as “targeting underlying defects in lipid handling, which are also thought to be associated with acquiring insulin resistance.” 

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