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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

  • Peptide Therapeutics

    Heather Halem, Ph.D., manager of experimental endocrinology at Ipsen Pharmaceuticals, is focused on targeted therapeutics for oncology, endocrinology, and neurology.

    Dr. Halem and other members of the endocrinology group are working on the development of peptide therapeutics for treatment of metabolic diseases based on ghrelin and melanocortin as target systems. The team’s role is to progress candidate compounds from initial in vivo screening on through to proof-of-concept studies in animal models of metabolic disease. Clinical trial work is done elsewhere in the Ipsen network.

    In a typical screening effort the team starts with several hundred peptide variants based on the natural hormone and uses in vitro assays to select the top candidates. Those candidates are then studied in animal models to monitor the impact on food intake, body weight, and other key parameters.

    Ghrelin, a hormone produced by the cells lining the fundus of the human stomach and epsilon cells of the pancreas, is a current therapeutic target for the lab, based on the observation that ghrelin is involved in a number of metabolic disorders. First, plasma levels of ghrelin are lower in obese individuals than the levels found in leaner individuals. Further, patients suffering from anorexia nervosa have significantly higher plasma levels. Ghrelin levels are also high in patients that have cancer-induced cachexia and other chronic disease states.

    Dr. Halem presented data on “the impact of a ghrelin analog, BIM-28131 on normal and prostate cancer-bearing rats. In the normal rats we found that the drug candidate increases body weight through an increase in both fat and lean mass. Similar increases were also observed in the prostate tumor-bearing rats, thus alleviating the severe cancer-induced cachexia observed in this model,” said Dr. Halem. “The proof-of-concept work is complete, and we have transferred the effort to those that will focus on the preparation for clinical development.”

    Another case study that Dr. Halem presented at the meeting is based on work to target the melanocortin-4 (MC-4) receptor. Feeding pathways associated with the MC-4 receptor have the opposite affect of ghrelin. The MC-4 receptor is a GPCR receptor that normally binds a-melanocyte stimulating hormone, and is predominately located in the arcuate nucleus of the hypothalamus in the brain.

    When stimulated, the MC-4 pathway inhibits food intake and increases energy expenditure. Targeted disruption of this receptor leads to obesity in mice. Administration of the MC-4 receptor agonist, BIM-22493, in obese animal models leads to decreased food intake, body weight loss, and an improvement in glucose clearance. The overall effort is to identify a medication that will be used to treat obesity and the associated metabolic disorders.

    Peptide therapeutics have inherent advantages over small molecules as they are derived from the naturally occurring hormone, she said. Studies to date have been performed in diet-induced obese rodents, the genetically obese/diabetic Zucker rat model, and will be completed in the coming year in obese primates. 

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