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

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

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.” 

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.

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. 

Animal Models

Alain Stricker-Krongrad, Ph.D., senior scientific advisor at Charles River Laboratories, works with client researchers to plan and develop animal models that are scientifically valid for their disease state of interest. Dr. Stricker-Krongrad employs the use of animal models that provide his clients with an assessment of the efficacy and drug safety of the drugs they’re developing. The rodent models used include rats and mice that have been bred to display cardiovascular and or diabetic indications consistent with these disease states. 

“Our process is to monitor different biomarkers of metabolic disease while keeping an eye on cardiovascular involvement,” Dr. Stricker-Krongrad said. “In the development of drug therapeutics for obesity, the challenge continues to be the ability to monitor the impact of the therapeutic intervention. Specifically, our work is focused on the development of a meaningful animal model that will enable researchers to screen drug impacts and determine outcomes earlier in the development process. The term coined for this approach, translational medicine, is a broad term that I don’t like to use because it detracts from the real question: How predictive is the animal model for the human condition?”

At the meeting, Dr. Stricker-Krongrad introduced a new animal model now available at Charles River while focusing on the current tools available to calculate cardiovascular risk. In drug development, the observation is that off-target effects of a drug given to normal patients don’t always reveal themselves. Unless the target patient population is tested you can’t determine the off-target impact of the drug candidate. 

That is, it is likely that the obese patient with diabetic or cardiac issues may show an adverse off-target effect not otherwise observed. The key is to identify or develop a good animal model to monitor the level of risk early in the development process.  All drugs have a toxicity risk to some level, Dr. Stricker-Krongrad said, the key is to identify just how severe that risk is. Among the biomarkers of choice for this risk assessment are the troponins, and these markers can serve to differentiate risk populations.

Biomarker Profiling

Three researchers at Duke University, Svati Shah, M.D., department of medicine, division of cardiology and center for human genetics; Bill Kraus, M.D., department of medicine, division of cardiology; and Chris Newgard, Ph.D., at the Sarah W. Stedman Center for Nutrition and Metabolism are taking a targeted approach to metabolic and biomarker profiling to identify markers that segregate with metabolic disease states, obesity, and diabetes. 

The group employs mass spectroscopy-based methods to investigate the relationship of over 70 targeted, quantitative metabolites derived from lipid, protein, and carbohydrate metabolism with human disease. 

Dr. Shah outlined the potential role of profiling these small molecule metabolites, which are byproducts of cellular metabolism, in understanding disease mechanism and as biomarkers of disease risk. She detailed examples of her group’s work in using these quantitative metabolomic profiles, and showed how they have led to a deeper understanding of obesity and cardiovascular disease. She also described the team’s effort to link to other omics in their studies for a systems biology approach. 

Dr. Shah shared data from two studies conducted by the group. In the Genecard study, they evaluated whether these metabolite profiles were heritable in families heavily burdened with early-onset coronary artery disease, with the eventual goal of identifying markers predictive of cardiovascular disease prior to overt clinical presentation. These investigations built upon prior reports in plants and mice that these small molecule metabolites are heritable.

“Specifically, we are looking for blood markers that could report on risk,” Dr. Shah said. “The study uses samples taken from families where at least two siblings presented with cardiovascular disease before the age of 51 in men and before the age of 56 in women. Eight families sampled over three generations revealed that these small molecule metabolites were more similar within families than between families, even after adjusting for shared environmental effects, suggesting a strong genetic component to variability in these profiles.

“The profiles themselves suggest that disturbances in mitochondrial function may be mediating cardiovascular disease in these families. We are continuing to expand these studies, to study different ethnicities and expand the study to other geographies.”

Based on an unbiased statistical approach using principal components analysis the team found that metabolites in three pathways tended to track together: a signature reporting on urea cycle activity in mitochondria, one reporting on arginine metabolism, and one reporting on branched chain amino acid metabolism. 

In a different study, Dr. Newgard’s group has shown that obese patients who also display insulin resistance show aberrant branched chain amino acid metabolism. Further, the team found that this aberrancy was associated with insulin resistance independent of the patient’s weight. 

Having established the heritability of these metabolite profiles in families burdened with early-onset cardiovascular disease, the team then investigated whether they could serve as biomarkers of coronary artery disease status. Dr. Kraus initiated a study called Cathgen in the cardiac catheterization laboratory at Duke in 2001, where all consenting patients are enrolled in a biorepository of DNA, RNA, and plasma samples combined with carefully collected clinical data. 

From this study of over 8,000 individuals, the team then conducted a case-control study in two independent subsets and found that metabolic profiles similar to ones in the Genecard study could differentiate patients with coronary artery disease from those without, and importantly, these profiles seem to add to what we already know about a person’s clinical risk of cardiovascular disease based on age, race, sex, and risk factors. 

Finally the team discussed what they called “Retro-Translation,” which refers to their work to understand the underlying biology of metabolic signatures in human disease. These mechanisms can only be investigated by animal testing where it’s possible to be more invasive to look for cause and effect. In fact, Dr. Newgard’s group has done such studies of branched chain amino acid metabolism in obese rats.

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