New First In Class Drug Helps to Improve Insulin Resistance and Reduce Inflammation

It seems that every week we are reporting on a new drug that works differently than other drugs to control diabetes. Triolex™ is another example of a first in class drug that treats the inflammation in the blood vessels that can occur in people with diabetes.

Hollis-Eden Pharmaceuticals, Inc. presented positive interim data from its on-going Phase I/II clinical trial with its investigational oral drug candidate TRIOLEX™ (HE3286) in obese insulin resistant subjects

The data extend findings previously reported in a corporate symposium held in conjunction with the 68th Scientific Sessions of the American Diabetes Association demonstrating that TRIOLEX is safe and well tolerated to date, and that it significantly improved insulin sensitivity and lowered fasting blood glucose and insulin levels in obese insulin resistant subjects treated orally with 5 or 10 milligrams of the compound administered twice daily for 28 days, as compared to placebo-treated subjects.

Dr. Flores-Riveros presented additional data showing that insulin resistant subjects, displayed a significantly exacerbated inflammatory response characterized by higher levels of the pro-inflammatory cytokines MCP-1, TNF-alpha, IL-6 and IL-1beta produced in LPS stimulated peripheral blood mononuclear cells (PBMC) from these patients. In contrast to more insulin sensitive subjects (M>5), treatment of these insulin resistant subjects (M<5) with TRIOLEX was associated with a positive trend towards lowering these inflammatory cytokines, which in turn was accompanied by signs of glucose lowering in the same subjects.

Dr. Flores-Riveros also presented new data showing that retinol-binding protein 4 (RBP4), a protein secreted by fat cells that is associated with insulin resistance, was markedly decreased in the insulin resistant subjects treated with TRIOLEX compared to placebo-treated subjects. In addition, C-reactive protein (CRP) was significantly decreased in the insulin resistant subjects compared to placebo-treated subjects (p = 0.018). CRP is a well-known serum marker of inflammation, which has been linked to cardiovascular risk.

“The findings to date from this on-going clinical trial suggesting that initial serum CRP and levels of MCP-1, TNF-alpha, IL-6 and IL-1beta secreted by PBMC are elevated in insulin resistant subjects provide further rationale for the belief that insulin resistance is closely linked with inflammation,” stated William Cefalu, M.D., of Pennington Biomedical Research Center in Baton Rouge, Louisiana. “The trend observed to date in this on-going study that TRIOLEX appears to decrease these elevated inflammatory markers, as well as the previously reported interim data showing that TRIOLEX significantly improved insulin sensitivity in these subjects when compared to placebo-treated subjects, lend support for the continued clinical development of TRIOLEX. If successfully developed, TRIOLEX has the potential to be an anti-inflammatory pharmaceutical that may provide benefit in type 2 diabetes without the side effects associated with the current glitazone class of insulin sensitizing agents as well as potentially providing benefit for diabetes-associated cardiovascular events.”

TRIOLEX may represent a novel, first-in-class insulin sensitizer that Hollis-Eden believes acts by modulating inflammatory pathways. Leading academic researchers have linked inflammation and type 2 diabetes, reporting that chronic, subclinical inflammation can result in impaired insulin signaling by a variety of mechanisms. The involvement of inflammation through this pathway in causing insulin resistance and type 2 diabetes is well described in the scientific literature. In addition, activation of NF-kappaB due to inflammatory mediators or oxidative stress leads to a feed forward cycle of increased production of inflammatory cytokines such as MCP-1, TNF-alpha, IL-6 and IL-1beta.

The therapeutic approach inherent in TRIOLEX is to restore the biological activity of cellular signaling pathways disrupted by disease and aging. In the setting of type 2 diabetes, the Company believes that the mechanism of action for TRIOLEX may be the regulation of the NF-kappaB pathway and other proinflammatory pathways, particularly when these are stimulated through the TLR4 receptor. TLR4 is a receptor expressed on the cell surface of macrophages and other cells that is stimulated by certain pathogens such as bacteria and viruses or certain chemicals such as dietary fatty acids. Upon stimulation of the TLR4 receptor, a cascade of proinflammatory kinases that include IKK, JNK and p38 is activated, setting off a complex network of signaling pathways, which culminate with the activation of NF-kappaB and a number of genes involved in the inflammatory and cell stress response. Based on experiments conducted to date, TRIOLEX appears to act independently of the PPAR-gamma pathway and down regulates proinflammatory kinases JNK, IKK and p38, which have been associated with impairment of the insulin receptor substrate-1 protein (IRS-1) function, an important cellular mediator of insulin signaling, ultimately causing inappropriate insulin action. Since this mechanism for improving insulin sensitivity does not seem to occur primarily through the PPAR-gamma pathway, TRIOLEX may avoid the side effects associated with the current glitazone class of insulin sensitizing agents, such as Avandia® and Actos®, which work through PPAR-gamma. Side effects reported to date with the glitazone class of drugs include weight gain, edema and increased cardiovascular events. To date, experiments in vitro have shown no evidence that TRIOLEX directly binds and/or transactivates the PPAR-gamma receptor. Unlike the glitazones, TRIOLEX does not cause body weight gain when administered to mice or rats

If TRIOLEX is successfully developed, it may have the ability to regulate both glucose homeostasis and inflammation and can result in a better and safer insulin sensitizer and make a significant advancement in the treatment of type 2 diabetes as well as potentially be beneficial in mitigating the serious consequences associated with uncontrolled inflammation in cardiovascular disease.

Data presented last week at the 6th World Congress on Insulin Resistance Syndrome, September 25th – 27th in Los Angeles, California. Dr. Jaime Flores-Riveros, Vice President, Endocrinology and Metabolism at Hollis-Eden Pharmaceuticals, presented the data.

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DID YOU KNOW:
Bacteria Protect Against Type 1 Diabetes: The finding supports the so-called hygiene hypothesis — the theory that a lack of exposure to parasites, bacteria and viruses in the developed world may lead to increased risk of diseases such as allergies,  asthma and other disorders of the immune system as in Type 1 diabetes.  Understanding how gut bacteria work on the immune system to influence whether diabetes and other autoimmune diseases occurs is very important, Li said. This understanding may allow us to design ways to target the immune system through altering the balance of friendly gut bacteria and protect against diabetes. journal Nature, Sept.  See This Weeks’ Item #14

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