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Triolex® (HE3286): Metabolic Disorders

Triolex®, discovered by Harbor Therapeutics scientists, is an oral drug candidate in development for the treatment of diseases with underlying chronic inflammation. In metabolic disorders, our initial proof-of-concept clinical studies were performed in patients with type 2 diabetes mellitus (T2DM). Diabetes mellitus is a metabolic disease in which the body does not respond to and/or produce sufficient quantities of insulin. Insulin is a hormone that stimulates the movement of sugar (glucose) from the blood into cells, where it is converted to energy. When insulin is not present in sufficient quantity (the predominant feature of type 1 diabetes) or when the body fails to respond to it (the predominant feature of T2DM), dangerously high levels of glucose are maintained in blood. Features of T2DM predominate in approximately 90% of diabetics. In either case, over time, chronically elevated blood glucose can lead to a number of severe medical conditions such as kidney failure, blindness, ulcerations, limb amputations, coronary artery disease and death.

Clinical studies in patients with Type 2 Diabetes Mellitus

Our initial clinical trial was designed to study the safety, tolerability, pharmacokinetics and potential activity of Triolex® at three dosing levels — 5 mg once daily, 5 mg twice daily and 10 mg twice daily. Preliminary data from this clinical trial, reported in an oral presentation at IBC’s 6th Annual Conference, Targeting Metabolic Disorders, indicated that Triolex® was safe and well tolerated at all doses studied, and suggested that the compound reduced fasting blood glucose levels, improving insulin sensitivity.

A drop in pro-inflammatory cytokines including TNFá, IL-6, IL-1â and MCP-1 production (measured in LPS-stimulated peripheral blood mononuclear cells taken from subjects treated with the compound compared with those taken from placebo-treated subjects) confirmed an anti-inflammatory mechanism of action. Based on this positive preliminary data, we conducted a Phase II, 12-week clinical trial in patients T2DM. This trial, which was completed early in 2010, confirmed (by retrospective analysis) that Triolex® decreased inflammation and insulin resistance in an obese subset of T2DM patients.

Potential Mechanism of Action Suggested by Studies in T2DM

Harbor Therapeutics believes the anti-inflammatory mechanism of action for Triolex® may be the regulation of the NFêB and MAPK pathways, particularly when stimulated through the TLR4. TLR4 is a receptor expressed on the cell surface of macrophages and other cells. This receptor can be stimulated by pathogenic bacteria or even by certain components of the human metabolome when present in excess, such as dietary fatty acids. Upon stimulation of the TLR4, a cascade of pro-inflammatory kinases that include IKK, JNK, p38 and ERK are activated. This sets off a complex network of signaling pathways that culminate with the activation of NFêB, and AP-1 together with a number of genes involved in the inflammatory response. These include several pro-inflammatory cytokines and chemokines. Stimulation of the inflammatory kinases also impair insulin signaling by inhibiting the biological function of IRS-1, a protein that acts as a major mediator of insulin action in target cells. This leads to insulin resistance and is well characterized in the scientific literature (“TLR4 Links Immunity and Fatty Acid-Induced Insulin Resistance,” The Journal of Clinical Investigation, 2006, Volume 116, Number 11, pp 3015-25; “Macrophages, Inflammation, and Insulin Resistance” Annu Rev Physiol, 2010, Volume 72, pp 219-46). In experiments with macrophages in vitro, Triolex® attenuated the response of IKK, JNK, p38 and ERK to TLR4 stimulation.

Importantly, Triolex® appears to act independently of the PPARã pathway, and thereby may avoid the side effects associated with the current thiazolidinedione class of insulin sensitizing agents that work through the PPARã pathway. Experiments in vitro have shown no evidence that Triolex® directly binds and/or activates (transactivates) the PPARã receptor. Consequently, when administered to mice or rats, Triolex® does not cause body weight gain, one side effect of thiazolidiones use in humans.

T2DM Market

Approximately 160 million people worldwide have T2DM. The incidence of the disease is increasing rapidly as a result of an aging population and a global obesity epidemic. Only 36% of T2DM patients are able to achieve what is considered the adequate glucose control using current drug therapy. Peak sales of currently approved insulin sensitizers are well over $6 billion per annum, accounting for half of the $12 billion per year global oral anti-diabetic market.

Accelerated paths to market in metabolic disease: Non Alcoholic fatty liver disease and Steatohepatitis (NAFLD and NASH)

T2DM is a common component of metabolic syndrome, which is itself a constellation of dysregulated features of glucose and lipid metabolism and hypertension that correlates with age, increased body mass index (BMI) and visceral (abdominal fat) adiposity. Metabolic syndrome is widespread and steadily increasing in the United States and Europe, and is now common in developing nations as well. These observations, along with results from our pre-clinical and clinical studies, suggest a potentially accelerated development opportunity for Triolex® in patients with NAFLD and NASH, common and dangerous liver manifestations of metabolic syndrome that are highly associated with obesity-inducedT2DM.

NAFLD and NASH market

NAFLD is the most common cause of elevated liver enzymes and also one of the most common forms of liver disease in the world. It is now estimated to affect about 20% to 30% of people in the United States and other Western countries. The incidence of NAFLD is expected to rise further with the increase in obesity in the United States. The prevalence of NASH, a much more dangerous form of liver disease, is approximately 2% to 3% of the population in the United States. The relationship between obesity, insulin resistance, liver disease and inflammation in metabolic syndrome is now well established. Currently, there is no approved treatment for NASH, which is a critical unmet medical need.