METABOLIC DISEASES

The incidence of diabetes and dyslipidemia is growing at exceptional rates globally. New treatment options are needed that address the underlying cause of disease. Limerick is developing a novel, first-in-class approach that has the potential to modify the course of disease and offer an attractive new treatment modality for patients and physicians.

UNMET MEDICAL NEEDS

In the U.S. alone, there are approximately 25 million persons living with diabetes and 44 million persons with hypertriglyceridemia or mixed dyslipidemia recommended for treatment, as well as up to 15 million persons with non-alcoholic steatohepatitis (NASH). These conditions are growing rapidly, along with the rise in obesity. In fact, projections indicate that by 2020, as much as 75% of the U.S. population will be overweight.

Insulin resistance is the defining feature of metabolic diseases that are associated with nutritional overload and sedentary behavior. Except for the thiazoladinedione class (TZD) of drugs (pioglitazone and rosiglitazone), which are associated with serious side effects including weight gain and cardiovascular risk, there are no approved therapeutic agents which directly affect the problem of insulin resistance. This leaves a substantial gap in the armamentarium to treat diabetes; there are several therapies offering diverse mechanisms to increase insulin secretion or decrease glucose production, but oral therapies that address the underlying cause of disease and directly sensitize the body to insulin are lacking.

LIMERICK SOLUTION

Limerick’s compounds have been optimized specifically to maximize their impact on hyperglycemia and dyslipidemia and can be used as stand-alone therapy or in combination with currently available products. The Company’s approach has the potential to alter the underlying disease state, rather than treating the symptoms of disease, and could generate blockbuster sales in these growing marketplaces.

Clinical and preclinical development studies are in progress. In diabetic and obese rodent models, Limerick compounds have been shown to:

Significantly normalize blood glucose and improve oral glucose tolerance
Significantly lower plasma and liver triglyceride levels
Improve insulin sensitivity without the weight gain associated with currently marketed insulin sensitizers
Reduce cytokine release in fat laden islets
Improve glycemic control in healthy volunteers

Preclinical Studies Demonstrating the Effect of Limerick Compounds as Insulin Sensitizers

In the Zucker Diabetic Fatty Rat (ZDF), LIM Compounds effectively reduce HbA1c without the weight gain associated with Rosiglitazone (Rosi).

Parallel groups were dosed with daily Rosiglitazone, Vehicle, or LIM. Food and water was available ad libitum. After 6 weeks of dosing, HbA1c, and glucose were decreased in the treated animals in a manner similar to Rosi. Weights in treated animals were similar to Vehicle.

Preclinical Studies Demonstrating the Effect of LIM Compounds on Liver Triglycerides

Hepatic steatosis is a hallmark of the insulin resistant state and leads to NASH and ultimately cirrhosis. LIM-0705 treatment in a overfed mouse model led to a marked decrease in liver triglyceride levels, as seen by immunohistochemistry and direct biochemical measurements of hepatic triglyceride content.

Immunohistochemistry for liver triglyceride staining in vehicle treated (left panel) and LIM treated high fat diet/obese C57B/6 mice (right panel) at study termination. Steatosis is quite marked in the vehicle treated mouse but is substantially ameliorated in the treated animal.

Clinical Studies Demonstrating the Effect of Limerick Compounds on Glycemic Control

In a recent study in healthy volunteers, subjects received LIM for 14 days. Oral glucose tolerance tests were performed. Subjects treated with LIM compound showed significant improvement in their ability to metabolize glucose as measured by OGTT.

Oral glucose tolerance 2 hour glucose results in healthy volunteers following 14 days of oral LIM treatment. While all of these subjects had normal glucose tolerance at the beginning of this study, a striking reduction in 120 min glucose excursion is observed after only 8 days of treatment and continues to day 14. Significant reduction is also seen in glucose levels at other time points beginning day 8 (not shown).

COMMERCIAL OPPORTUNITY

Oral combination therapy and insulin dominate the current standard of care for diabetes and generate global sales of $23 billion, with projected growth to $38 billion by 2015. For dyslipidemias, oral therapies are standard including fibrates, niacins and omega-3-fatty acids and generate sales of $3 billion in the U.S. alone, with substantial growth due to the recent introduction of branded omega-3-fatty acid products. There are no specific therapies currently available to treat NASH.

Limerick’s compounds have been optimized to maximize their impact on hyperglycemia and dyslipidemia and can be used as stand-alone therapy or in combination with current agents. Limerick has designed its program to address a key gap in the treatment landscape for physicians and patients. This approach has the potential to alter the underlying disease state, rather than treating the symptoms of disease, and could generate blockbuster sales in this growing marketplace.