Metabolic Solutions Development Co.

Origins of TZDs

Insulin-sensitizing thiazolidinediones (TZDs) were discovered more than 25 years ago by scientists at Takeda Pharmaceutical Company. At the time these compounds were discovered, researchers did not understand their potential mechanism of action. Today, it is generally believed that these compounds are activators of the nuclear receptor PPARγ.

The founders of Metabolic Solutions have recognized that PPARγ activation is the cause of the side effects associated with TZDs, while the useful pharmacology is secondary to the prevention of metabolic inflammation in the energy-producing cellular organelles called mitochondria.

Scientists’ failure to understand the mechanism of action of insulin sensitizers also explains why, in spite of considerable effort, no new insulin-sensitizing drugs have been developed since the first TZDs were first produced almost 20 years ago.

Insulin Resistance

The basis of insulin resistance is a metabolic inflammation that ensues from inappropriate oxidative metabolism in the energy-producing mitochondria. This metabolic inflammation, characterized as an insulin resistance, is at the heart of metabolic disease. The peripheral tissues’ resistance to insulin puts pressure on the β-cells of the pancreatic islets, causing them to produce and secrete more and more insulin.

In individuals who are genetically predisposed to type 2 diabetes, the function of the pancreatic β-cells progressively declines, eventually leading to a rise in circulating glucose (sugar) levels. The changes in pancreatic islet function are manifest first as a loss in the regulation of circulating glucose levels after meals and eventually as a rise in fasting glucose levels. Once circulating glucose levels are elevated above established standards, an individual is classified as having type 2 diabetes.

Although circulating glucose is elevated only after pancreatic β-cell function has declined, there is an entire pathology fueled by the metabolic inflammation that affects key risk factors for cardiovascular disease. This pathology occurs both in individuals who are susceptible to and in those who are resistant to developing type 2 diabetes. This pathology is called metabolic syndrome, or cardiometabolic syndrome.

Metabolic Syndrome and PPARγ Activation

Metabolic syndrome consists of a clustering of factors that are known to predispose individuals to the main causes of cardiovascular death, namely heart attacks and strokes. These well-known risk factors include:

Elevated glucose or insulin resistance
Elevated triglycerides
Elevated blood pressure
Low levels of HDL (good) cholesterol
Increased waist size or body weight
Factors that favor the formation of blood clots, including the underlying inflammation

Pre-clinical (animal) and clinical (human) studies have shown that TZD insulin sensitizers can partially correct all of these risk factors. These compounds are so broadly effective because they attack the metabolic inflammation that is the molecular cause of the syndrome. However, in addition to reducing the metabolic inflammation and improving insulin sensitivity, the first-generation TZDs also activate the expression of other factors that have a negative impact.

TZDs can also activate the nuclear transcription factor PPARγ, which can generate unwanted side effects, including:

Fat deposits
Increased fluid retention (and edema)
Changes in the vascular and circulating lipids (e.g., bad cholesterol)

All of these side effects limit the drugs’ effectiveness.

PPARγ-Sparing Solutions

At Metabolic Solutions, our purpose is to develop therapeutics that are PPARγ-sparing insulin sensitizers. These compounds will have improved profiles over the first-generation TZDs, because they will correct all of the risk factors for cardiovascular disease (listed above).

Our compounds will be useful not only in treating type 2 diabetes, but also in preventing the development of diabetes and cardiovascular disease (which is associated with type 2 diabetes and metabolic syndrome).

We have completed pre-clinical development and begun clinical trials with our first PPARγ-sparing TZD, MSDC-0160 (Mitoglitazone™), with the help of our Michigan-based partners. We are developing MSDC-0160 as a primary treatment for type 2 diabetes. Importantly, our development program not only focuses on controlling glucose levels, but also includes all of the key parameters involved in improving cardiovascular outcomes – since cardiovascular outcomes are the key endpoint for an anti-diabetic medicine.

We are also evaluating optimal combinations with other agents to control the key cardiovascular risk factors, including lipids and blood pressure. Our powerful partnerships will enable us to thoroughly evaluate these healthcare outcomes and pursue expansions of indications for the prevention of both diabetes and the cardiovascular deaths associated with metabolic inflammation (i.e., metabolic syndrome).

Benefits of PPARγ-Sparing TZDs
Side-Effect Profile Reduced incidence of edema Reduced weight gain Reduced bone loss	Efficacy Profile Increased antihypertensive activity Increased HDL/total cholesterol Increased blood glucose lowering Improved cardiovascular outcomes Prevention of diabetes

Early Intervention, Prevention

The dyslipidemia and hypertension associated with metabolic syndrome are currently treated with “cocktails” of lipid-lowering and antihypertensive drugs. These treatments neither address the causes of these risk factors nor optimally treat them. Thus, statins, which lower bad cholesterol, do not address the problems with low good cholesterol. And blood pressure medications only affect individual components of established hypertension, such as altered characteristics of blood vessels, increased activity of the nervous system, or altered function of the fluid control systems.

In contrast, we will develop combinations that target these risk factors at their cause, so that outcomes can improve with the minimal number of medicines.

Our goal is to treat metabolic disease early in its course, before an additional pathology is established (4, 5). We intend to provide metabolic solutions that prevent diabetes and cardiovascular disease.

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