Targeting cellular energy to treat chronic disease
Therapeutic interventions aimed at restoring the cellular bioenergetics balance are promising approaches for treating metabolic diseases, in particular, treat type 2 diabetes and non-alcoholic steatohepatitis (NASH), among others. We have focused our research and development activities on targets that are important in the regulation of the cellular bioenergetics:
- Mitochondrial respiratory chain (MRC)
- Direct activation of adenosine monophosphate-activated protein kinase (AMPK)
- Targeting inhibition of the mitochondrial pyruvate carrier (MPC)
Mitochondria - The Cell’s Energy Producing Machine
We believe that Imeglimin is able to regulate mitochondrial energy production by counteracting the mitochondrial dysfunction associated with the diabetes pathology and its associated microvascular and macrovascular complications.
The mitochondria is the power center of the cell generating energy through the production of adenosine triphosphate, or ATP, the primary unit of cellular energy, by oxidizing nutrients such as glucose and lipids, and contributing to the regulation of energy balance and, therefore, improves metabolic function.
In the pathophysiology of diabetes, excess food and a sedentary lifestyle lead to a disequilibrium in the energy balance and are linked to the fact that the supply of nutrients is higher than the demand for energy. This disequilibrium causes an increase in the production of reactive oxygen species, or ROS, from the mitochondrial respiratory chain, which further impairs the functioning of the chain, leading to insufficient insulin secretion in response to glucose and to impaired insulin sensitivity.
We believe that Imeglimin improves mitochondrial function by modulating mitochondrial respiratory chain complex activities and by decreasing ROS overproduction in this unhealthy context. Through this mitochondrial action, Imeglimin has been observed to restore the organs’ sensitivity to glucose and insulin, and to be associated with:
- an increase in glucose-dependent insulin secretion by the pancreas;
- a decrease in the excess production of glucose by the liver; and
- an increase in the absorption and use of glucose by the muscles.
Imeglimin has also been observed to prevent the mitochondrial permeability transition pore from opening and to prevent cell death in the pancreas’ beta cells and in human endothelial cells. We believe Imeglimin’s beneficial effect on the pancreas’ beta cell mass preservation could lead to delaying the disease progression. Imeglimin’s effect on improving endothelial dysfunction leads us to believe that the Imeglimin may have an early vascular protective effect that may potentially delay the occurrence or decrease the progression of vascular complications in the type 2 diabetes population.
The diagrams below set forth a representation of the mitochondria and its membranes within a diabetic cell, and illustrates Imeglimin’s mechanism of action on mitochondria:
The AMPK Enzyme - Cellular Energy Sensor
The AMPK enzyme is an energy sensor whose role is to maintain cellular energy homeostasis. Depending on the cellular bioenergetics status, AMPK activation enhances catabolic processes and down-regulates anabolic pathways. Based on its central metabolic role, targeting AMPK offers the opportunity to pursue a wide range of indications to treat chronic metabolic diseases, such as NASH. For NASH, targeting AMPK is important because it has the potential to trigger benefits on the key pathophysiology processes involved in disease development: liver steatosis, inflammation, ballooning and fibrosis. AMPK activation also has the potential to treat NASH comorbidities, specifically targeting cardiovascular risk factors, such as hyperglycemia, insulin resistance, dyslipidemia, inflammation and obesity.
Based on clinical trials and preclinical studies to date, PXL770, our direct AMPK activator, has been observed to:
- improve sensitivity to insulin;
- inhibit the two main sources of steatosis, DNL and lipolysis;
- reduce inflammation in the liver and fat tissue;
- reduce profibrogenic pathways leading to fibrosis; and
- reduce CV risk factors.
Targeting Inhibition of MPC – Fuel Gatekeeper
The mitochondrial pyruvate carrier is a fuel gatekeeper and inhibition of it promotes fat utilization, increases insulin sensitivity, and decreases inflammation.
PXL065, the R stereoisomer, is a targeted inhibitor of the MPC with little or no observed PPARy activation effects and associated adverse effects that appear to be related to the S stereoisomer of pioglitazone. In preclinical animal models, PXL065 exhibits the anti-inflammatory and NASH activity associated with pioglitazone with little or no weight gain or fluid retention, side effects which are associated with the S-stereoisomer. Based upon preclinical and Phase 1 results to date, Poxel believes that PXL065 may have a better therapeutic profile than pioglitazone for NASH.
How is Type 2 Diabetes Characterized?
Type 2 diabetes pathophysiology is characterized by a deregulation of the body's metabolic and cellular bioenergetics balances. This is linked to high food supply and low energy demand due to a sedentary lifestyle of diabetic patients and leads to mitochondrial dysfunction.
In diabetes pathophysiology, metabolic misbalance creates a pressure onto the mitochondria, which leads to their dysfunction, overproduction of reactive oxygen species (ROS), reduction of oxidative capacity, and subsequently to the accumulation of lipids in insulin-sensitive tissues and, lastly, to insulin resistance and diabetes.
What's Going on Inside the Body of a Type 2 Diabetes Patient?
Scientific investigations support the concept that type 2 diabetes is fundamentally tied to changes in mitochondrial content or oxidative capacity in insulin-sensitive tissues (liver, muscle, adipose tissue) and in the pancreas of insulin-resistant patients. Studies have demonstrated that this oxidation failure and inappropriate lipid storage in the tissues can be correlated with a decline in both insulin sensitivity and metabolic flexibility, due to a defect in insulin signaling.
Diabetes Market Overview
According to the International Diabetes Federation, or IDF, in 2017 an estimated 425 million people between the ages of 20 and 79 were affected by diabetes globally, with more than 90% of those affected having type 2 diabetes. The IDF also estimated that in 2017, in the United States alone, 30.2 million individuals, or 9.3% of the population, had diabetes.
Decision Resources, an independent market analysis firm, estimates that diabetes treatments generated sales of over $61 billion in 2017 in the United States, Japan, Germany, Italy, the United Kingdom, France and Spain, which we refer to as the G7 countries, and that sales in these markets are projected to grow to $76 billion by 2027.
About Non-Alcoholic Steatohepatitis (NASH)
Non-alcoholic steatohepatitis (NASH) is a metabolic disease with no clear disease origin that is quickly becoming a worldwide epidemic. It is characterized by the accumulation of fat in the liver causing inflammation and fibrosis. The disease can be silent for a long period of time, but may progress towards severe damage and liver fibrosis, which ultimately can even result in liver failure and/or liver cancer. Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and diabetes. Currently no curative or specific therapies are available.
NASH Market Overview
According to analyses conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, NAFLD, which results in an accumulation of fat in the liver, is one of the most common liver diseases in the United States. It affects approximately 20% of the world’s population and up to 70% of type 2 diabetes patients.
NASH is a severe form of NAFLD. These liver diseases aggravate cases of cirrhosis and hepatocellular carcinoma. According to published estimates, about 10% to 30% of NAFLD patients also suffer from NASH.