LBS
009
PRECLINICAL
THE PATH TO METABOLIC DISEASE
For Non-Alcoholic Fatty Liver Disease & Type 2 Diabetes
LBS-009, currently in preclinical development, is an anti-RBP4 oral therapy targeting liver disease, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and type 2 diabetes (T2D), which we estimate to cumulatively impact more than 2.4 billion people worldwide. LBS-009 is a small molecule designed to compete with retinol for binding to RBP4, the primary carrier of vitamin A (retinol) from the liver to extra-hepatic target tissues. When bound to LBS-009, RBP4 can no longer bind to retinol and, therefore, cannot interact with a key accessory protein (transthyretin) that would otherwise prevent elimination of RBP4 from circulation. Consequently, the RBP4-LBS-009 complex ends up being removed from circulation by renal filtration. The available data suggest that modulation of circulating RBP4 with an RBP4 antagonist, like LBS-009, has the potential to provide a therapeutic benefit for patients suffering from metabolic diseases, including NAFLD, NASH, and T2D.
DISEASE PROFILE
NAFLD/NASH
Non-alcoholic fatty liver disease (NAFLD) occurs when an excess accumulation of fat damages the liver. Over time, damage to the liver and the associated inflammation can lead to the development of NASH. NAFLD can lead to cirrhosis and, eventually, complete liver failure. NAFLD and NASH are a growing unmet need for which no FDA-approved treatments are currently available.
Type 2 Diabetes
Type 2 diabetes (T2D) is a chronic disease in which two interrelated problems are at work. The pancreas does not produce enough insulin, a hormone that regulates the movement of sugar into your cells, and cells respond poorly to insulin and take in less sugar. The health impact of T2D is profound, potentially causing damage to the heart, blood vessels, eyes, kidneys, and nerves. Type 2 diabetes is on the rise .(Source: WHO)
MECHANISM OF ACTION
RBP4 is a Pro-Inflammatory Metabolic Cytokine
RBP4 has been identified as a pro-inflammatory cytokine in preclinical models of insulin resistance and liver disease. Consequently, RBP4 is currently being investigated as a clinical biomarker for human metabolic diseases. In response to the impaired glucose uptake associated with obesity, fat cells will increase their production and release of RBP4. Elevated concentrations of RBP4 in adipose tissue have been shown to cause inflammation through the activation of antigen presenting cells in the immune system, which elicits an adaptive immune response. The proliferation of CD4 T cells further amplifies inflammation, primarily in visceral adipose tissue. This is currently thought to be the driving force in RBP4-mediated insulin resistance. Increased RBP4 production in enlarged adipocytes also instigates a cascade of responses that result in a redistribution of free fatty acids from adipose tissue to the liver, leading to excessive accumulation of hepatic fat. While the role of RBP4 in inducing metabolic dysregulation is both complex and multifaceted, data suggests that modulating RBP4 concentrations systemically with an RBP4 antagonist, like LBS-009, may have tremendous therapeutic potential for treating patients suffering from RBP4-induced metabolic diseases.
