THBA Platform - Bile acid imbalance

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1 - Bile acid imbalance Bile acids play an important role in maintaining human health by means of signaling molecules in the regulation of bile formation, liver function and metabolism. The detergent effect of Bile acids has a significant impact in the digestion of vital fatty nutrients while the regular flow of bile helps to remove toxins and waste products form the body. Unfortunately an imbalance of bile acids may lead to inflammation, infection and the development autoimmune diseases in the liver and gastrointestinal (GI) system. The accumulation of toxic bile acids in the liver may lead to the development of cholestatic diseases that can lead to liver failure and death. Our proprietary THBA platform allows us to identify and develop less toxic synthetic bile acid molecules as therapy for a wide variety of liver and GI related diseases. This medicinal platform has the potential to restore a damaged liver and provide benefits in other therapeutic Indications.

2 - Discovery of THBA Tetrahydroxylated bile acids (THBA) are a novel species of bile acids that are not normally present in the mouse or human bile THBA were serendipitously discovered in the Ling lab through the study of Bsep knockout mice (Bsep-/-), which are a model of human progressive familial intrahepatic cholestasis type II (PFIC2) BSEP is the main transporter of primary bile acids in the liver THBA structure

3 - Discovery of THBA Human PFIC2 is associated with greatly reduced bile salt in bile (~ 1% of normal), reduced bile flow, increased risk of liver fibrosis and cirrhosis, and is fatal without liver transplantation Unexpectedly, Bsep-/- mice are viable and have an overall normal morphology, albeit smaller than control mice (growth retardation and lower viability) The livers of Bsep-/- mice are enlarged compared to control mice and they show a non-progressive, mild cholestatic phenotype with normal levels of liver indicators and normal hepatocyte morphology Proposed mechanism: Mouse pups at 10.5 days old Bsep -/- mouse (top) Control wild-type mouse (bottom) Adult liver Bsep -/- mouse (right) Control wild-type mouse (left) THBA in Bsep-/- mice rescues the severe phenotype, detoxifies the hydrophobic bile acid pool, and reduces cholestasis PNAS. 2001;98:

4 Detoxification Clearance into bile Clearance into blood THBA is a novel bile acid class and has best-in-class profile as a bile acid therapy in the Liver and gastrointestinal space Stimulation of bile flow with high safety margin Renal elimination Efficient enterohepatic recirculation Stable active metabolite Competitive advantage THBA addresses the root cause (accumulation of toxic bile acids in the hepatocytes) Detoxifies bile acid pool Stimulates bile flow and promotes liver detoxification Reduction in cholangitis, inflammation, fibrosis and risk of liver failure and hepatocellular carcinoma Current competitors focus to decrease exposure to bile acid in the liver FXR agonists (decrease bile acid production) ASBT inhibitors (decrease recycling of bile acids from the intestine)

5 Mechanism of Action Stimulation of bile flow is an essential function of bile acids, including synthetic bile acids like UDCA, which promotes biliary clearance THBA were tested for their ability to promote bile flow compared to ursodeoxycholic acid (UDCA) through bile duct cannulation experiments THBA were shown to stimulate bile flow in a dose-dependent manner and are as efficient or better than UDCA at stimulating bile flow

6 Safety and Toxicology The toxicity of bile acids is related to their hydrophobicity (more hydrophobic bile acids are more toxic) Hydrophobicity is influence by the number of -OH groups and human bile acids are generally more hydrophobic and toxic than synthetic bile acids or bile acids identified in other animals In Hepatotoxicity assay, THBA was demonstrated to be at least 5X less toxic than Ursodeoxycholic acid (UDCA), Chenodeoxycholic acid (CDCA) and Cholic acid (OCA)

7 Pharmacokinetics THBA demonstrates to possess a very efficient enterohepatic circulation property. Preliminary results demonstrated that THBA, after oral dosing, is efficiently absorbed from the intestine and delivered into the liver where it is rapidly converted into its active conjugates and excreted into the bile, thereby detoxifying the endogenous hydrophobic bile acids. The parent THBA and its conjugate is then efficiently reabsorbed into the liver again. This efficient enterohepatic circulation of THBA plus its ability to stimulate bile flow is the key to its ability to prevent the build up of toxic bile acids, the reduces the risk of cirrhosis and fibrosis.

8 Isomers and Analogues Qing Bile Therapeutics Inc. uses the unique proprietary Tetrahydroxylated Bile Acid (THBA) Platform to screen various THBA for different therapeutic indications Qing Bile is developing customized analogues of the THBA molecule to strengthen our IP position