Emerging Therapies for Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Introduction

The two most frequent causes of cholestatic liver diseases in adults are primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Ursodeoxycholic acid (UDCA) treatment is safe and has been shown to improve survival, histology, and metabolic parameters in PBC patients. Alternative therapy is still required for patients who do not react to UDCA and those who have advanced histologic illness at presentation. In the same way, effective treatment is still to be found for pruritis (itching of the skin) and tiredness, which is not improved with UDCA. Unlike PBC, no confirmed medicinal therapy is beneficial for PSC patients. It is critical to appropriately address chronic cholestasis problems in PBC and PSC.

What Is Primary Sclerosing Cholangitis?

A chronic condition where the bile ducts get inflamed and injured is called primary biliary cholangitis. It gets destroyed eventually. As a result, the bile accumulated, leading to liver damage. The exact cause behind the condition is still not clear. However, experts believe that genes and environmental factors may have a role. An itchy skin and fatigue are the common symptoms seen in the condition. Blood tests, imaging studies, and liver biopsies help in diagnosis. The treatment of the condition may depend on the symptoms and complications seen in the patient. It may be medication, dietary changes, supplements, changes in lifestyle, and any procedures if required.

What Is Primary Biliary Cholangitis?

Primary biliary cholangitis is a chronic condition that affects the bile ducts. It gradually weakens the bile ducts, which makes it more difficult for the bile to pass through. As a result, bile accumulates, causing damage to the tissues. The liver gradually loses its ability to function as healthy tissue is replaced by scar tissue. This is called cirrhosis. The condition was previously called primary biliary cirrhosis. The condition progresses slowly. The end stages might require a liver transplant. However, advancements in diagnosis and medicine help to diagnose the condition, and appropriate medications help to slow down the progression of the disease.

What Is the Difference Between Primary Biliary Cholangitis and Primary Sclerosing Cholangitis?

There are many similarities between the two conditions. The fact that primary biliary cholangitis (PBC) exclusively affects the intrahepatic bile ducts—the bile ducts that are located inside the liver—is one significant distinction. The extrahepatic ducts are among the bile ducts that are affected by primary sclerosing cholangitis (PSC). In addition, different populations are typically affected by the two conditions. Furthermore, PSC has no proven treatment, whereas PBC can be managed with medication.

What Are the Approved Treatments?

• Ursodeoxycholic acid (UDCA): In traditional Chinese medicine, ursodiol has been in use for over three millennia. It was the first medication for primary biliary cholangitis to be approved by the US FDA United States Food and Drug Administration) in 1997. By passive non-ionic diffusion, UDCA is mostly absorbed in the small intestine. After the liver removes it from the portal circulation and conjugates it with taurine and glycine, it is secreted into the bile and circulated through the enterohepatic system. When the bile moves from the liver to the small intestine and returns to the liver, it is called the enterohepatic system. Evidence suggests that UDCA modifies the natural course of PBC. According to EASL (European Association for the Study of the Liver), Ursodiol should be given to patients with PBC at a dose of 13 to 15 mg/kg/day. UDCA treatment extended survival without requiring liver transplantation, regardless of disease stage; it also significantly decreased the risk of liver transplant-related death (LT) in a study involving PBC patients. The frequency of liver transplants and fatalities was decreased with long-term UDCA therapy. Thinning of the hair, weight gain, and flatulence are typical UDCA side effects.

• Obeticholic Acid (OCA): The FDA approved obeticholic acid (OCA) in 2016 as a monotherapy in patients who were intolerant to UDCA or as an adjunctive agent to UDCA for the treatment of PBC. Obeticholic acid is produced from chenodeoxycholic acid and, in comparison to endogenous chenodeoxycholic acid, imparts a hundred times greater agonism for the farnesoid X receptor (FXR). Bile acid synthesis is reduced by FXR activation. It has also been demonstrated that FXR agonists control bile acids by entering the enterohepatic circulation. The synthesis of bile acids is inhibited by fibroblast growth factor-19 (FGF-19), which is secreted more when FXR agonists are activated. Pruritis is the common side effect noted with this drug.

What Are the Emerging Treatments?

• Peroxisome Proliferator-Activated Receptors (PPAR) Agonists: The FDA has approved fibrates for the treatment of hyperlipidemia in patients. Peroxisome proliferator-activated receptors (PPAR) are the target of these medications. PPAR comes in three isoforms: α, δ, and γ. The affinity of fibrates for each isoform varies. The expression of genes related to lipid and bile acid metabolism is stimulated by PPARα. Additionally, the downregulation of genes linked to immune-related pathways is a consequence of its induction. Activation of PPARγ and δ has anti-fibrotic and anti-inflammatory effects. According to the American Association for the Study of Liver Diseases (AASLD) guidelines, fibrates should be regarded as an ‘off-label’ alternative treatment for PBC patients who do not respond well to ursodiol. There are more PPAR agonists under development. Biliary epithelial cells contain PPAR-δ, which plays a role in the trafficking and excretion of cholesterol.

• NOX Inhibitors: Essential enzymes in the progression of liver fibrosis are nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase (NOX) and NOX4. Hepatocytes undergo apoptosis when TGF-beta triggers it through NOX1 and NOX4 signaling. They also assist hepatic stem cells in differentiating into myofibroblasts through mediation. An inhibitor of both NOX1 and NOX4 is setanaxib. It has been demonstrated to help patients who have cardiotoxicity brought on by doxorubicin. It is presently being assessed as a possible treatment option for individuals suffering from primary biliary cholangitis and idiopathic pulmonary fibrosis.

• Non-Bile Acid FXR Agonists: Patients with PBC have undergone evaluations of non-steroidal farnesoid X receptor (FXR) agonists. Among them are EDP-305, cilofexor, and tropifexor. This study found that using tropifexor led to an improvement in gamma-glutamyltransferase (GGT) and ALP levels. Using tropifexor was linked to a 26 to 72 percent decrease in GGT from baseline when compared to placebo. Pruritus was the most common adverse event.

Conclusion

The understanding of the pathophysiology, treatment, and prognostication models in PBC patients has advanced significantly. The approval of obeticholic acid and ursodiol has altered both the drug development procedures and the natural course of PBC. For the drugs that are presently being studied, the majority of the trials have ALP reduction as the primary endpoint.