Primary Biliary Cholangitis (PBC) is a chronic liver disease where small bile ducts within the liver become inflamed and slowly destroyed. These ducts carry bile, a digestive fluid, from the liver to the small intestine. When damaged, bile builds up in the liver, leading to scarring and, over time, cirrhosis. PBC’s progressive nature highlights the need for effective treatments to slow its advance and manage symptoms. Recent advancements offer new hope for individuals living with this condition.
Overview of Recent Treatment Advances
Ursodeoxycholic acid (UDCA) has long been the primary treatment for PBC, but many patients do not respond adequately, requiring additional therapies. For these individuals, obeticholic acid (OCA), marketed as Ocaliva, is a second-line, FDA-approved medication. OCA is prescribed either in combination with UDCA for those with an inadequate response, or as a standalone treatment for individuals who cannot tolerate UDCA.
Beyond OCA, other treatments have emerged for PBC, including seladelpar (Livdelzi) and elafibranor (Iqirvo), both receiving accelerated FDA approval in 2024. Seladelpar is an oral, once-daily medication that reduces pruritus, a common symptom of PBC. Elafibranor, another oral drug, alleviates PBC symptoms and improves liver function markers like alkaline phosphatase (ALP) and bilirubin.
Fibrates, such as bezafibrate and fenofibrate, are another class of medications used in PBC, though often off-label or under investigation in clinical trials. Bezafibrate, in particular, has shown promising results in improving liver enzyme levels and reducing symptoms like itching in patients who do not fully respond to UDCA. These agents may help manage symptoms.
Mechanisms of Action for New Treatments
The effectiveness of these new treatments stems from their distinct ways of interacting with the body’s biological pathways. Obeticholic acid (OCA) primarily functions as an agonist of the farnesoid X receptor (FXR). FXR is a nuclear receptor found in liver and intestinal cells that regulates bile acid production and flow. By activating FXR, OCA reduces new bile acid synthesis and promotes excretion of existing bile acids from the liver into bile ducts. This dual action decreases harmful bile acid accumulation, lessening liver inflammation and fibrosis.
Fibrates, including bezafibrate and fenofibrate, exert their effects by activating peroxisome proliferator-activated receptors (PPARs). For instance, bezafibrate is considered a pan-PPAR agonist, activating PPAR-alpha, PPAR-delta, and PPAR-gamma. Activation of PPARs influences genes involved in lipid metabolism, inflammation, and bile acid synthesis.
Specifically, PPAR activation by fibrates upregulates genes that facilitate biliary phospholipid secretion, making bile less toxic. They also downregulate bile acid synthesis and reduce inflammatory pathways, such as the nuclear factor kappa B (NF-kB) pathway, contributing to liver inflammation in PBC. These actions contribute to the anti-cholestatic and anti-inflammatory effects of fibrates in PBC.
Seladelpar and elafibranor also target specific pathways. Seladelpar is a selective peroxisome proliferator-activated receptor delta (PPAR-delta) agonist. Elafibranor is a dual agonist of PPAR-alpha and PPAR-delta. By activating these receptors, both drugs regulate bile acid metabolism, reduce inflammation, and improve liver function.
Navigating Treatment Options
New treatments for PBC are considered when patients do not respond adequately to ursodeoxycholic acid (UDCA), the standard first-line therapy. An inadequate response is assessed after about one year of UDCA treatment, indicated by persistently elevated alkaline phosphatase (ALP) and/or bilirubin. Healthcare providers may then discuss adding a second-line medication.
Obeticholic acid (OCA) can cause side effects, with pruritus (itching) being the most common, often appearing early in treatment. This itching can range from mild to severe and is dose-dependent. Other common side effects include fatigue, abdominal pain, rash, and joint pain. Pruritus management can involve dose reduction, temporary interruption, or the use of bile acid sequestrants or antihistamines.
Fibrates are generally well-tolerated but can have side effects such as gastrointestinal upset, muscle pain (myalgia), and transient elevations in liver enzymes or serum creatinine. Close monitoring through regular blood tests is important, especially when treatment is initiated. Any significant changes should be discussed with a healthcare provider.
Shared decision-making with a healthcare provider is important when navigating these treatment options. The goal of these treatments is to slow disease progression, improve symptoms like itching, and normalize liver enzyme markers. Regular monitoring through liver function tests every 3-6 months is important to assess treatment effectiveness and manage side effects.