Author: Sarah Sizer, Ph.D.
Editor: Morgan McCullough
This article will describe Livdelzi, a drug developed by Gilead Sciences and recently granted Accelerated Approval by the Food and Drug Administration (FDA) for treating Primary Biliary Cholangitis (PBC). The approval was based on data from a phase 3 clinical trial demonstrating that Livdelzi normalized key indicators of disease progression, including severe itch and liver enzyme levels.
Overview of Primary Biliary Cholangitis
PBC is a rare autoimmune disease characterized by the gradual destruction of the liver by the immune system that affects between 1.91 and 40.20 per 100,000 people globally depending on the region.1 Like most autoimmune disorders, PBC is more prevalent in women than men (female:male ratio of 4.2:1); however, men experience more severe disease progression and are less responsive to available therapies for PBC.2,3 The onset of PBC is influenced by a combination of genetic and environmental factors, where individuals with a genetic predisposition to the disease encounter chemicals or pathogens (i.e., smoking, recurrent urinary tract infections, pollution, xenobiotics) that trigger an immune response against the small bile ducts that transport bile from the liver to the small intestine for fat absorption and digestion.4–6 Injury to the bile ducts impedes bile flow to the small intestine, causing bile acid accumulation and liver inflammation. Persistent damage to the bile ducts promotes the stiffening of liver tissue and eventually end-stage liver disease, yet early diagnosis and treatment can dramatically attenuate disease progression and reduce the incidence of liver transplants (Figure 1).7–9
While mid to late-stage PBC is associated with jaundice, fatigue, itching, diarrhea, nausea, and weight loss, approximately 60% of people with PBC are asymptomatic at the time of diagnosis and discover they have the disease through routine blood tests.9 Patients must meet two out of the three following criteria for a PBC diagnosis:
- Elevated alkaline phosphatase levels (1.5X the upper limit)
- Presence of antimitochondrial antibodies
- Histological evidence of bile duct destruction
Laboratory tests measure alkaline phosphatase levels and detect the presence of antimitochondrial antibodies in the blood. Because a small subset of patients with PBC do not produce antimitochondrial antibodies (5-10%), there are instances where a liver biopsy is necessary to assess the damage to the bile ducts.10 Liver biopsies may also determine the stage of PBC or rule out similar conditions like autoimmune hepatitis.
Pathogenesis of Primary Biliary Cholangitis
Biliary epithelial cells line the bile ducts and serve as critical modulators of bile synthesis and homeostasis by transporting bile acids, salts, and other solutes into the ducts for further processing. Biliary epithelial cells secrete bicarbonate and create a ‘bicarbonate umbrella’ around their cell membranes to shield themselves from prolonged contact with bile acids. In PBC patients, biliary epithelial cells become more vulnerable to injury due to the downregulation of the anion exchanger 2 (AE2) transporter (Cl–/HCO3–), a membrane protein responsible for shuttling bicarbonate into the bile ducts.11 Dysregulation of the AE2 transporter weakens the ‘bicarbonate umbrella’, ultimately leading to increased biliary epithelial cell alkalinity and irregularly acidic bile, cell stress, and apoptosis.
As the biliary epithelial cells undergo apoptosis, their plasma membranes fragment into portions of the cell membrane and cytoplasm called apoptotic blebs that contain a modified version of a mitochondrial protein called the pyruvate dehydrogenase complex E2 subunit, or PDC-E2.12 Whether modifications to PDC-E2 result from cell stress or molecular mimicry from environmental exposure is unclear; however, these alterations render immune cells unable to recognize PDC-E2 and promote a targeted response against biliary epithelial cells.5 Specifically, macrophages and dendritic cells present fragments of the protein to CD4+ T helper cells to determine whether PDC-E2 is foreign. Once CD4+ T helper cells classify PDC-E2 as an antigen, they release pro-inflammatory cytokines to activate multiple immune cell types, including B cells, T killer cells, hepatic stellate cells, and portal fibroblasts. B cells become plasma cells and produce antimitochondrial antibodies targeting PDC-E2, while activating CD8+ T killer cells and natural killer cells induces apoptosis and premature senescence of biliary epithelial cells. Hyperactivation of these pro-inflammatory and apoptotic pathways create a positive feedback loop driving the release of PDC-E2, recruitment of more immune cells, and further apoptosis and senescence. Portal fibroblasts and hepatic stellate cells respond to sustained inflammation by depositing collagen, which stiffens (fibrosis) the liver tissue and causes irreversible scarring called cirrhosis (Figure 2).
Current and Emerging Therapies for Primary Biliary Cholangitis
Prior to 2024, there were two FDA approved medications for PBC. While these drugs significantly reduce the progression of the disease, they both have limitations that necessitate the development of novel therapeutics for PBC. Last year, the FDA approved two medications from the same drug class for PBC (Iqirvo and Livdelzi) through their accelerated approval process. This section will discuss the two medications that were FDA-approved prior to 2024 (Ursodiol and Ocaliva) and one of the newest FDA-approved drugs for PBC, Livdelzi (Figure 3).13
Ursodiol (ursodeoxycholic acid) remains the first-line therapy for PBC. The pharmaceutical company Allergan initially developed Ursodiol in 1987 to treat gallstones. After clinicians discovered Ursodiol simultaneously reduces alkaline phosphatase levels, it was repurposed to treat PBC and became FDA-approved for this indication in 1997. Ursodiol is a naturally occurring secondary bile acid that incorporates itself into the bile pool and alters its composition, replacing toxic bile acids and reducing inflammation.15,16 Ursodiol protects the bile ducts by upregulating scaffolding proteins to stabilize the biliary epithelial cell barrier and promoting bicarbonate secretion to regenerate the ‘bicarbonate umbrella.’ Through these mechanisms, Ursodiol restores liver homeostasis and dampens the autoimmune response in people with PBC; however, up to 40% of individuals with PBC have an incomplete biochemical response to Ursodiol.17 Although Ursodiol is safe and can be prescribed during pregnancy, it can lead to an array of side effects, including vomiting, diarrhea, constipation, hives, weight gain, and hair loss.18 While Ursodiol improves the quality of life of many people with PBC, the inconsistent therapeutic effectiveness and side effect profile make it unsuccessful in treating everyone.17
Ocaliva (obeticholic acid) was FDA-approved in 2016 as a second-line therapy for PBC in patients who do not experience complete normalization of their alkaline phosphatase levels or who cannot tolerate Ursodiol.19,20 Ocaliva is a synthetic bile acid that activates a nuclear transcription factor called the farnesoid X receptor (FXR). Activation of FXR downregulates the transcription of enzymes critical for bile acid synthesis and increases bile flow to the small intestine. Improved clearance prevents the buildup of bile in the liver and attenuates the autoimmune response. However, Ocaliva is not a first-line therapy for PBC because it can worsen symptoms and present safety concerns. In a double-blind phase 3 clinical trial, Ocaliva caused a higher incidence of itching than placebo.21 Itching is a severe and irritating symptom of PBC that primarily occurs on the feet at nighttime and can significantly diminish the patient’s quality of life. Additionally, the FDA issued a black box warning for Ocaliva in 2018, indicating that it can cause severe liver injury in patients with advanced cirrhosis.22 The safety profile of Ocaliva suggests that it is a viable therapy for an even smaller subset of patients with PBC compared to Ursodiol.
Livdelzi (seladelpar) became the most recent FDA-approved drug for PBC in August 2024 and can be prescribed in combination with Ursodiol or as a monotherapy.13 Livdelzi activates the nuclear transcription factor called the peroxisome proliferator-activated receptor (PPAR-δ) to regulate the transcription of genes involved in bile acid synthesis. Since liver cells like hepatocytes, biliary epithelial cells, hepatic stellate cells, and Kupffer cells widely express PPAR-δ, the complete mechanism of Livdelzi is unclear. Preclinical and clinical studies suggest that Livdelzi activates a signaling pathway that decreases the expression of CYP7A1, an enzyme necessary for bile synthesis in hepatocytes. Downregulation of CYP7A1 decreases bile acid production and enhances bile flow to the small intestine.23–25 However, the FDA approval process for Livdelzi did not come without complications. In a separate phase 2 clinical trial for Livdelzi and the treatment of metabolic dysfunction-associated steatohepatitis (MASH), some patients experienced abnormal liver biopsy results that prompted a hold on the development of Livdelzi across all indications and the early termination of Livdelzi clinical trials.26 An independent committee of hepatologists and pathologists reviewed the MASH clinical trial data and unanimously concluded that there was “no chemical, biochemical, or histological evidence that the observed changes were directly attributed to [Livdelzi].”27 Consequently, the phase 3 clinical trial for PBC resumed and found that Livdelzi normalizes alkaline phosphatase levels and reduces the severity of itching in a greater percentage of participants than placebo.28 While Iqirvo (elafibranor) was FDA-approved in June 2024 and acts through a similar mechanism as Livdelzi, it did not significantly improve itching in phase 3 clinical trials.29 Regardless of their shortcomings, the development of Livdelzi and Iqirvo are exciting advancements in the field of liver diseases. The creation of these drugs provides options for people with PBC to find a treatment plan that is suitable for them that will slow the progression of the disease and increase their quality of life.
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Figure 1: Created in BioRender. Sizer, S. (2025) https://BioRender.com/g8cg9x6
Figure 2: Created in BioRender. Sizer, S. (2025) https://BioRender.com/1bhek0z