Seladelpar is an investigational medication developed for chronic liver conditions. This compound functions by interacting with specific pathways within the body, aiming to modify disease progression and alleviate symptoms. Its development offers a more targeted therapy for liver disorders.
How Seladelpar Works
Seladelpar operates as a selective agonist of peroxisome proliferator-activated receptor delta (PPARδ). PPARδ is a type of protein located inside cells, specifically within the nucleus, where it acts as a receptor. When activated, PPARδ forms a complex with another receptor, the retinoid X receptor (RXR), binding to specific DNA sequences and regulating the transcription of various genes.
This regulation influences metabolic and inflammatory pathways across different tissues, including the liver, muscle, fat, and intestinal tissues. In the liver, PPARδ activation by seladelpar can impact hepatocytes, cholangiocytes, Kupffer cells, and stellate cells, all cell types involved in liver function and disease. Seladelpar reduces bile acid synthesis by decreasing the activity of an enzyme called CYP7A1, which converts cholesterol into bile acids.
The compound also has anti-inflammatory and anti-fibrotic effects, reducing inflammation and the formation of scar tissue in the liver. It achieves this by influencing genes involved in inflammation, lipid metabolism, and fibrotic processes.
Conditions Seladelpar Targets
Seladelpar is primarily being investigated for the treatment of primary biliary cholangitis (PBC), a chronic autoimmune liver disease. PBC is characterized by the gradual destruction of small bile ducts within the liver. These ducts are responsible for transporting bile, a digestive fluid, from the liver to the small intestine.
When damaged, bile accumulates in the liver, leading to inflammation and scarring. This scarring can progress to cirrhosis, a severe condition where healthy liver tissue is replaced by scar tissue, impairing liver function and potentially leading to liver failure. PBC predominantly affects women, with a median age of onset around 50 years. While ursodeoxycholic acid (UDCA) is a standard first-line treatment, many patients do not respond adequately or cannot tolerate it, highlighting the need for additional therapies. Seladelpar is also being explored for its potential in non-alcoholic steatohepatitis (NASH), another liver condition involving fat accumulation and inflammation.
Clinical Trial Findings and Safety
Clinical trials have evaluated seladelpar’s effects on patients with primary biliary cholangitis (PBC). In the ENHANCE Phase 3 study, patients receiving seladelpar demonstrated significant improvements in liver biochemistry and a reduction in pruritus, or itching, a common and often debilitating symptom of PBC. A 10 mg daily dose of seladelpar led to a statistically significant decrease in pruritus scores compared to placebo.
The RESPONSE study, another Phase 3 trial, showed that 62% of patients treated with seladelpar achieved a composite biochemical response at 12 months, compared to 20% in the placebo group. This response is defined by specific improvements in liver enzyme levels, such as alkaline phosphatase (ALP). Normalization of ALP levels, a marker of liver health, occurred in 27.3% of patients on 10 mg seladelpar, whereas no patients on placebo achieved this. Regarding safety, common side effects reported during trials included headache, abdominal pain, abdominal distension, and nausea. While some adverse events were more frequent in the seladelpar group, overall serious treatment-related adverse events were not observed.
Development Status and Availability
Seladelpar has received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of primary biliary cholangitis (PBC). This approval, granted in August 2024, allows its use in adults with an inadequate response to ursodeoxycholic acid (UDCA) or as a standalone treatment for those unable to tolerate UDCA. The FDA’s decision was based on data from the Phase 3 RESPONSE study, which showed seladelpar’s effectiveness in reducing alkaline phosphatase (ALP) levels.
The drug, marketed under the brand name Livdelzi, also received Breakthrough Therapy Designation and Orphan Drug Designation from the FDA. Accelerated approval means that continued approval may depend on further verification of clinical benefit in ongoing or future confirmatory trials. Seladelpar’s application has also been accepted for review by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA), indicating potential availability in other regions.