Recently, Gilead announced that the European Commission (EC) has conditionally approved Seladelpar for marketing in combination with ursodeoxycholic acid (UDCA) to treat patients with primary biliary cholangitis (PBC) who have an insufficient response to UDCA alone; or as a single drug to treat PBC patients who are intolerant to UDCA treatment.

Seladelpar is the first and only therapy to achieve significant improvements in biochemical responses, alkaline phosphatase normalization, and pruritus relief compared to placebo. This approval means that patients with rare liver diseases in the European Economic Area (EEA) will have an important new treatment option.

From the MASH dilemma to the PBC breakthrough,

Seladelpar's research and development journey has been full of twists and turns. Originally developed by CymaBay, in 2006, Johnson & Johnson and CymaBay Therapeutics reached a comprehensive development and commercialization agreement on metabolic disease drugs, and Johnson & Johnson obtained the licensing rights for three drugs including Seladelpar. In February 2024, Gilead spent $4.3 billion to acquire CymaBay Therapeutics and acquired its core pipeline drug Seladelpar. On August 9, 2024, just one week before Seladelpar's U.S. FDA PDUFA date (August 14), Gilead quickly acted and purchased Seladelpar's global royalties from Johnson & Johnson for US$320 million.

Behind this series of actions, Gilead not only demonstrates its strategic planning in the treatment of primary biliary cholangitis, but also highlights its high hopes for Seladelpar, striving to reshape the competitive landscape in the PBC field.

The drug has been approved for marketing in many places around the world. In the United States, Seladelpar (trade name Livdelzi) received accelerated approval from the FDA in August 2024; in the United Kingdom, it was approved for marketing in January 2025; and in the European Union, it was approved for marketing in February 2025 for the treatment of PBC. Seladelpar has received Breakthrough Therapy Designation and Orphan Drug Designation for PBC patients from the FDA, as well as PRIME designation from the European Medicines Agency.

From the perspective of pharmacological mechanism, Seladelpar is an oral, potent and selective peroxisome proliferator-activated receptor δ (PPARδ) agonist. As a nuclear receptor, PPARδ plays a key role in regulating bile acid metabolism, inflammation and fibrosis. Seladelpar can effectively improve cholestasis, reduce liver inflammation and fibrosis by activating PPARδ, thereby improving the symptoms and prognosis of PBC patients.

The EU approval is based on the results of the pivotal RESPONSE study. RESPONSE is a double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate the efficacy and safety of seladelpar in adult PBC patients who have an inadequate response or intolerance to first-line UDCA treatment. The trial enrolled 193 participants worldwide. In the trial, subjects took 10 mg of Seladelpar or placebo orally daily, and alkaline phosphatase (ALP) and treatment endpoints related to liver function and patient quality of life were evaluated.

The results showed that after 12 months of continuous observation, up to 62% of the subjects treated with Seladelpar successfully achieved the key primary endpoint of comprehensive biochemical response, while only 20% of the placebo group achieved this. In terms of normalization of ALP values, 25% of subjects in the seladelpar group achieved normalization at month 12, while no such change was achieved in the placebo group. Considering the key secondary endpoint of change in itch scores from baseline at Month 6, patients treated with Seladelpar demonstrated a statistically significant reduction in itch compared to placebo.

However, Seladelpar has not had an easy journey. When it was previously developed for the treatment of metabolic dysfunction-associated fatty liver disease (MASH), a Phase 2 study showed that its benefits were less than placebo and there were potential safety issues. CymaBay then terminated the research and development of the drug in the MASH field. As Gilead explored its mechanism of action in depth, it saw its potential in treating PBC, and ultimately helped Seladelpar get approved in the treatment of PBC, bringing hope to many patients.

A multi-billion dollar market is waiting to be opened, and existing drug options are limited.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that patients must fight throughout their lives, and the root cause of the disease has not yet been fully deciphered by the scientific community. The main characteristics of PBC are obstructed bile flow and accumulation of toxic bile acids in the liver, which triggers inflammation and causes gradual damage to the intrahepatic bile duct, which is reflected in the biochemical indicators of increased levels of ALP, alanine aminotransferase (ALT), γ-glutamyl transferase (GGT) and total bilirubin. Currently, PBC still cannot be cured, and the treatment goals focus on delaying disease progression and alleviating cholestasis-related symptoms, such as biliary pruritus.

According to statistics, approximately 163,000 people in Europe suffer from PBC. Despite the rising incidence, available treatment options are extremely limited. Ursodeoxycholic acid (UDCA) is the first-line treatment for PBC and was approved for marketing by the US FDA in 1998. Although UDCA can slow down liver damage and prevent disease progression to a certain extent, about 40% of patients do not respond to it and the risk of disease progression still exists. Even with existing treatment options, many patients still have abnormal liver function test results and their itching symptoms are difficult to improve.

Obeticholic acid (OCA) was approved by the US FDA in 2016 as a second-line treatment for PBC, used in combination with UDCA to treat patients who have a poor response to UDCA, or as a single agent for patients who are intolerant to UDCA. However, as the research deepened, the limitations of OCA gradually became apparent. In terms of adverse reactions, itching is the most prominent problem. Many studies have shown that its incidence rate is close to 60% and it has obvious dose dependence. According to feedback on treatment effects, about 50% of patients failed to achieve the expected therapeutic effect after OCA treatment.

Currently, the treatment pathway for PBC is usually to evaluate one year after the initiation of standardized UDCA treatment, and patients who do not respond well to UDCA are treated with second-line drugs. Therefore, a good response to UDCA is a key goal of clinical treatment. Even so, although some patients respond well, if ALP does not completely return to normal, the risk of adverse events is still high, especially in young patients with liver fibrosis. In view of this, ALP normalization has become the intensive direction of PBC treatment.

In this context, the emergence of Seladelpar has undoubtedly opened a new door of treatment for PBC patients.

According to relevant industry statistics, the global PBC treatment market size was US$526 million in 2017, and is expected to grow at a compound growth rate of 36.3% in the next 10 years, and is expected to reach US$8.593 billion by 2026. It can be seen that there are a large number of unmet clinical needs in the field of PBC treatment.

Globally, there are more than 20 new drugs for primary biliary cholangitis (PBC) entering the clinical stage, most of which are in Phase 2 clinical trials. At this stage, new drug types mainly include PPAR agonists, FXR agonists, IBAT inhibitors, etc., especially FXR agonists and PPAR agonists are the most widely deployed. Elafibranor, developed by Genfit, is a PPARα/δ agonist. Its new drug application for the treatment of PBC has been accepted by the US FDA. Linerixibat, developed by GSK, is an oral ileal bile acid transporter selective inhibitor designed to treat PBC-related cholestatic pruritus. Phase 2 study results showed that it effectively reduced cholestatic pruritus without causing serious adverse events.

Many domestic companies have also invested in the development of PBC indications, and the research and development progress has reached clinical phase 2. ASC42, independently developed by Ascletis, is a novel, highly effective and selective non-steroidal FXR agonist. According to its Phase 1 clinical trial data, in healthy subjects, ASC42 has good overall safety and good human tolerance, whether it is a single dose of up to 100 mg or multiple daily doses of up to 15 mg within 14 days. Obeticholic acid magnesium tablets (ZG5266) independently developed by Zejing Pharmaceutical are also FXR agonists and are currently in Phase 1/2 clinical trials for the treatment of primary cholestatic cirrhosis.

Gilead's blueprint in the field of liver disease

In recent years, Gilead has been making continuous moves in the field of liver disease, from acquiring CymaBay to obtain the breakthrough drug Seladelpar, to entering the MASH treatment market, trying to seize the commanding heights in the liver disease treatment landscape.

The $4.3 billion acquisition in 2024 allowed Gilead to take over CymaBay's core product Seladelpar, focusing on the treatment of primary biliary cholangitis. Seladelpar is now available in many places, filling the gap in PBC treatment and laying a solid foundation for Gilead's layout in the field of liver disease. Through this acquisition, Gilead not only controls the global rights to Seladelpar, but also further consolidates its position in the treatment of rare diseases.

In addition to PBC, Gilead's layout in the MASH field is also eye-catching. Through a series of acquisitions and collaborations, a complete MASH product line has been built, covering TGFβ antibodies, ASK-1 inhibitors, ACC inhibitors and FXR agonists. Even though some clinical trials of MASH drugs have been frustrated, Gilead has not given up easily. For example, its ACC inhibitor Firsocostat significantly reduced liver fat content in clinical trials, with liver fat content falling by more than 30% in some patients. In addition, Gilead has teamed up with artificial intelligence company Insitro to use machine learning technology to accelerate the development of MASH drugs.

Gilead has been deeply involved in viral hepatitis for many years. Taking hepatitis C as an example, the Epclusa (Sofosbuvir + Velpatasvir) developed by it has almost rewritten the history of hepatitis C treatment. It has a high cure rate for multiple hepatitis C genotypes, a relatively short treatment course, and fewer side effects. In the field of hepatitis B treatment, Vemlidy (tenofovir alafenamide fumarate) performs excellently, achieving highly effective viral suppression at low doses and having better safety for the kidneys and bones. In 2023, Gilead reached a cooperation agreement with Assembly Biosciences to introduce three antiviral drugs to advance the research and development of new antiviral therapies for herpes virus, hepatitis B virus, hepatitis D virus, etc., and continue to empower long-term layout.

Gilead's financial report shows that total revenue in 2024 reached US$28.754 billion; of which liver disease business revenue was US$3.021 billion, a year-on-year increase of 9%; liver disease business revenue accounted for 10.5% of total revenue. The two drugs, sofosbuvir + velpatasvir for hepatitis C and tenofovir alafenamide for hepatitis B, will generate annual revenue of more than $2.5 billion in 2024. Seladelpar has also contributed $30 million in revenue to Gilead since its launch in 2024.

Seladelpar has received accelerated approval from the FDA for the treatment of PBC. As one of the conditions for accelerated approval by the FDA, Gilead has committed to conducting a confirmatory long-term outcomes study called AFFIRM, which has now been initiated in patients with compensated cirrhosis. The study will monitor the treatment effects and safety of patients over a long period of time, further verify the clinical value of Seladelpar, lay a solid foundation for its long-term and widespread application, and is expected to continue to benefit more liver disease patients.

https://news.yaozh.com/archive/45076.html