Seladelar is currently the first and only therapy that has achieved significant improvements in biochemical reactions, normalization of alkaline phosphatase, and relief of itching compared to placebo. This approval means that rare liver disease patients in the European Economic Area (EEA) will have an important new treatment option.

From MASH dilemma to PBC breakthrough

The development process of Seladelar is full of twists and turns. Originally developed by CymaBay, in 2006, Johnson&Johnson reached a comprehensive development and commercialization agreement with CymaBay Therapeutics for metabolic disease drugs. Johnson&Johnson obtained authorization for three drugs, including Seladelar. In February 2024, Geely Dehao invested $4.3 billion to acquire CymaBay Therapeutics, acquiring the core pipeline drug Seladelar. On August 9, 2024, just one week before the FDA PDUFA date of Seladelar in the United States (August 14), Gilead quickly made a move and purchased Seladelar's global royalties from Johnson&Johnson for $320 million.

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

At present, the drug has been approved for marketing in multiple parts of the world. In the United States, Seladelar (trade name Livdelzi) received FDA accelerated approval for marketing in August 2024; Approved for listing in the UK in January 2025; Approved for marketing in the European Union in February 2025 for the treatment of PBC. Seladelar has received breakthrough therapy recognition from the FDA, orphan drug status for PBC patients, and PRIME status from the European Medicines Agency.

From a pharmacological perspective, Seladelar is an orally administered potent selective peroxisome proliferator activated receptor delta (PPAR delta) agonist. PPAR δ, as a nuclear receptor, plays a crucial role in regulating bile acid metabolism, inflammation, and fibrosis processes. Seladelar can effectively improve bile stasis, alleviate liver inflammation and fibrosis by activating PPAR δ, thereby improving the symptoms and prognosis of PBC patients.

The EU's approval this time is based on the results of a critical Response study. Response is a double-blind, placebo-controlled phase 3 clinical trial aimed at evaluating the efficacy and safety of Seladelpar in adult PBC patients with inadequate or intolerant response to UDCA first-line treatment. The experiment recruited 193 participants worldwide. In the experiment, participants were orally administered 10 milligrams of Seladelpar or placebo daily to evaluate alkaline phosphatase (ALP) levels and treatment endpoints related to liver function and patient quality of life.

The results showed that after 12 months of continuous observation, up to 62% of the subjects receiving Seladelar treatment successfully achieved the key primary endpoint of comprehensive biochemical response, while only 20% of the placebo group. In terms of normalizing ALP values, 25% of participants in the Seladelpar treatment group achieved this by the 12th month, while there was no such change in the placebo group. Considering the change in itch score compared to baseline at 6 months as a key secondary endpoint, patients treated with Seladelpar showed statistically significant reduction in itch compared to placebo.

However, Seladelpar did not go smoothly all the way. Previously developed for the treatment of metabolic dysfunction associated steatohepatitis (MASH), a phase 2 study showed that its benefits were not as good as placebo and there were potential safety issues. CymaBay subsequently terminated the development of this drug in the field of MASH. With a deeper exploration of its mechanism of action, Gilead recognized its therapeutic potential in the field of PBC and ultimately assisted Seladelpar in obtaining approval for PBC treatment, bringing hope to numerous patients.

The billion dollar market is waiting to be opened, and the selection of existing drugs is limited

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that patients need to fight for their entire lives, and its root cause has not been fully elucidated by the scientific community to this day. The main characteristic of PBC is obstruction of bile flow, accumulation of toxic bile acids in the liver, causing inflammation and gradual damage to intrahepatic bile ducts, reflected in biochemical indicators such as elevated levels of ALP, alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), and total bilirubin. At present, PBC still cannot be cured, and treatment goals focus on delaying disease progression and reducing symptoms related to bile stasis, such as biliary itching.

According to statistics, about 163000 people in Europe suffer from PBC. Although the incidence rate is on the rise, the choice of treatable drugs is extremely limited. Ursodeoxycholic acid (UDCA) is a first-line treatment for PBC and was approved for marketing by the US FDA in 1998. Although UDCA can alleviate 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. Many patients, even with existing treatment plans, still have abnormal liver function test results and difficulty improving itching symptoms.

Obeticolic acid (OCA) was approved by the US FDA in 2016 as a second-line treatment for PBC. It is used in combination with UDCA to treat patients with poor UDCA response or as a monotherapy for UDCA intolerant patients. But as research deepens, the limitations of OCA gradually become apparent. In terms of adverse reactions, itching is the most prominent issue, with multiple studies showing an incidence rate of nearly 60% and a significant dose dependence. According to the feedback on treatment effectiveness, about 50% of patients who received OCA treatment did not achieve the expected therapeutic effect.

At present, the treatment pathway for PBC is usually evaluated one year after initiating standardized UDCA treatment, and second-line drug therapy is used for patients with poor UDCA response. Therefore, the key goal of clinical treatment is for patients to have a good response to UDCA. Nevertheless, although some patients respond well, the risk of adverse events remains high if ALP does not fully return to normal, especially in young patients with liver fibrosis. In view of this, normalization of ALP has become a strengthening direction for PBC treatment.

In this context, the emergence of Seladelar undoubtedly opens a new door for the treatment of PBC patients.

According to industry statistics, the global PBC treatment market size was $526 million in 2017, and is expected to climb at a compound annual growth rate of 36.3% over the next 10 years, reaching $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 over 20 new drugs for primary biliary cholangitis (PBC) that have entered the clinical stage, most of which are in Phase 2 clinical trials. At present, the types of new drugs mainly include PPAR agonists, FXR agonists, IBAT inhibitors, etc., with the layout of FXR agonists and PPAR agonists being the most extensive. Elafibror developed by Genfit is a PPAR alpha/delta agonist, and 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 aimed at treating PBC related cholestatic itching. Phase 2 research results have shown that it effectively reduces cholestatic itching without causing serious adverse events.

Many domestic enterprises have also entered the field of PBC indication development, with the research and development process reaching up to Phase 2 clinical trials. ASC42, independently developed by Geli Pharmaceutical, is a novel highly efficient and selective nonsteroidal FXR agonist. According to its Phase 1 clinical trial data, ASC42 has good overall safety and good tolerability in healthy subjects, whether given a single dose of up to 100 milligrams or multiple daily doses of up to 15 milligrams within 14 days. The magnesium obeticolate tablets (ZG5266) independently developed by Zejing Pharmaceutical are also FXR agonists and are currently undergoing phase 1/2 clinical trials for the treatment of primary cholestatic cirrhosis.

Gilead's blueprint for liver disease field

In recent years, Gilead has been making continuous moves in the field of liver disease, from acquiring the breakthrough drug Seladelpar through the acquisition of CymaBay, to laying out the MASH treatment market, attempting to seize the high ground in the liver disease treatment landscape.

The $4.3 billion acquisition in 2024 allowed Gilead to take over Seladelpar, the core product of CymaBay, and focus on the treatment of primary biliary cholangitis. Now Seladelpar is listed in multiple 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 equity of Seladelpar, but also further consolidates its position in the field of rare disease treatment.

In addition to PBC, Gilead's layout in the MASH field is also noteworthy. Through a series of acquisitions and collaborations, a complete MASH product line has been established, covering TGF β antibodies, ASK-1 inhibitors, ACC inhibitors, and FXR agonists. Even though some MASH drug clinical trials have suffered setbacks, Gilead has not given up easily. Firsokostat, an ACC inhibitor under the company, significantly reduced liver fat content in clinical trials, with some patients experiencing a decrease of over 30% in liver fat content. In addition, Gilead has partnered with artificial intelligence company Insitro to accelerate the MASH drug development process through machine learning technology.

Gilead has been deeply involved in viral hepatitis for many years. Taking hepatitis C as an example, its developed Epclusa (Sofosbuvir+Velpatasvir) has almost rewritten the history of hepatitis C treatment, with high cure rates for multiple hepatitis C genotypes, relatively short treatment courses, and minimal side effects. In the field of hepatitis B treatment, Vemlidy (propofol tenofovir fumarate) has excellent performance. Low dose can achieve efficient virus inhibition, and has better safety for kidneys and bones. In 2023, Gilead reached a cooperation agreement with Assembly Biosciences to introduce three antiviral drugs and promote the research and development of new antiviral therapies for herpes virus, hepatitis B virus, hepatitis D virus, etc., to continuously empower long-term layout.

According to Gilead's financial report, the total operating revenue for 2024 reached 28.754 billion US dollars; The revenue from liver disease business was 3.021 billion US dollars, a year-on-year increase of 9%; Liver disease business revenue accounts for 10.5% of total revenue. In 2024, the annual revenue of the two drugs, namely, Sophobuvir+Vipatavir for hepatitis C and Propofol Tenofovir for hepatitis B B, will exceed 2.5 billion dollars. Seladelpar has also contributed 30 million dollars to Gilead's revenue since its launch in 2024.

conclusion

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