FDA Grants Accelerated Approval for the First Primary Biliary Cholangitis (PBC) Treatment, ‘Seladelpar’

Following the FDA approval of resmetirom (brand name Resdyfra) in April, a treatment for metabolic-associated steatohepatitis (MASH), interest in the development of metabolic-related drugs has been growing.

In one of the latest developments, Gilead Sciences, a U.S. pharmaceutical company, announced its acquisition of CymaBay Therapeutics, a company specializing in liver disease treatments, during the first quarter of 2024. This acquisition significantly bolstered Gilead's liver disease treatment pipeline, with much anticipation surrounding further research on seladelpar, a drug initially developed by CymaBay.

What is PBC, the disease granted FDA accelerated approval?

Primary Biliary Cholangitis (PBC) is an autoimmune disease characterized by bile duct obstruction, cholestasis, cholangitis, and cirrhosis. It progressively destroys the small bile ducts in the liver, leading to bile accumulation, fibrosis, and eventually cirrhosis. The condition primarily affects middle-aged women, and about 60% of cases are detected due to elevated liver enzyme levels, often without initial symptoms. The global PBC market is expected to grow at a CAGR of 10%.

Currently, there is no cure for PBC, and treatments mainly aim to slow disease progression and manage symptoms. Ursodeoxycholic acid (UDCA) is the first-line treatment, but it has been associated with side effects like pruritus (itching) and fatigue, significantly reducing patients' quality of life (BMC Health Serv Res. 2022; 22: 155). This has highlighted the need for new therapies to address these issues.

FDA Accelerated Approval

Then, in August 2024, seladelpar, the first treatment for PBC, received accelerated approval from the FDA!

What is FDA Accelerated Approval?

Introduced in 1992, the FDA's Accelerated Approval Program aims to fast-track the approval of drugs that treat life-threatening diseases, such as cancer and rare conditions, especially when existing treatments are insufficient. The program’s goal is to make new therapies available to patients more quickly in cases where treatment options are limited. However, drugs approved under this program are granted conditional approval, requiring further confirmation of their clinical benefits through post-marketing trials (BMC Pulm Med. 2022; 22: 53).

Key Differentiators and Features of Seladelpar:

Mechanism of Action: Seladelpar has been developed as a highly selective agonist for PPARδ, acting more specifically on this subtype compared to other PPAR subtypes (α, γ). This selectivity has resulted in an improved side effect profile compared to other PPAR agonists (The Lancet Review Volume 393, Issue 10171, pp. 587-593, February 9, 2019). Treating liver diseases via PPARδ activation represents a novel approach, providing therapeutic effects through a different mechanism than existing treatments.
Improved Side Effects: Compared to the existing PBC treatment, OCA (Obeticholic Acid), Seladelpar shows a lower incidence of pruritus and improves lipid profiles, potentially reducing cardiovascular risk (Circulation Volume 147, Issue 13, March 28, 2023, p. 1050).
Administration: It is taken orally and, due to its long half-life, requires only once-daily dosing.
Efficacy: Through PPARδ activation, Seladelpar exerts direct anti-inflammatory effects and inhibits liver fibrosis. It also improves insulin sensitivity and regulates lipid metabolism, showing potential in treating liver diseases associated with metabolic syndrome. Clinical trials have demonstrated a more rapid reduction in alkaline phosphatase (ALP) levels compared to existing treatments.
Expansion Potential: Although there were attempts to develop Seladelpar as a treatment for non-alcoholic steatohepatitis (NASH), the clinical trial for NASH (Phase 2b) was discontinued in November 2019 due to atypical liver damage/hepatitis. Given its history as a PBC treatment, further expansion of its application seems limited.
Combination Therapy Results: Thus far, the focus has been on combining Seladelpar with UDCA (https://clinicaltrials.gov/study/NCT04620733). However, pharmacokinetic studies indicate that Seladelpar shows no significant interactions with major CYP enzymes, suggesting potential for combination with other drugs (Respir Care. 2021 Apr; 66(4): 635–643).

Future Development Directions for PBC

Thanks to its unique features, Seladelpar has gained recognition as a promising candidate in the treatment of liver diseases. As more clinical experience is gathered, the drug's true value and role in the therapeutic landscape are expected to become clearer. After a series of clinical setbacks in 2019-2020, which marked a difficult period for many metabolic disease candidates, Seladelpar has successfully made a comeback through innovative approaches and relentless persistence. Its development journey highlights the arduous path to achieving "first-in-class" status.

If we use HyperLab to examine the binding with the target protein here, what would we find?

Seladelpar exhibits uniquely high selectivity in its binding to PPARδ. According to X-ray structural analysis, Seladelpar forms a stable interaction in the ligand-binding domain of PPARδ through a hydrogen bond with Threonine 253 and a pi-pi interaction with Histidine 413 (PDB: 8huo). These interactions represent key molecular mechanisms that support Seladelpar’s efficacy, contributing to its high selectivity and therapeutic effects.