A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Abstract

Nuclear receptors are central regulators of metabolism, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR); it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis, liver fibrosis, primary biliary cholangitis and primary sclerosing cholangitis. Transcriptomic analyses reveal that, unlike long-acting FXR agonists, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF19, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C4, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases.

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Published: 10 June 2026

DOI:10.1038/s41586-026-10633-1

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