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

Abstract

Nuclear receptors are central regulators of metabolism¹, 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)²; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics^3-5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis⁶, liver fibrosis⁷, primary biliary cholangitis and primary sclerosing cholangitis^8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists^10,11, 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 FGF19^12-14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C4¹⁵, 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.