Abstact

Nuclear receptors are central regulators of metabolism(1), 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 steatohepatitis(6), liver fibrosis(7), 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 C4(15), 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.