Chinese Scientists Propose "First Principle of Drug Design" with Novel Pulsatile FXR Agonist Linafexor
核心洞察
Researchers from the Shanghai Institute of Materia Medica (搜索) have proposed a "first principle of drug design" that mimics the body's natural physiological rhythms, published in Nature on June 10.
Linafexor (CS0159), a novel non-bile-acid FXR agonist, was designed as a "quick-in, quick-out" molecule with a half-life under one hour, achieving pulsatile FXR activation synchronized with bile-acid fluctuations.
In a completed U.S. Phase I trial, Linafexor showed no drug-related adverse events, with FGF19 and C4 biomarkers returning to baseline within 24 hours, recapitulating the pulsatile pattern seen in preclinical models.
A team of researchers led by H. Eric Xu and LI Jia from the Shanghai Institute of Materia Medica (搜索) of the Chinese Academy of Sciences has proposed what they call the "first principle of drug design"—designing drugs whose delivery mimics the body's physiology—and introduced a novel FXR agonist, Linafexor (CS0159), that embodies this principle. The study was published in Nature on June 10.
The new approach challenges a long-standing paradigm in drug development. Over the past two decades, nearly all of the 20-plus FXR agonists that have entered clinical trials have been long-acting, reflecting a drug-delivery strategy centered on long half-life and sustained exposure. Yet many of the body's physiological processes are inherently rhythmic and pulsatile, meaning that long-acting drugs may be mismatched with the body's natural rhythms—a condition that may gradually impair receptor responsiveness.
A "Quick-In, Quick-Out" Molecule
Linafexor was designed as a "quick-in, quick-out" molecule that engages its target in pulses—similar to pressing a switch then releasing it. Once in the body, it is rapidly metabolized and cleared, achieving pulsatile FXR activation synchronized with the natural fluctuations of bile acids. The receptor is briefly and strongly activated after each dose, then falls back and is allowed to recover, avoiding what the researchers describe as "chronic fatigue," which they propose underlies the gradual loss of receptor responsiveness.
Linafexor exhibited a half-maximal effective concentration (EC50) of 0.35 nM, indicating very high potency, on par with the long-acting tropifexor and roughly 800 times more potent than obeticholic acid. The researchers solved the crystal structure of the drug bound to FXR and revealed that it fits well into the ligand-binding pocket. Compared with the clinically tested tropifexor, the two adopt almost identical binding poses in the pocket, confirming Linafexor's efficient binding at the molecular level.
Unlike long-acting FXR agonists with half-lives of 14–24 hours, Linafexor was designed for rapid clearance. In preclinical species, its half-life is under one hour. Distribution studies showed that after dosing, Linafexor concentrated where it was needed most: the liver, small intestine, and stomach. It was cleared from all tissues within 24 hours, achieving intended pulsatile exposure synchronized with bile-acid rhythms.
Preclinical Efficacy Across Multiple Liver Disease Models
In MASH, liver fibrosis, PBC, and PSC animal models, Linafexor significantly improved markers of liver injury, inflammation, and fibrosis. Notably, when the researchers switched the identical Linafexor molecule from pulsatile to continuous dosing, the animals developed severe systemic toxicity; once-daily pulsatile dosing, by contrast, was safe and effective.
This finding suggests that the duration of receptor activation, rather than molecular structure alone, may be a key determinant of a drug's safety and efficacy. Associated with this finding, the researchers proposed the concept of "bile-acid resistance," analogous to insulin resistance, wherein chronic, excessive signaling desensitizes the receptor and disrupts the signaling pathway.
Phase I Clinical Data Confirms Pulsatile Pattern in Humans
In the Phase I trial completed in the United States, the human data closely matched the researchers' design expectations. After oral dosing, Linafexor was rapidly absorbed and cleared, with a half-life again under one hour. The drug precisely "lit up" its target: FGF19, a marker of FXR activation, rose markedly, while C4, a marker of bile-acid synthesis, fell significantly. Both biomarkers returned to baseline within 24 hours, recapitulating in humans the pulsatile activation pattern seen in animal models.
Safety has long been the Achilles' heel of FXR-class drugs. Yet across all single- and multiple-ascending-dose groups in this Phase I study, the Linafexor groups showed no drug-related adverse events, in contrast with some FXR agonists.
Advancing Toward the Clinic
Linafexor has already completed Phase II clinical trials and has now entered Phase III trials, with preliminary data showing efficacy and safety in both PBC and MASH. The diseases targeted—metabolic dysfunction-associated steatohepatitis (MASH) (搜索), primary biliary cholangitis (PBC) (搜索), and primary sclerosing cholangitis (PSC) (搜索)—are progressive chronic liver diseases linked to abnormal bile-acid metabolism. Although these diseases differ in origin, they all lead to a similar outcome: abnormal hepatic accumulation of bile acids and liver injury.
The farnesoid X receptor (FXR) (搜索) is a protein inside cells that acts as a transcription factor, functioning primarily as the body's sensor for bile acids. Delivering an FXR agonist is one of the strategies for treating these diseases by reducing the build-up of bile acids.
A Broader Principle for Drug Discovery
This study proposes a new principle for drug discovery: the design of drugs should take into account natural signaling rhythms to reduce the risk of toxicity caused by sustained drug delivery. This principle may be particularly applicable to physiological processes such as hormone signaling, immune regulation, and circadian metabolism, all of which depend on rhythmic rather than sustained signaling.