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Larsucosterol (DUR-928) is DURECT’s lead product candidate, an endogenous sulfated oxysterol and an epigenetic regulator. Epigenetic regulators are compounds that regulate patterns of gene expression without modifying the DNA sequence. For instance, the addition of methyl groups to certain regions of DNA, facilitated by the epigenetic regulating enzymes DNA methyltransferases (DNMTs), will generally result in downregulation of gene expression, while demethylation results in upregulation. DNA methylation/demethylation can regulate the expression of relevant genes that further modulate crucial cellular activities. Epigenetic dysregulation, which may be caused by DNA hypermethylation, has been found to be associated with many acute or chronic diseases, such as alcohol-associated hepatitis (AH) or nonalcoholic steatohepatitis (NASH), respectively.
Unique mechanism of action (MOA): Larsucosterol binds to and inhibits the activity of DNMTs, DNMT-1, 3a and 3b, inhibiting DNA methylation, and thereby regulating the expression of genes that modulate crucial cellular activities, including those associated with cell death, stress response, and lipid biosynthesis.1 These modulations may lead to improved cell survival, and reduced lipid accumulation and inflammation, as has been observed in various in vivo animal models and in results from DURECT’s completed clinical trials in AH and NASH.
Demonstrated safety profile: Nearly 300 subjects have been dosed with larsucosterol by oral (PO), intramuscular (IM), or intravascular (IV) administration in a series of completed Phase 1 and Phase 2 clinical trials. Larsucosterol was well tolerated at all doses in these trials. There was minimal food effect in the oral administration studies and no accumulation with repeat dosing in multiple pharmacokinetics (PK) studies.
Promising clinical profile: Larsucosterol has demonstrated positive efficacy and safety in a Phase 2a clinical trial in alcohol-associated hepatitis (AH), via intravenous administration, and a Phase 2b trial in AH patients (AHFIRM) is currently underway.
Encouraging topline data were also observed in a Phase 1b trial in nonalcoholic steatohepatitis (NASH), via oral administration.
Given its proposed mechanism of action as an epigenetic regulator, demonstrated safety profile, and promising efficacy signals, there is strong rationale for investigating larsucosterol for the treatment of multiple acute organ injury and chronic liver diseases.
Larsucosterol is an investigational product and has not been approved by the FDA for marketing in the U.S. for any indication.
1. Wang, Yaping, Xiaobo Li, and Shunlin Ren. 2021. "Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage" Metabolites 11, no. 1: 9. https://doi.org/10.3390/metabo11010009