Epigenetic hero

Epigenetic Modulation

The potential of epigenetic therapy to treat disease

Epigenetic modulators are compounds in the body that operate within the nucleus of the cell to regulate or influence the expression of multiple genes, but without changing the DNA sequence of the genome. DNA hypermethylation, the addition of extra methyl groups to DNA, is an example of epigenetic dysregulation. When the epigenome becomes “dysregulated,” cellular functioning is compromised or altered, leading to disease. Many diseases, including acute organ injury and cancer, may benefit from therapeutics that modulate the dysregulated epigenome, such as dysregulated DNA methylation.1-4

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Larsucosterol

Our lead candidate, larsucosterol (DUR-928), is an endogenous epigenetic modulator with the potential to change the course of acute organ injury and chronic liver disease. Larsucosterol modulates the expression of many different genes that are important in maintaining cellular function.5

Larsucosterol has not been approved for any indication.

How it works

One form of epigenetic modification is DNA methylation (addition of methyl groups to DNA), which is regulated by enzymes called DNA methyltransferases (DNMTs).6 The addition of extra methyl groups to DNA may alter gene expression. This type of epigenetic alteration is associated with many types of acute organ injuries (eg, alcohol-associated hepatitis, or “AH”) and chronic liver diseases (eg, metabolic dysfunction-associated steatohepatitis, or “MASH”, previously known as NASH.).1-4 Larsucosterol binds to and inhibits the activity of DNMTs, decreasing DNA hypermethylation, thereby modulating the expression of genes involved in important cell signaling pathways to potentially reduce cell death, lipotoxicity, inflammation and oxidative stress, and potentially improve hepatic regeneration in AH.5

Illustration of how Larsucosterol works
1. Epigenetic Dysregulation in AH Patients
Changes in DNA methylation state have been associated with severe AH1

2. Epigenetic Modulation of Gene Expression
DNMTs are one such modulator that add methyl groups to certain regions of DNA

3. Larsucosterol Inhibits DNMTs
By binding to and inhibiting DNMTs (1, 3a, & 3b), larsucosterol reduces DNA hypermethylation, thereby modulating important cell signaling pathways

Illustration of how Larsucosterol works

Image Source: Wang Y et al, Journal of Lipid Research. 2021; 62: 100063

Doctor talking to elderly patient

Broad therapeutic potential

Given larsucosterol’s unique mechanism of action as an epigenetic modulator and clinical results to date, there is strong scientific rationale for investigating the therapeutic potential of larsucosterol in the treatment of multiple acute organ injuries and chronic liver diseases.

  • Larsucosterol demonstrated a promising effect on mortality and safety in Phase 2a and Phase 2b (AHFIRM) clinical trials in AH7,8. It also led to positive data in a Phase 1b trial in MASH.9
  •  Promising preclinical data in other animal models suggests its potential to treat other acute organ injuries and chronic liver diseases.
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Publications

Read about larsucosterol and its promising potential in the treatment of disease.

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References

  1. Argemi J, Latasa MU, Atkinson SR, et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun. 2019;10(1):3126. doi:10.1038/s41467-019-11004-3
  2. Mazzone R, Zwergel C, Artico M, et al. The emerging role of epigenetics in human autoimmune disorders. Clin Epigenetics. 2019;11(1):34. doi:10.1186/s13148-019-0632-2
  3. Herman A, Occean JR, Sen P. Epigenetic dysregulation in cardiovascular aging and disease. J Cardiovasc Aging. 2021;1:10. doi:10.20517/jca.2021.16
  4. Zhao F. Dysregulated Epigenetic Modifications in the Pathogenesis of NAFLD-HCC. Adv Exp Med Biol. 2018;1061:79-93. doi: 10.1007/978-981-10-8684-7_7. PMID: 29956208.
  5. Wang Y, Lin W, Brown JE, et al. 25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes. J Lipid Res. 2021;62:100063.
  6. Gibney E, Nolan C. Epigenetics and gene expression. Heredity.2010; 105: 4–13. https://doi.org/10.1038/hdy.2010.54
  7. Hassanein T, McClain CJ, Vatsalya V, et al. Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis. Am J Gastroenterol. 2023;10.14309/ajg.0000000000002275.
  8. Company announcement: DURECT Corporation Announces Topline Results from Phase 2b AHFIRM Trial of Larsucosterol in Alcohol-Associated Hepatitis with Promising Effect on Mortality
  9. Lawitz E, Hassanein T, Denham D, et al. Efficacy signals of 4-week oral DUR-928 in NASH subjects. Presented at: 2021 International Liver Conference; June 23-26, 2021; virtual. Poster no. 1198.
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