Alison MacKinnon, PhD, Preclinical Research Consultant, Galecto Biotech AB
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major health problems without approved therapies. The prevalence of NASH fibrosis leading to cirrhosis is growing and it is at present, the second leading cause for liver transplantation. Galectin-3, a beta-galactoside-binding lectin, is a key regulator of fibrosis and inflammation in multiple organs, including the liver. Mice deficient in galectin-3 are protected from CCl4-induced fibrosis and exhibit reduced scarring in response to injury. Galectin-3 regulates myofibroblast differentiation (the major source of collagens during tissue fibrosis) and also has profound effects on profibrotic macrophage polarization. An inhaled galectin-3 inhibitor - TD139 - is currently undergoing phase IIa clinical development for idiopathic pulmonary fibrosis. However, the identification of systemically active galectin-3 inhibitors will be required for the development of effective therapies for NASH. GB1107 significantly reduced fibrotic collagen deposition in the hepatic parenchyma as assessed by PSR staining at 10, but not 2 mg/kg. This was accompanied by a reduction in LgalS3, alpha-SMA, Col1A2, and Col1A3 transcripts. At 2h, post-dose plasma levels of GB1107 were 1670 ± 310 nM in the 10 mg/kg group, and 213 ± 24 nM in the 2 mg/kg group. GB1211 also reduced fibrosis when administered twice daily during the last 3 weeks of a 6-week CCl4 regimen. Both GB1107 and GB1211 inhibited TGF-beta induced transcription of Col1A2, alpha-SMA, LgalS3 and TIMP1 in human liver fibroblasts in vitro.
These inhibitors show promise as potential new oral anti-fibrotic agents for the treatment of NASH. GB1211 is undergoing clinical development for NASH. Results from a first-time, in-human study indicate that GB1211 is both safe and well-tolerated in man with PK that supports twice daily dosing. A phase IIb study is planned in NASH patients.