BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.
RCT Entities:
BACKGROUND:Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.
Authors: David J R Fulton; Xueyi Li; Zsuzsanna Bordan; Yusi Wang; Keyvan Mahboubi; R Daniel Rudic; Stephen Haigh; Feng Chen; Scott A Barman Journal: Antioxid Redox Signal Date: 2019-03-29 Impact factor: 8.401
Authors: Scott A Barman; Feng Chen; Xueyi Li; Stephen Haigh; David W Stepp; Dmitry Kondrikov; Keyvan Mahboubi; Zsuzsanna Bordan; Peter Traber; Yunchao Su; David J R Fulton Journal: Am J Respir Crit Care Med Date: 2018-06-01 Impact factor: 21.405
Authors: Scott A Barman; Xueyi Li; Stephen Haigh; Dmitry Kondrikov; Keyvan Mahboubi; Zsuzsanna Bordan; David W Stepp; Jiliang Zhou; Yusi Wang; Daniel S Weintraub; Peter Traber; William Snider; Danny Jonigk; Jennifer Sullivan; G Ryan Crislip; Joshua T Butcher; Jennifer Thompson; Yunchao Su; Feng Chen; David J R Fulton Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-02-06 Impact factor: 5.464
Authors: Hani Shamseddeen; Eduardo Vilar-Gomez; Naga Chalasani; Robert P Myers; G Mani Subramanian; Harold H Shlevin; Adam E Allgood; Eric S Orman Journal: Drug Saf Date: 2020-03 Impact factor: 5.606