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Randomised clinical study: GR ‐ MD ‐02, a galectin‐3 inhibitor, vs. placebo in patients having non‐alcoholic steatohepatitis with advanced fibrosis
Author(s) -
Harrison S. A.,
Marri S. R.,
Chalasani N.,
Kohli R.,
Aronstein W.,
Thompson G. A.,
Irish W.,
Miles M. V.,
Xanthakos S. A.,
Lawitz E.,
Noureddin M.,
Schiano T. D.,
Siddiqui M.,
Sanyal A.,
NeuschwanderTetri B. A.,
Traber P. G.
Publication year - 2016
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.13816
Subject(s) - medicine , steatohepatitis , tolerability , fibrosis , pharmacodynamics , placebo , cirrhosis , pharmacokinetics , adverse effect , clinical endpoint , gastroenterology , clinical trial , fatty liver , pharmacology , pathology , alternative medicine , disease
Summary 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 .