The Pharmacokinetics of GS-4997, an Inhibitor of Apoptosis Signal-Regulating Kinase 1 (ASK1), in Subjects with Mild, Moderate, and Severe Hepatic Impairment
AASLD LiverLearning®. Nelson C. Nov 12, 2016; 144011
Topic: Steatosis and Steatohepatitis
Cara Nelson
Cara Nelson
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TITLE: The Pharmacokinetics of GS-4997, an Inhibitor of Apoptosis Signal-Regulating Kinase 1 (ASK1), in Subjects with Mild, Moderate, and Severe Hepatic Impairment

Gilead Sciences, Inc.

GS-4997 is a selective and potent small molecule inhibitor of ASK1 in clinical development for the treatment of nonalcoholic steatohepatitis (NASH) and severe alcoholic hepatitis. This study evaluated the short-term safety and PK of GS-4997 in subjects with mild, moderate, or severe hepatic impairment (HI) and subjects with normal hepatic function to support development of GS-4997 dosing recommendations in patients with cirrhosis.

Subjects with stable mild, moderate, or severe HI (Child-Pugh-Turcotte A, B, or C, respectively [n=10 per group]) and healthy controls with normal hepatic function, matched for age (±10 years), gender, and BMI (±20%) (n=10 per HI group) received a single, 6 mg oral dose of GS-4997 followed by intensive PK sampling over 120 hours. Safety was monitored and a parametric analysis of variance using a mixed effects model was used to fit logarithmically-transformed PK parameters (AUC and Cmax). The 90% confidence intervals (CIs) were constructed for the geometric mean ratios (GMR) of these parameters between each HI group and matched control subjects. Since HI may alter protein binding, the free fraction of GS-4997 in plasma was also determined and summarized by hepatic function.

All subjects completed the study; all treatment-emergent adverse events (AEs) were mild (Grade 1) or moderate (Grade 2). Only one AE (Grade 1 headache) occurred in more than one subject (n=4). Total plasma exposures (Cmax and AUC) were similar in subjects with mild or moderate HI compared to healthy controls (Table 1). There was a modest increase in AUC in subjects with severe HI versus control subjects. Compared with control subjects, the free fraction of GS-4997 was increased in subjects with severe HI, but not with mild or moderate HI as compared to controls (7.0% unbound vs 5.3% unbound).

The safety results from this study were consistent with the overall safety profile for GS-4997. GS-4997 exposures were similar in subjects with mild or moderate HI as compared to those with normal hepatic function and subjects with severe HI had modestly higher exposures. The results of this study support continued clinical development of GS-4997 in patients with liver dysfunction due to NASH or alcoholic hepatitis without dose adjustment regardless of presence of HI.
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