Gilead Sciences, Inc. announced the top-line results from three phase 2 studies of GS-4997 (selonsertib), an investigational inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in nonalcoholic steatohepatitis (NASH), pulmonary arterial hypertension (PAH) and diabetic kidney disease (DKD). GS-4997 demonstrated anti-fibrotic activity in an open-label phase 2 clinical trial that included 72 patients with NASH and moderate to severe (F2-F3) liver fibrosis, who received treatment with GS-4997 (18 mg or 6 mg orally once daily) alone or in combination with simtuzumab (SIM), an investigational antibody directed against lysyl oxidase-like-2 (LOXL2), or SIM alone (125 mg administered via weekly subcutaneous injections) for 24 weeks.
Top-line efficacy data for fibrosis-related endpoints from 67 evaluable patients are summarized in the table below. Complete results will be presented at The Liver Meeting 2016 in Boston. Overall, GS-4997 was well tolerated with no dose-related increase in the incidence of treatment-emergent adverse events or serious adverse events. The most common adverse events were headache, nausea and sinusitis.
“We are committed to advancing our pipeline of investigational molecules that separately target metabolic dysfunction, inflammation and/or fibrosis associated with NASH,” said Norbert Bischofberger, PhD, executive vice president, research and development and chief scientific officer, Gilead Sciences. “We are encouraged by these data demonstrating the anti-fibrotic effect of GS-4997 in patients with NASH after only 24 weeks of treatment, and look forward to sharing the complete results with the hepatology community. Additionally, pending discussions with regulatory agencies, we plan to initiate a phase 3 clinical trial program of GS-4997 in patients with NASH.”
Separately, a phase 2 study of GS-4997 in PAH did not achieve its primary endpoint and a phase 2 study in DKD did not achieve its primary endpoint based on a preliminary analysis. Due to insufficient evidence of efficacy, Gilead has decided not to pursue phase 3 studies of GS-4997 in PAH or DKD at this time. Data from these studies will be submitted for presentation at upcoming scientific conferences.
ARROW was a phase 2, dose-ranging, randomized, double-blind, placebo-controlled study designed to determine the safety, efficacy and tolerability of three doses of GS-4997 in 151 patients with PAH (WHO Group 1). Patients were randomized (1:1:1:1) to receive placebo or GS-4997 doses of 2 mg, 6 mg or 18 mg administered once daily on top of stable PAH therapy. The primary endpoint was change from baseline versus placebo in pulmonary vascular resistance (PVR) at week 24, as measured by right heart catheterization.
GS-4997 and simtuzumab are investigational products and have not been determined to be safe or efficacious. GS-4997 is an investigational small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress normally occurs at low levels in healthy states, but can be increased in many pathological conditions such as NASH.
