Detailed results from an open-label phase 2 trial evaluating the investigational apoptosis signal-regulating kinase 1 ( ASK1 ) inhibitor Selonsertib ( formerly GS-4997 ) alone or in combination with the monoclonal antibody Simtuzumab in patients with nonalcoholic steatohepatitis ( NASH ) and moderate to severe liver fibrosis ( fibrosis stages F2 or F3 ), were announced.
The data have demonstrated regression in fibrosis that was, in parallel, associated with reductions in other measures of liver injury in patients treated with Selonsertib for 24 weeks.
These data were presented at The Liver Meeting 2016 in Boston.
Patients receiving Selonsertib demonstrated improvements in several measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness ( measured by magnetic resonance elastography, MRE ) and liver fat content ( measured by magnetic resonance imaging (MRI)-proton density fat fraction, PDFF ).
As no differences were observed between combination and monotherapy, results are presented for Selonsertib ( 18 mg and 6 mg ) with/without Simtuzumab and for Simtuzumab alone.
Additionally, patients with fibrosis improvement demonstrated reductions in hepatic collagen content, liver biochemistry ( e.g., serum ALT ) and the apoptosis marker, cytokeratin-18, supporting the biological activity of Selonsertib.
Selonsertib demonstrated no dose-related increases in treatment-emergent adverse events or serious adverse events. Headache, nausea and sinusitis were the most common adverse events in patients receiving Selonsertib.
Currently, no approved treatments exists for NASH, and patients with advanced fibrosis would potentially benefit from new options to halt and/or reverse the progression of their disease.
After only 24 weeks of therapy, Selonsertib exhibited promising anti-fibrotic activity in this study, which was the first known multi-center NASH clinical trial to use centrally-assessed MRE, MRI-PDFF, in addition to liver biopsy as endpoints.
Based on these data, Selonsertib represents an important investigational drug candidate for further clinical trials in patients with NASH and significant fibrosis.
Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis ( cell death ) and fibrosis in settings of oxidative stress.
Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.
This phase 2, randomized, open-label trial evaluated the safety, tolerability and efficacy of Selonsertib alone or in combination with Simtuzumab in 72 patients with NASH and fibrosis stages F2 ( n=25 ) or F3 ( n=47 ).
Eligible patients were randomized ( 2:2:1:1:1 ) to receive Selonsertib 6 mg ( n=20 ), Selonsertib 18 mg ( n=22 ), Selonsertib 6 mg plus Simtuzumab 125 mg ( n=10 ), Selonsertib 18 mg plus Simtuzumab 125 mg ( n=10 ) or Simtuzumab 125 mg alone ( n=10 ) for 24 weeks.
Selonsertib was administered orally once daily and Simtuzumab was administered via weekly subcutaneous injection. ( Xagena )
Source: Gilead, 2016