Date: 2016-11-14
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at The Liver Meeting® 2016
Company: Gilead Sciences (USA - CA)
Product: selonsertib (GS-4997)
Action mechanism: enzyme inhibitor/kinase inhibitor. GS-4997 is a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1 or mitogen-activated protein kinase kinase kinase 5 (MAP3K5)), which promotes inflammation, apoptosis and fibrosis in settings of increased oxidative stress associated with NASH pathogenesis. Upon oral administration, ASK1 inhibitor GS-4997 binds to the catalytic kinase domain of ASK1, thereby preventing its phosphorylation and activation. This prevents the phosphorylation of downstream kinases, such as c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK). By preventing the activation of ASK1-dependent signal transduction pathways, GS-4997 prevents the production of inflammatory cytokines, down-regulates the expression of genes involved in fibrosis, suppresses excessive apoptosis and inhibits cellular proliferation.
Disease: NASH (non-alcoholic steatohepatitis)
Therapeutic area: Liver diseases - Hepatic diseases
Country: Canada, USA
Trial details: Study GS-US-384-1497 was a Phase 2, randomized, open-label clinical trial designed to evaluate the safety, tolerability and efficacy of GS-4997 alone or in combination with simtuzumab in 72 patients with NASH and fibrosis stages F2-F3. Eligible patients were randomized (2:2:1:1:1) to receive GS-4997 6 mg (n=20), GS-4997 18 mg (n=22), GS-4997 6 mg plus simtuzumab 125 mg (n=10), GS-4997 18 mg plus simtuzumab 125 mg (n=10) or simtuzumab 125 mg alone (n=10) for 24 weeks. GS-4997 was administered orally once daily and simtuzumab was administered via weekly subcutaneous injection. Since no differences were observed between combination and monotherapy, data in the table above are presented by GS-4997 treatment group only. (NCT02466516 )
Latest
news: * On November 14, 2016, Gilead Sciences announced detailed results from an open-label Phase 2 trial evaluating the apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997) alone or in combination with simtuzumab (SIM) in patients with nonalcoholic steatohepatitis (NASH) and moderate to severe liver fibrosis (fibrosis stages F2 or F3). The data demonstrate 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 in a late-breaking abstract session at The Liver Meeting® 2016 in Boston (#LB-3).
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). Data for these efficacy endpoints are summarized in the table below. As no differences were observed between combination and monotherapy, results are presented for selonsertib (18 mg and 6 mg) with/without SIM and for SIM 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.
*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.
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.
* On October 20, 2016, Gilead Sciences announced the top-line results from a Phase 2 study of GS-4997 (selonsertib), an investigational inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in nonalcoholic steatohepatitis (NASH). 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. Complete results will be presented at The Liver Meeting® 2016 in Boston.
Top-line efficacy data for fibrosis-related endpoints from 67 evaluable patients are summarized in the table below:
Endpoint (Week 24) GS-4997 18 mg GS-4997 6 mg SIM
± SIM ± SIM
Fibrosis Improvement ?1 Stage 43% (n=13/30) 30% (n=8/27) 20% (n=2/10)
from Baseline*
Progression to Cirrhosis 3% (n=1/30) 7% (n=2/27) 20% (n=2/10)
*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.
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. Pending discussions with regulatory agencies, Gilead plans to initiate a Phase 3 clinical trial program of GS-4997 in patients with NASH.
Endpoint (Week 24)
Selonsertib
18 mg ± SIM
Selonsertib
6 mg ± SIM
SIM
Fibrosis Improvement =1 Stage from Baseline*
43%
(n=13/30)
30%
(n=8/27)
20%
(n=2/10)
Progression to Cirrhosis
3%
(n=1/30)
7%
(n=2/27)
20%
(n=2/10)
=15% Reduction in Liver Stiffness by MRE
20%
(n=5/25)
32%
(n=7/22)
0%
(n=0/7)
=30% Reduction in Liver Fat by MRI-PDFF
26%
(n=8/31)
13%
(n=3/24)
10%
(n=1/10)
