Date: 2016-10-20
Type of information: Results
phase: 2
Announcement: results
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: pulmonary arterial hypertension (PAH)
Therapeutic area: Rare diseases - Cardiovascular diseases
Country: Canada, France, Germany, Netherlands, Spain, UK, USA
Trial details: 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. (NCT02234141)
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