Jecure Therapeutics to Present at EASL 2018 Meeting on Development Candidate JT194
Feb 28, 2018
Jecure Therapeutics announced today that they will present at the 2018 EASL Meeting on their lead NLRP3 inflammasome assembly blocker (NAB) program. Included in the presentation will be data on development candidate, JT194, which is now progressing toward IND filing.
Discovery of Inhibitors of the NLRP3 Inflammasome for the Treatment of NASH and Liver Fibrosis
Christopher McBride1, Milos Lazic1, Davide Povero1, Geza Ambrus1, Angelina Santini1, Ryan Stansfield1, Lynnie Trzoss1, Casey Johnson2, James Veal*1, Jeffrey Stafford1, Ariel E. Feldstein2
1Jecure Therapeutics, San Diego, 2Department of Pediatrics, University of California San Diego, La Jolla, United States
Background and Aims: Persistent NLRP3 inflammasome activation has been shown to result in caspase-1 dependent hepatocyte pyroptosis and transdifferentiation/activation of hepatic stellate cells. Here we describe the discovery of novel small-molecule inhibitors of the NLRP3 inflammasome that have the potential to block the progression of NASH and liver fibrosis.
Methods: Phenotypic screening was used to identify selective inhibitors of the NLRP3 inflammasome. Compounds were tested on human peripheral blood mononuclear cells (PBMCs), human Kupffer cells (KCs), and mouse bone marrow-derived macrophages (BMDMs). Secreted levels of IL-1β, IL-18 and TNFα were measured in response to distinct inflammasome activators. Effects on pyroptotic cell death and caspase activation were evaluated, and immunofluorescence imaging was used to characterize the mechanism of action of the inhibitor class. Pharmacokinetic profiles of selected compounds were determined in mice. In vivo efficacy studies were performed in NLRP3A350V/+ CreT Muckle Wells Syndrome (MWS) and diet-induced NASH models.
Results: We identified novel molecules that dose dependently inhibited the cellular release of IL-1β and IL-18, following NLRP3 inflammasome stimulation. Lead molecules JT194 and JT349 demonstrated sub-100nM cellular potency. Production of TNFα was not affected by the compounds. IL-1β; secretion was blocked by the inhibitors when cells were stimulated by NLRP3 activators, nigericin or ATP, but not by NLRP1, AIM2 or NLRC4 specific stimuli. Inhibition of cellular caspase-1 activity, but not caspase enzymatic function, was also observed. Analysis of cell viability in treated PBMCs and BMDMs showed a cytoprotective effect consistent with an anti-pyroptotic phenotype. Immunofluorescence for ASC in stimulated cells detected NLRP3-ASC specks whose formation were abrogated by JT194 and JT349 treatment, revealing an activity of these compounds on the assembly of the NLRP3 inflammasome complex. Dosed orally in mice, JT194 and JT349 each provided excellent plasma exposure, and in vivo blockade of IL-1β production was demonstrated following a single dose below 5 mg/kg in a mouse acute LPS+ATP challenge model. In both NLRP3A350V/+ CreT mouse and diet induced NASH models, daily oral administration of JT194 was well tolerated and significantly inhibited markers of inflammation and liver fibrosis.
Conclusions: Our studies identified novel compounds JT194 and JT349 that potently and selectively inhibited NLRP3 inflammasome activation in vitro and in vivo. These NLRP3 assembly inhibitors demonstrated favorable pharmacokinetics in mice suitable for oral administration, and efficacy was observed in advanced NASH and liver fibrosis studies. The results support advancement of NLRP3 inflammasome inhibitors into further safety studies and ultimately into clinical trials.