Our Science
Addressing Urgent, Unmet Medical Needs for
Metabolic, Inflammatory and Fibrotic Diseases
Chronic Inflammation has
Created a Global Health Burden
The dramatic rise in the incidence of chronic inflammatory diseases presents a global health burden. Diseases such as type 2 diabetes, atherosclerosis, neuroinflammation, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and others are on a rapid rise and are in desperate need for new therapies. The increasing incidence of these diseases can be attributed to genetics, lifestyle choices, environmental factors, and advanced age of the population. In many of these diseases, the severity and resolution can be mediated by the control or diminishment of the underlying inflammation.
Chronic Inflammation has
Created a Global Health Burden
The dramatic rise in the incidence of chronic inflammatory diseases presents a global health burden. Diseases such as type 2 diabetes, atherosclerosis, neuroinflammation, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and others are on a rapid rise and are in desperate need for new therapies. The increasing incidence of these diseases can be attributed to genetics, lifestyle choices, environmental factors, and advanced age of the population. In many of these diseases, the severity and resolution can be mediated by the control or diminishment of the underlying inflammation.
Our Pioneering Approach
The Elgia targets, caspase-1, caspase-2, caspase-6 and TBK1/IKKε, are differentiated from current clinical approaches, and our inhibitors disrupt key cellular processes involved in metabolic, inflammatory, and fibrotic diseases. Gene knockouts and specific inhibitors of the targets in Elgia’s pipeline have demonstrated proof-of-concept efficacy in relevant disease models. The R&D projects are highly enabled with drug-like chemical matter, protein co-crystal structures and established in vitro and PK/PD assays. Through screening and structure-based drug design (SBDD), Elgia scientists have created novel active-site, targeted covalent and allosteric inhibitors.
Elgia is harnessing deep knowledge and know-how of untapped therapeutic targets to address severe diseases such as fibrosis, neuroinflammation, NASH, cryopyrin-associated periodic syndrome (CAPS), and inflammatory bowel disease (IBD).
Caspase-6
Halting the Inflammation Process
The roles of caspase-6 in inflammation, cell death, and fibrosis are well understood from our founders’ research. Apoptosis is held in check by phosphorylation of pro-caspase-6 by (AMP)-activated protein kinase (AMPK), which is inactivated in both NASH and chronic kidney disease (CKD). Thus, AMPK activation, and, in turn, caspase-6 inhibition, have been associated with reduced fibrosis and improved energy status in NASH and CKD models. Elgia has potent, selective inhibitors of the inactive (zymogen) and active forms of caspase-6. Our preclinical plans focus on achieving proof-of-concept in models of kidney disease and fibrosis to support clinical development for these common and devastating indications. Additionally, evidence from caspase-6 KO models indicates that ablation of caspase-6 protects neurons from inflammation; thus, inhibitors may prevent or delay neurodegenerative diseases such as AD.
TBK1/IKKε
Proprietary Biology Insight
Knockout of TBK1 and IKKε kinases results in increased energy expenditure and resolution of many of the hallmarks of obesity, including fatty liver and insulin resistance. The founders have also demonstrated a reduction in atherosclerosis by a small molecule inhibitor of TBK1 and IKKε in advanced models. When induced in adipocytes, IKKε produces catecholamine resistance, while TBK1 inhibits the activity of AMPK; these two pathways together are responsible for repressed energy expenditure in obesity. In many diseases, including fibrosis and lupus, AMPK is also suppressed and triggers the activation of pro-inflammatory processes. AMPK activation is also associated with reduced ER stress and a concomitant resolution of renal fibrosis. Inhibitors of TBK1 may therefore offer a novel therapeutic for treating ER stress-mediated fibrosis and chronic inflammatory diseases.
Caspase-1
Regulation Beyond NLRP3
The innate immune system and inflammatory responses play a critical role in the pathogenesis of numerous inflammatory diseases. Inflammasome assembly is a key molecular event in the inflammatory response and leads to the activation of caspase-1, which subsequently results in the cleavage and release of IL-1β family of cytokines. Elgia founders have identified NLRP3-mediated caspase-1 activation as a central contributor to inflammation and fibrosis. A caspase-1 inhibitor could therefore dampen the inflammasome response and could be an attractive therapeutic approach to inhibit inflammatory and fibrotic diseases, including cryopyrin-associated periodic syndrome (CAPS) and IBD. Clinically, interruption of IL-1 signaling by anti-inflammatory agents has been shown to improve patient outcomes for colitis. Similar positive responses have been achieved in RA and CAPS clinical studies of anti-inflammatory agents that attenuate cytokine (IL-1) signaling. Our caspase-1 inhibitors will provide an optimal, novel intervention for inflammasome modulation.
Caspase-2
A Novel NASH Target with Differentiated Biology
Caspase-2 inhibition offers another specific and effective strategy for preventing or treating ER stress-mediated fibrosis. Data from the founders show that caspase-2, whose expression is ER stress-inducible and is elevated in human NASH, controls de novo lipogenesis (DNL) and cholesterol accumulation in NASH pathogenesis by activating sterol regulatory element binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 ablation or pharmacological inhibition prevents high fat diet induced liver steatosis and NASH progression while increasing energy expenditure. Additionally, it has been demonstrated that a caspase-2 inhibitor can prevent the cleavage of tau, re-establish synaptic function and prevent neuron impairment in AD models. These findings suggest that a caspase-2 inhibitor may provide a novel therapy for inflammatory and fibrotic diseases.