TTP4000 is a fusion between the ligand binding domains of RAGE and IgG. The receptor for advanced glycation endproducts (RAGE) is an immunoglobulin supergene family member. RAGE is expressed on multiple cell types including vascular endothelium, macrophages, podocytes, neurons, and microglial cells and is promiscuous in that it binds multiple functionally and structurally diverse ligands including amyloid beta (Aβ), advanced glycation endproducts (AGEs), S100 (proinflammatory member of the calgranulin family), serum amyloid A (SAA), and amphoterin. These interactions initiate signal transduction pathways including the activation of the transcriptional mediator of inflammatory signaling, NF-kB.  Furthermore, RAGE expression is upregulated at sites of inflammation or oxidative stress.

RAGE was initially identified as a receptor for AGEs, molecules whose expression are upregulated in diabetes and associated with the pathology of diabetic complications.  Subsequent studies have demonstrated that RAGE itself is essential to the pathophysiology of diabetic complications and multiple other diseases characterized by inflammation or oxidant stress.  RAGE activation has been linked to ischemia/reperfusion injury and to the pathogenesis of autoimmune disease and chronic inflammation. Subsequent research demonstrated a critical role for RAGE in the pathophysiology of Alzheimer’s disease.  RAGE is a receptor for Aβ as well as other amyloidogenic proteins including SAA and amylin. 

TTP4000 binds RAGE ligands with high affinity and inhibits RAGE/ligand signaling.
 
TTP4000 has an excellent PK profile and has demonstrated efficacy in several animal models of RAGE-mediated disease models. 

TTP4000 administered in animal models of AD have reduced both amyloid burden and Aβ phenotypes in the brains of treated animals. In addition, TTP4000 was associated with a marked improvement in cognitive function with the animals evaluated. 

TTP4000 is entering a clinical study in Alzheimer’s patients in association with Duke University.