TTP488 is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE).
An overproduction of amyloid beta (Aβ) has been implicated as the leading mechanistic factor in AD pathology. Aβ is known to bind to RAGE, an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery (Yan et al., 1996; Schmidt et al., 2009). RAGE is found on the cells of the neurovascular compartment: endothelial cells and microglia prominently express RAGE whose expression is upregulated in AD (Yan et al., 2007; Yan et al, 2009). RAGE ligands include Aβ, S100b, HMGB1, and Advanced Glycation Endproducts. RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation, and AD (Stern et al., 2002; Bierhaus et al., 2005). RAGE has been proposed to contribute to AD pathology by: promoting vascular leakage, promoting influx of peripheral Aβ into brain; mediating Aβ‑induced oxidative stress and Aβ‑mediated neuronal death (Deane et al., 2003; Carrano et al., 2011; Hartz et al., 2012; Kook et al., 2012).
The pleiotropic role of RAGE in AD pathology has been described using rodent models. Mice expressing the human amyloid precursor protein (APP) transgene in neurons develop significant biochemical and behavioral changes reminiscent of human AD. Double transgenic mouse overexpressing wild type RAGE in the APP transgene background exhibit accelerated behavioral changes, whereas double transgenic animals expressing a dominant negative mutant of RAGE are protected (Arancio et al., 2004). This data suggests that RAGE plays a role in augmenting the chronic inflammatory state caused by overproduction of Aβ.
RAGE is thought to be involved in the transport of Aβ from peripheral to central nervous system compartments (Tanzi et al., 2004). In vivo, Aβ uptake into brain is dependent on RAGE as shown in RAGE null mice (Deane et al., 2003). Similarly, Aβ uptake in brain can be inhibited using either the secreted, soluble form of RAGE (called sRAGE) or an anti-RAGE antibody (Deane et al., 2003). In addition, plaque formation in a mouse model of cerebral amyloidosis was inhibited using sRAGE (Yan et al., 2000; Rocken et al., 2003). These data suggest that RAGE is intimately involved in the pathogenesis of AD, and that sustained Aβ interaction with RAGE on blood-brain barrier and/or neuronal cells is an important element of amyloid plaque formation and chronic neuronal dysfunction.
These data taken together suggest that inhibition of RAGE with an orally available small molecule inhibitor presents an attractive therapeutic rationale for the treatment of Alzheimer’s disease.
TTP488 has completed phase 1 studies in healthy volunteers and 10 week (Sabbagh et al, 2011) and 18 month Phase 2 studies in patients with mild to moderate Alzheimer’s disease. Studies have supported identification of a safe, well-tolerated and efficacious dose for further study in Phase 3 registration trials.
TTP488 has been granted Fast Track designation by the United States Food and Drug Administration and has successfully completed an End of Phase 2 meeting. A phase 3 trial under a Special Protocol Assessment (SPA) is planned to start in 2015