ESB1609 (S1P5 Selective Agonist), Initially for Development in Niemann-Pick C Disease

ESB1609 is a novel, orally-administered, brain-penetrant and highly-selective sphingosine 1-phosphate 5 (S1P5) receptor agonist.  S1P5 receptors are preferentially expressed within the CNS.  ESB1609 selectively binds to S1P5 receptors which regulate CNS lipid transporters. Results from preclinical studies have demonstrated the potential of ESB1609 to restore dysfunctional CNS lipid homeostasis and reduce downstream markers of neurodegeneration in animal models of neurodegeneration including Niemann-Pick C (NPC). 

NPC is a rare neurodegenerative lipid storage disorder ranging from a rapidly fatal neonatal disease to an adult-onset chronic neurodegenerative disease. Almost all patients that survive the neonatal period develop progressive neurodegeneration leading to motor dysfunction, difficulties swallowing and speaking, and cognitive deterioration.  These symptoms ultimately lead to premature death.  NPC patients have a defect in the gene encoding the NPC1 transporter. It is hypothesized that NPC1 is a critical sphingosine and cholesterol transporter since mutations in NPC1 cause lysosomal storage of sphingosine and cholesterol, along with a lipid maldistribution within cells.  The resulting effect within the CNS is a chronic loss of neurons, especially Purkinje cells.