ESB1609 is a novel, orally administered, brain-penetrant and selective sphingosine-1-phosphate 5 (S1P5) receptor agonist being developed for Niemann-Pick C disease (NPC) and potentially other neurodegenerative disorders.
S1P5 receptors are one of five receptors within the G-protein-coupled S1P receptor family (S1P1–S1P5). S1P5 couples to Gi and G12 and is predominantly expressed in the central nervous system (CNS) and natural killer (NK) cells. The endogenous ligand for S1P5 is sphingosine-1-phosphate (S1P), a sphingolipid that plays a significant role in many aspects of cellular homeostasis and proliferation. Activation of S1P5 upregulates several CNS lipid transporters and has been shown to normalize brain ceramide and sphingosine phosphate levels and promote clearance of aggregation-prone proteins across multiple pre-clinical models of neurodegeneration.
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. There are currently no therapies approved in the United States for the treatment of NPC.
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 NPC. ESCAPE has initiated a Phase 1, randomized, double-blind, placebo-controlled, safety, tolerability, and pharmacokinetic multiple ascending dose study testing various doses of ESB1609 over a period of up to 25 days.