ESB1609 is a novel, oral, 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.
Multiple genetic forms of neurodegeneration cause perturbations in the sphingolipid pathway and ultimately, lysosomal dysfunction
APOE4, apolipoprotein E 4; GBA, glucocerebrosidase; IND, investigational new drug; LRRK2, leucine-rich repeat kinase 2; Ph2, Phase 2; S1P5, sphingosine 1-phosphate receptor 5.
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.
ESCAPE is developing novel, oral, brain-penetrant and highly-selective LRRK2 G2019S kinase inhibitors for the potential treatment Parkinson’s disease (PD) patients with the G2019S LRRK2 variant.
The G2019S LRRK2 mutation is the most common pathogenic cause of familial PD, occurring in 1–3% of PD patients. Almost all G2019S LRRK2 PD patients carry two versions of LRRK2 protein: one mutant variant with excessive kinase activity (up to 10-fold) and one healthy version, critical for regulating intracellular vesicular trafficking throughout the body.
Role of LRRK2
Normal LRRK2 acts on downstream Rab GTPases, which orchestrate critical biological functions, such as vesicular trafficking, autophagy,
and lysosomal and mitochondrial function. G2019S mutation elevates kinase activity via autophosphorylation at Phosphoserine 1292 (pS1292).
Kinase inhibitors that do not discriminate between the LRRK2 variant and healthy version (non-selective inhibitors) have caused renal and pulmonary toxicity in preclinical toxicology studies. Though these toxicities have been shown to be reversible in non-human primate studies, they are not monitorable during human dosing and pose safety concerns to long-term treatment.
ESCAPE’s G2019S-selective small molecule inhibitors have demonstrated, in preclinical models and in human blood cells, the ability to dampen excessive and causal kinase activity while sparing the healthy LRRK2 protein.
ESCAPE’s structure modulator approach aims to treat ApoE4 carriers with Alzheimer’s disease and stems from work of Dr. Robert Mahley and Dr. Yadong Huang from the Gladstone Institutes. Their work led to the identification of unique structural features of ApoE4 that drive ApoE4-specific biology. ESCAPE is expanding on this fundamental biology to develop small-molecule allosteric modulators that alter ApoE4 protein structure to restore normal ApoE function.
ApoE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease. Individuals carry one of three variants of the ApoE gene: ApoE2, ApoE3, or ApoE4. Carriers of the ApoE4 allele have an increased risk of developing Alzheimer’s at an earlier age of onset and increased rate of progression in a gene dose dependent manner. 65–80% of all Alzheimer’s disease patients have at least one ApoE4 allele, and 20% of all Alzheimer’s disease patients are homozygotes for ApoE4.