On Monday, June 1, ENDECE presented the following abstract to the Michael, Marcia, and Christa Parseghian Scientific Conference for NPC Research | Virtual Symposiums 

NDC-1308: A novel anti-inflammatory and remyelinating therapeutic in late pre-clinical studies for stopping / slowing disease progression and reversing functional losses in patients diagnosed with Niemann-Pick Disease type C (NPC)

Dr. James Yarger and James Hoyes, ENDECE, LLC, Mequon, WI 53092

A primary cause of Niemann-Pick Disease type C (NPC) is loss-of-function mutations in either NPC1 or NPC2 genes leading to a disruption in cholesterol and lipid transport out of endosomes and lysosomes. The accumulation of free cholesterol within the endosomes/lysosomes leads to progressive levels of neurodegeneration. Two key pathologies that drive this neurodegenerative process in NPC are 1) chronic, progressive neuroinflammation and 2) demyelination/hypomyelination.

ENDECE has discovered and is developing NDC-1308 as a novel anti-inflammatory and remyelinating small molecule therapeutic to stop/slow disease progression and reverse functional losses in patients diagnosed with NPC. NDC-1308 activity is derived from its ability to upregulate key genes, and their respective proteins, in signaling pathways representing both pathologies within central nervous system (CNS) tissues. NDC-1308 has a dual mechanism of action. First, NDC-1308 directly polarizes macrophages to the M2-like, anti-inflammatory/prorepair state by upregulating the lipoprotein lipase (LPL) gene and functional protein expression within CNS macrophages. This ability to polarize macrophages to the M2-like state is important since the first evidence of neuroinflammation in the NPC mouse is early activation of microglia (M1-like, pro-inflammatory macrophages) which begins the neurodegenerative cascade (Baudry et al 2003; Smith et al 2009; Cologna et al 2014). Second, NDC-1308 directly induces oligodendrocyte progenitor cells (OPCs) to differentiate into mature myelinating oligodendrocytes by upregulating key genes and functional proteins (Olig2, MBP, MOG, DNER) within CNS OPCs which induce remyelination of demyelinated/hypomyelinated axons. This ability to induce remyelination is important since progressive Purkinje cell degeneration is an important neuropathological feature of NPC (Pentchev et al 1984; Higashi et al,1993) along with myelin loss in the pre-frontal cortex, corpus callosum and hippocampus in NPC 1 mice (Yan et al 2011; Caporali et al 2016).

ENDECE has completed several important pre-clinical studies that support this novel therapeutic profile. M2- polarization with NDC-1308 has been confirmed in neonatal primary rat microglia cultures. In addition, prophylactic dosing in EAE mouse models demonstrates NDC-1308 provides dose-dependent, anti-inflammatory benefits consistent with an M2-like macrophage phenotype. Induced remyelination has been confirmed using the cuprizone mouse model. In this model, NDC-1308 reproducibly demonstrates remyelination of the pons, hippocampus, and cortex consistent with OPC differentiation into mature oligodendrocytes.

Importantly, NDC-1308 demonstrates a strong safety profile; it does not upregulate the expression of 38 genes known to be involved in cell proliferation and migration (i.e. has a low carcinogenic profile). Nor does NDC-1308 appear to be uterotropic, mutagenic, genotoxic, or pro-arrhythmic. An SBE-β-cyclodextrin based formulation has been developed for nasal administration of NDC-1308 across the olfactory epithelium into the brain and spinal cord. We believe NDC-1308 possesses many desirable attributes of an effective NPC therapy and we are ready to progress NDC-1308 into IND-enabling and then Phase 1/2 clinical studies.

Baudry, M et al, 2003, Exp Neurol, 184:887-903
Caporali P et al, 2016, Acta Neuropathol Comm, 4:94
Cologna, SM et al, 2014, J Inherit Metab Dis, 37:83-92
Higashi Y et al, 1993, Acta Neuropathol 85:175-184
Pentchev PV et al, 1984, J Biol Chem 259:5784-5791
Smith, D et al, 2009, Neurobiol Dis, 36:242-251
Yan X et al, 2011, Metab Brain Dis, 26:29-306
ENDECE, LLC. Data on File.