Summary

■Aging-related diseases, especially neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), are commonly characterized by chronic inflammation, CD38 NADase elevation, and the subsequent irreversible decline of NAD+. Down-regulation of NAD+ causes the dysfunction of the NAD+ consuming enzymes, such as PAPR and SIRT family members, leading to destruction of mitochondrial biogenesis, fusion/fission, and mitophage. The damaged mitochondria not only fail to supply energy to the cells, especially neurons, but also exacerbate inflammation by releasing mitochondrial DNA, which stimulates cGAS-STING-inflammasome pathway. IPG8294 is a potent and specific CD38 NADase inhibitor, which robustly reverse the NAD+ decline and the subsequent mitochondrial damage, thereby rescuing the affected cells.

■Preclinical studies have demonstrated that in Alzheimer’s disease mouse models, IPG8294 significant elevates brain NAD+, reverses the decreased genes associated with mitochondrial biogenesis, fusion/fission, and mitophage, significantly improves the quality of neuronal mitochondria, and robustly rescues synaptic loss, leading to marked improvement of cognitive functions. In mitochondrial myopathy mouse models, IPG8294 treatment also up-regulates NAD+ in the muscle tissues, associated with improvement of mitochondrial quality and muscle functions.

■With the IND approval and Orphan Drug Designation granted by US FDA, Phase I trial is under the way. 

Mechanism of Action

■Mitochondrial quality control pathways are tightly regulated and interconnected, including mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis, 

■Dysregulation of CD38 NADase plays a substantial role in mitochondrial dysfunction.

■Blockade of CD38 NADase by IPG8294 holds the potential to restore mitochondrial function and improve the progression of associated diseases.

Key differentiation

■IPG8294 represents a groundbreaking small-molecule inhibitor of CD38 NADase with significant potential in addressing mitochondrial dysfunction. 

■IPG8294 is a disease-modifying agent for the treatment of mitochondrial myopathy, neurodegenerative disorders, and various other aging-related diseases.

In vivo properties

1. Efficacy of IPG8294 in AD mouse models

■IPG8294 improves mitochondrial quality in the brain of APP/PS1 mice 

TEM: The percentage of damaged mitochondria (Type II, III, IV) was significantly decreased by IPG8294 treatment (Statistic data was expressed as mean ± SEM. **** P < 0.0001, compared to vehicle)

■IPG8294 increases expression of PSD-95 and Synaptophysin in a dose-dependent manner in the brain of APP/PS1 mice.

WB: Synapse loss was significantly prevented by IPG8294 treatment in APP/PS1 mice brain (Statistic data was expressed as mean ± SEM. *** P < 0.001, **** P < 0.0001 compared to vehicle)

■IPG8294 reverses synaptic loss in a dose-dependent manner in the brain of APP/PS1 mice.

2. Efficacy of IPG8294 in mitochondrial myopathy mouse models

■IPG8294 increases the expression of NRF2 in the muscle of mitochondrial myopathy mouse models, suggesting improvement of mitochondrial biogenesis.

■IPG8294 improves the muscle function and decrease lactic acids in muscle tissues in mitochondrial myopathy mouse models.

Current status

■IND approved from US FDA

■ODD granted from US FDA

■Phase I trial is underway