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 has completed. Phase II trial is under the way. 

Mechanism of Action

■ Mitochondrial dysfunction is an important hallmark of Alzheimer’s disease (AD) and other neurodegenerative disorders.

■ APOE ε4 allele (ApoE4), the primary genetic risk factor expressed in 40–65% of all AD patients, interacts with mitochondria, causing mitochondrial dysfunction and neurotoxicity.

■ NAD+, a key coenzyme required for mitochondrial quality control, declines in the course of AD, and NAD+ replenishment prevents neurodegeneration.

 ■ The target NADase, a key consumer of NAD+, is elevated during aging, and its deficiency protects neurons from damage and ameliorates  AD pathologies. 

Key differentiations

■ IPG8294 is a highly potent inhibitor of CD38, with IC50 values of 10.7 nM for the human target and 9.7 nM for the murine ortholog. By selectively inhibiting the NADase activity of CD38, IPG8294 exerts multiple pharmacological effects:

■ Restores NAD+ Homeostasis: treatment with IPG8294 elevates NAD+ levels in the brains of Alzheimer's disease (AD) mouse models and in the muscles of mouse models of mitochondrial myopathy.

■Enhances Mitochondrial Function: IPG8294 robustly increases Sirt1 and Sirt3 expression, leading to upregulated levels of proteins involved in mitochondrial biogenesis and mitophagy, indicative of improved mitochondrial health.

■ Reduces Mitochondrial Damage: IPG8294 decreases the accumulation of damaged mitochondria in the brains of AD mouse models.

■Improves Physical Function: In mitochondrial myopathy mouse models, IPG8294 alleviates exercise intolerance and reduces blood lactate levels.

■ Preserves Synaptic Integrity and Cognitive Function: IPG8294 significantly increases synaptic density and markedly improves learning and memory in AD mouse models.

■ Modulates Neuroinflammation: IPG8294 suppresses the cGAS-STING pathway and reduces the release of pro-inflammatory cytokines such as IL-18.

■ Promising Safety Profile in Phase 1 clinical: Throughout the Phase 1 clinical evaluations, IPG8294 demonstrated a favorable safety and tolerability profile, with no Adverse Events (AEs) exceeding Grade 2 across all dose groups. 

Publication

Li, Yue, Yuanyuan Liu, Yong Zhang, Yong Wu, Zili Xing, JianFei Wang, and Guo-Huang Fan. 2023. 'Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy', Journal of Medicinal Chemistry, 66: 12762-75.