Summary

IPG8294 is a potent, highly selective CD38 NADase inhibitor and a first-in-class small-molecule therapeutic targeting aging-related neurodegenerative and mitochondrial disorders.

Aging and neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are universally characterized by chronic neuroinflammation, elevated CD38 NADase activity, and subsequent irreversible NAD+ depletion. Declining NAD+ levels impair the function of NAD+-dependent enzymes such as the PARP and SIRT families, disrupting mitochondrial biogenesis, fusion/fission dynamics, and mitophagy. Damaged mitochondria fail to supply sufficient energy to neurons and other cells, and further amplify inflammation by releasing mitochondrial DNA that activates the cGAS-STING-inflammasome pathway.

By potently and specifically inhibiting CD38 NADase, IPG8294 robustly reverses NAD+ decline and downstream mitochondrial damage, restoring cellular function in affected tissues. Preclinical studies have confirmed its therapeutic efficacy across multiple disease models, supporting its broad potential in neurodegenerative disorders and mitochondrial myopathies.

Mechanism of Action

Mitochondrial dysfunction is a core pathological hallmark of Alzheimer’s disease (AD) and a wide range of neurodegenerative disorders. Multiple interconnected pathways drive progressive neuronal damage:

• The APOE ε4 (ApoE4) allele—the strongest genetic risk factor for AD, present in 40–65% of all AD patients—directly interacts with mitochondria to induce dysfunction and neurotoxicity.

• NAD+, an essential coenzyme for mitochondrial quality control, declines progressively during AD pathogenesis. Restoring NAD+ levels has been shown to protect against neurodegeneration in preclinical models.

• CD38, the primary NAD-consuming NADase in cells, is upregulated with aging and neuroinflammation. Genetic or pharmacological reduction of CD38 activity protects neurons from damage and ameliorates key AD pathologies.

In glial cells, aging drives increased CD38 expression, triggering a cascade of pro-inflammatory factor release and senescence-associated secretory phenotype (SASP) in astrocytes. This drives sustained mitochondrial dysfunction, oxidative stress, and protein misfolding/accumulation, ultimately leading to neuronal degeneration, demyelination, and impaired energy production.

IPG8294 acts by potently and selectively inhibiting the NADase activity of CD38, blocking the primary pathway of NAD+ depletion. This action restores cellular NAD+ homeostasis, rescues mitochondrial function, reduces neuroinflammation, and preserves neuronal integrity.

Key differentiations

• Highly Potent, Selective Target Engagement: IPG8294 is a highly potent CD38 inhibitor with IC₅₀ values of 10.7 nM against the human target and 9.7 nM against the murine ortholog. By selectively inhibiting the NADase activity of CD38, it exerts multifaceted pharmacological effects across disease pathways.

• Restores NAD+ Homeostasis: IPG8294 treatment elevates NAD+ levels in the brains of AD mouse models and in skeletal muscle of mitochondrial myopathy mouse models, correcting the core metabolic deficit driving disease progression.

• Enhances Mitochondrial Quality Control: IPG8294 robustly upregulates Sirt1 and Sirt3 expression, increasing levels of proteins involved in mitochondrial biogenesis and mitophagy, and improving overall mitochondrial health.

• Reduces Mitochondrial Damage: IPG8294 decreases the accumulation of damaged mitochondria in the brains of AD mouse models, reducing oxidative stress and pro-inflammatory signaling.

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

• Modulates Neuroinflammation: IPG8294 suppresses the cGAS-STING pathway and reduces the release of pro-inflammatory cytokines including IL-18, breaking the cycle of inflammation and neuronal damage.

• Improves Physical Function in Mitochondrial Disease: In mitochondrial myopathy mouse models, IPG8294 alleviates exercise intolerance and reduces blood lactate levels, improving functional outcomes.

• Favorable Safety Profile in Phase 1: Across all Phase 1 clinical evaluations, IPG8294 demonstrated a well-tolerated safety profile, with no Adverse Events (AEs) exceeding Grade 2 across all dose cohorts.

Current Development Status

• IPG8294 has received IND approval and Orphan Drug Designation from the U.S. FDA.

• Phase 1 (Completed): The Phase 1 clinical trial has been successfully completed, confirming a favorable safety, tolerability, and pharmacokinetic profile.

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.