Pharmacological profiling of intravenous MP-04: sustained NAD⁺ augmentation, immune modulation, and renal protection...

Systemic inflammation and mitochondrial bioenergetic failure are central drivers of multi-organ dysfunction in advanced liver disease, sepsis, and acute kidney injury (AKI). Currently available therapies remain largely supportive and fail to directly address intracellular NAD⁺ depletion and immune-metabolic dysregulation. We investigated MP-04, a novel intravenous formulation of dihydronicotinamide riboside (NRH), for its ability to restore NAD⁺ homeostasis, modulate immune metabolism, and confer organ protection in relevant preclinical models.

The NAD⁺-enhancement activity of nicotinamide riboside (NR) and MP-04 was evaluated in human hepatoma (HepG2), T-cell (Jurkat), kidney (HEK293) cell lines, and peripheral blood mononuclear cells (PBMCs). Cellular bioenergetics were assessed using Seahorse extracellular flux analysis. Immunomodulatory effects were examined in polyclonally activated human PBMCs and in a murine endotoxin-induced systemic inflammation model. Pharmacokinetics and pharmacodynamics were assessed following intravenous (IV) dosing in rats, and organ protection was evaluated in a cisplatin-induced AKI mouse model. Safety of MP-04 was evaluated in rat and dog Good Laboratory Practice (GLP) toxicology studies.

MP-04 produced rapid, distinct, and dose-dependent increases in intracellular NAD⁺ across all tested human cell types and was markedly more potent than NR. IV administration in rats resulted in sustained elevations of NAD⁺ and NADH in blood, liver, and kidney that persisted beyond the systemic clearance of MP-04, with strong correlations between blood and tissue NAD⁺ levels. In activated immune cells, MP-04 reduced reliance on aerobic glycolysis, and significantly attenuated pro-inflammatory cytokine production without affecting resting cells. In vivo, MP-04 reduced systemic inflammatory cytokines following endotoxin challenge and conferred significant biochemical and histological protection against cisplatin-induced AKI. MP-04 was safe and well tolerated in rat and dog following once daily IV administration for 7 days.

MP-04 is a safe and highly potent intravenous NAD⁺ precursor that modulates cellular metabolism, reduces maladaptive immune activation, and protects against inflammation-associated organ injury in preclinical models. These findings support MP-04 as a promising metabolic-immunomodulatory therapeutic strategy for conditions characterized by systemic inflammation and organ failure, including hepatorenal syndrome-associated AKI, beyond the limits of current supportive care.