Targeted therapeutics for pancreatitis.

Importance: Acute pancreatitis (AP) can result in significant morbidity and mortality. Its complications include persistent organ failure, necrosis, and death. Recurrent episodes of AP may also result in chronic pancreatitis (CP), a fibroinflammatory condition characterized by chronic pain and endocrine and exocrine failure. Despite improved supportive care, approved disease-modifying targeted therapies for AP or CP are lacking. Observations: Mechanistic studies identify early pathways within acinar and ductal cells that lead to injury, providing potential therapeutic targets before necrosis and other complications develop. Sustained cytosolic calcium elevation drives premature enzyme activation and mitochondrial failure, maintained by store-operated calcium entry through Orai1. Calcium overload promotes increased mitochondrial permeability, ATP depletion, and necrotic cell death. Potential early interventions include Orai1 inhibition (CM4620/Auxora with early-phase human safety data and phase 2b signals), mitochondrial pore inhibition (NIM811) and other mitochondrial protectants. When systemic inflammation escalates, preclinical containment targets include NLRP3 inflammasome signaling, neutrophil extracellular traps, damage-associated molecular pattern signaling (including HMGB1), and upstream cytokine shedding via ADAM17/TACE. Pragmatic strategies under study, such as early high-energy feeding, test whether modifiable supportive inputs can shift early severity trajectories. In chronic pancreatitis, long-term disease modification centers on targeting pancreatic stellate cells, which are critical drivers of fibrosis. Furthermore, the highly morbid chronic pain of CP can be modified through treatment of neuroimmune pain sensitization. The emerging clinical pipeline includes repurposed anti-fibrotic or immunomodulatory agents (pirfenidone, paricalcitol, tocilizumab, proglumide), genotype-matched therapy (CFTR modulation in selected populations), and cell-based approaches. Conclusion and Relevance: The current targeted therapeutic landscape in pancreatitis is promising, but difficulties lie in trial enrichment as the timing of drug administration is critically dependent on the timeline of disease. Therefore, progress will depend on matching treatment timing to target biology, identifying patients using practical early severity and inflammatory features, and using endpoints that reflect disease modification (organ failure, necrosis, recurrence, fibrosis progression, pancreatic function, and pain trajectories). Trial designs matching these therapeutics to their target biology will help understand the real clinical value of mechanism-based regimens across the AP-RAP-CP continuum.