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Targeted therapy for acute pancreatitis (AP) remains absent from the essential management toolkit, despite an increasing worldwide disease burden, an extensive range of preclinical research, and numerous clinical trials. Preclinical promise in identifying key drug targets and demonstrating significant impacts of compounds in experimental models has too often not been translated into clinical trials. When translation has been achieved, trials have been unsatisfactory in design or conduct, leaving treatment for AP at an early stage of evolution [1]. Where deficits lie, however, opportunity exists. A critical mass of international researchers has now gathered with the common goal of successfully establishing pharmacological treatment for AP, providing essential light at the end of a long tunnel [2].

Over the last few decades a major step‐change in AP clinical management has resulted from advances in intensive care support for patients with severe AP [3]. In the light of this, one may ask why do we still require a pharmacological treatment for AP? Strong justification arises if we consider several crucial points. AP remains the most common gastroenterological emergency and the average stay in hospital for severe disease is over one month, often requiring high dependency or critical care [4]. This poses a significant economic burden on both patient and healthcare provider. Infected pancreatic necrosis usually requires repeated invasive procedures for debridement, whilst mortality from severe AP remains significant. Among those who recover, long‐term sequelae remain substantial and overall longevity is decreased [4]. Despite these unmet clinical needs, there has been a major drop in overall research investment in some countries, with the United States experiencing a greater than 50% fall in research funding for gastrointestinal inflammatory disorders over the last 50 years [2]. Nevertheless, the need for targeted therapy remains ever present.

Establishing successful pharmacological treatment for any disease condition depends primarily on (i) an understanding of the fundamental pathobiology of the disease with the identification of a key drug target using relevant and reproducible in vitro and in vivo disease models; (ii) identification of established therapies that may be repositioned or development of novel drug discovery pipelines for major identified targets; and (iii) adequately powered and well‐designed clinical trials with relevant and clearly defined end points to evaluate any potential pharmacological treatment.

Preclinical research has identified pivotal mechanisms central to AP pathogenesis associated with a range of cell types. The pancreatic acinar cell is the initial site of injury, commonly from bile or ethanol excess [5,6] and investigation of acinar cell responses to toxins that induce AP remains crucial for the investigation of key mechanisms and identification of new drug targets. Physiologically, calcium signaling plays a critical role in normal stimulus–secretion and stimulus–metabolism coupling; it has long been known that pathologically raised intracellular calcium results in toxicity [7]. This led to the hypothesis over 20 years ago that prolonged cytosolic calcium elevation is the key trigger of AP [8]. This has been borne out by a wealth of evidence confirming that sustained elevation of cytosolic calcium ([Ca²⁺]_C) is a vital trigger for pancreatic acinar cell injury and necrosis [9–11], leading to mitochondrial dysfunction [12,13], premature digestive enzyme activation, and initiation of the systemic inflammatory response. The overwhelming inflammatory response that ensues in severe disease is primarily orchestrated by the activation of key immune cells, particularly neutrophils and monocyte/macrophages, accompanied by the release of damage‐associated molecular patterns (DAMPs) [14] from acinar cells that act in concert to create a devastating cytokine storm [15]. The front‐running candidate drugs and their associated disease mechanisms are discussed in the subsequent sections of this chapter, followed by suggested improvements to trial design and funding to pave the way for future successful drug treatment.