Acute pancreatitis future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[2]
Future or Investigational Therapies
Despite decades of research, no FDA-approved disease-modifying targeted therapy exists for acute pancreatitis — management remains entirely supportive.[1][2] Several mechanistically promising agents are now in early-phase clinical trials.
Calcium Signaling Modulators: Zegocractin (formerly Auxora/CM4620)
The most advanced targeted therapy in the clinical pipeline is zegocractin (formerly Auxora/CM4620), a selective inhibitor of calcium release-activated calcium (CRAC/Orai1) channels. Sustained cytosolic calcium elevation is a central early event in acinar cell injury, driving premature trypsinogen activation, mitochondrial failure, ATP depletion, and necrotic cell death.[1][3]
Zegocractin blocks store-operated calcium entry (SOCE) through Orai1 channels, reducing acinar cell necrosis, trypsin activation, and inflammatory responses in both parenchymal and immune cells in preclinical models.[4]
A phase 2a open-label study (n=21) in patients with acute pancreatitis, SIRS, and hypoxemia demonstrated a favorable safety profile. Patients receiving zegocractin showed improvement in CT severity index, better solid food tolerance, less persistent SIRS, and reduced hospitalization compared with standard of care alone.[5]
The phase 2b trial (Sutton et al., EClinicalMedicine 2026; n=216) — the largest RCT of a targeted therapy in acute pancreatitis — was negative for the primary endpoint of time to solid food tolerance in the overall population. However, a dose-response relationship was found for prevention of new-onset severe respiratory failure, and the 2.0 mg/kg dose reduced necrotizing pancreatitis at day 30 and prolonged hospitalizations (>21 days). In a pre-specified subgroup with high hematocrit or Balthazar D/E scores at screening, improvement in time to solid food tolerance was observed. These results identified a suitable dose, patient population, and endpoints for a potential phase 3 trial.[6]
Other calcium-targeted approaches under preclinical investigation include mitochondrial permeability transition pore inhibitors (NIM811), TMEM16A inhibitors, and calcineurin inhibitors (cyclosporin A, tacrolimus), though none have entered clinical trials for acute pancreatitis.[3][1]
Anti-Inflammatory and Immunomodulatory Agents
Despite the central role of dysregulated inflammation in acute pancreatitis, clinical trials of immunomodulatory agents have been largely disappointing to date.[2][7]
- Corticosteroids: The CRISP trial (NCT05160506), a multicenter double-blind RCT, is evaluating hydrocortisone 100 mg IV every 8 hours for 3 days versus placebo in severe acute pancreatitis, with the primary endpoint of 72-hour change in SOFA score. This represents the first rigorous trial of corticosteroids specifically in severe acute pancreatitis.[8]
- TNF-α inhibition: Infliximab is under investigation in an RCT for acute pancreatitis of all severity grades (ISRCTN16935761). A small proof-of-concept study of pentoxifylline (oral TNF-α antagonist) in predicted severe acute pancreatitis (n=28) showed fewer ICU admissions and shorter hospital stay, but larger trials are needed.[7]
- Tocilizumab (IL-6 receptor blockade): Shown promise in animal models of acute and chronic pancreatitis and is being studied in chronic pancreatitis patients (NCT06426160); no completed acute pancreatitis trial data yet.[1]
- Pirfenidone: An antifibrotic agent that reduced acute pancreatitis severity in preclinical models. A multicenter randomized pilot trial (NCT05350371) is currently enrolling 60 patients to evaluate safety, tolerability, and efficacy (PAN-PROMISE score reduction, inflammatory markers) in acute pancreatitis within 48 hours of diagnosis.[9]
- Lexipafant (PAF antagonist) and IV antioxidants both failed in adequately powered RCTs, and probiotics (PROPATRIA) increased mortality — these approaches have been abandoned.[7][2]
Ongoing Supportive Care Optimization Trials
- WATERLAND trial (NCT05781243): An international multicenter RCT comparing lactated Ringer solution versus normal saline on clinical outcomes in acute pancreatitis — the first adequately powered trial to address this question definitively.[10]
- GOULASH trial (Gut 2026; n=636): Compared high-energy (30 kcal/kg/day from day 1) versus gradually increasing energy enteral nutrition. The trial was stopped early for futility — high-energy feeding did not reduce mortality/severity and showed a signal toward increased organ failure (16.7% vs 9.1%, uncorrected P=0.007; corrected P=0.13) and pain relapse (27.1% vs 19.0%, uncorrected P=0.03; corrected P=0.23) — neither survived correction for multiple testing, but the direction of effect was consistent. This reinforces the current approach of gradual nutritional advancement rather than immediate high-calorie feeding.[11]
Biomarker-Driven Approaches and Precision Medicine
Circulating DAMPs (histones, cell-free DNA, mitochondrial DNA) and immune biomarker panels (Angiopoietin-2, HGF, IL-8, resistin, sTNF-αR1) show higher predictive accuracy for severe acute pancreatitis than existing clinical scores and may enable future trial enrichment — selecting patients most likely to benefit from targeted therapies.[12]
The IAP 2025 revised guidelines explicitly identify targeted therapies for controlling systemic inflammation and mitigating organ dysfunction as the primary area for future research.[13]
Preclinical-Stage Approaches
Several approaches remain preclinical without human trial data in acute pancreatitis:
- NLRP3 inflammasome inhibitors — target a key inflammatory pathway, but no acute pancreatitis-specific clinical trials.[1]
- Neutrophil extracellular trap (NET) inhibitors — emerging preclinical target.[1]
- HMGB1/DAMP pathway inhibitors — preclinical only.[1]
- Recombinant IL-37 and IL-35 modulators — proposed cytokine-targeted interventions based on preclinical evidence of anti-inflammatory effects in acute pancreatitis models.[14]
- Mesenchymal stem cells (MSCs) — animal studies show reduced inflammation, necrosis, and multi-organ injury via NF-κB/NLRP3 pathway suppression, but no human acute pancreatitis trials have been conducted.[15][16]
- Genotype-matched therapy — CFTR modulator therapy (e.g., elexacaftor/tezacaftor/ivacaftor) could potentially benefit selected patients with CFTR-related recurrent acute pancreatitis, though this remains theoretical.[1]
Key Context for Clinicians
A fundamental challenge in developing acute pancreatitis-specific therapies is that the timing of drug administration is critically dependent on disease biology — interventions targeting early acinar cell injury (calcium modulators) must be given within hours, while anti-inflammatory agents targeting the systemic phase may have a different therapeutic window.[1]
Progress will depend on matching treatment timing to target biology, practical early severity identification, and endpoints reflecting disease modification (organ failure, necrosis) rather than surrogate markers.[1]
The 2023 update by van den Berg and Boermeester summarized the current state concisely: immunomodulation using cytokine removal or anti-inflammatory drugs remains "an attractive idea, but up to now the results of clinical trials are disappointing."[2]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 Alsaleh T, George J (2026). "Targeted Therapeutics for Pancreatitis". Front Physiol. 17: 1795419. doi:10.3389/fphys.2026.1795419.
- ↑ 2.0 2.1 2.2 2.3 van den Berg FF, Boermeester MA (2023). "Update on the Management of Acute Pancreatitis". Curr Opin Crit Care. 29 (2): 145–151. doi:10.1097/MCC.0000000000001017.
- ↑ 3.0 3.1 Chooklin S, Chuklin S (2026). "Breaking the Calcium Overload Cycle in Acute Pancreatitis: Emerging Pharmacological Strategies". Dig Dis Sci. 71 (7): 3159–3186. doi:10.1007/s10620-026-09768-y.
- ↑ Waldron RT, Chen Y, Pham H; et al. (2019). "The Orai Ca2+ Channel Inhibitor CM4620 Targets Both Parenchymal and Immune Cells to Reduce Inflammation in Experimental Acute Pancreatitis". J Physiol. 597 (12): 3085–3105. doi:10.1113/JP277856.
- ↑ Bruen C, Miller J, Wilburn J; et al. (2021). "Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome: Clinical Development of a Calcium Release-Activated Calcium Channel Inhibitor". Pancreas. 50 (4): 537–543. doi:10.1097/MPA.0000000000001793.
- ↑ Sutton R, Garg PK, Miller J; et al. (2026). "Zegocractin for Acute Pancreatitis With Systemic Inflammatory Response Syndrome: A Randomized, Controlled, Dose-Ranging, Phase 2b Trial". EClinicalMedicine. doi:10.1016/j.eclinm.2026.103138.
- ↑ 7.0 7.1 7.2 Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
- ↑ Vine J, Berlin N, Moskowitz A; et al. (2024). "Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) Protocol and Statistical Analysis Plan: A Prospective, Multicentre, Double-Blind, Randomized, Placebo Controlled Clinical Trial". Contemp Clin Trials. 139: 107486. doi:10.1016/j.cct.2024.107486.
- ↑ Bava EP, Jain T, Al-Obaidi M; et al. (2025). "Safety, Tolerability and Therapeutic Efficacy of Anti-Inflammatory Drug Pirfenidone in Acute Pancreatitis Patients: Protocol for a Randomized Pilot Clinical Trial". Pancreatology. 25 (2): 214–220. doi:10.1016/j.pan.2025.01.004.
- ↑ Trikudanathan G, Yazici C, Evans Phillips A, Forsmark CE (2024). "Diagnosis and Management of Acute Pancreatitis". Gastroenterology. 167 (4): 673–688. doi:10.1053/j.gastro.2024.02.052.
- ↑ Márta K, Engh MA, Vincze Á; et al. (2026). "High Versus Gradually Increasing Energy Nutrition in the Early Phase of Acute Pancreatitis (GOULASH): A Multicentre Double-Blind Randomised Clinical Trial". Gut. 75 (5): 995–1002. doi:10.1136/gutjnl-2025-335970.
- ↑ Lee PJ, Papachristou GI, Speake C, Lacy-Hulbert A (2024). "Immune Markers of Severe Acute Pancreatitis". Curr Opin Gastroenterol. 40 (5): 389–395. doi:10.1097/MOG.0000000000001053.
- ↑ "International Association of Pancreatology Revised Guidelines on Acute Pancreatitis 2025". Pancreatology. 2025. doi:10.1016/j.pan.2025.04.020.
- ↑ Yan H, Dang X, Du G; et al. (2026). "IL-35, IL-37, and IL-38 in Acute Pancreatitis: Proposed Immunopathogenic Mechanisms and Therapeutic Potential". Front Immunol. 17: 1728737. doi:10.3389/fimmu.2026.1728737.
- ↑ Wang A, An Y, Wang X; et al. (2025). "Mesenchymal Stem Cells Derived From Different Adipose Tissue Depots Ameliorate Severe Acute Pancreatitis by Inhibiting NF-κB/NLRP3/Caspase-1 Pathways". Stem Cell Rev Rep. 21 (7): 2200–2217. doi:10.1007/s12015-025-10922-8.
- ↑ Ren R, Ren W, Zhang Y; et al. (2024). "Breaking the Chain in Organ Failure: Role of Umbilical Cord and Bone Marrow Derived Mesenchymal Stem Cells in Treatment of Severe Acute Pancreatitis". Heliyon. 10 (16): e35785. doi:10.1016/j.heliyon.2024.e35785.