Randomized, double-blind phase II trial of Lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis

Abstract

The aims of the study were to determine whether the platelet-activating factor antagonist Lexipafant could alter the clinical course and suppress the inflammatory response of human acute pancreatitis. In a double-blind, placebo-controlled study 83 patients were randomized to receive Lexipafant 60 mg intravenously for 3 days, or placebo. Clinical progression was assessed by daily Acute Physiology And Chronic Health Evaluation (APACHE) II score and organ failure score (OFS). The magnitude of the inflammatory response on days 1-5 was assessed by serial measurement of interleukin (IL) 8, IL-6, E-selectin, polymorphonuclear elastase-alpha1-antitrypsin (PMNE-alpha 1-AT), and C-reactive protein (CRP). At entry, patients receiving Lexipafant (n = 42) or placebo (n = 41) were matched for age and sex, aetiology, APACHE II score and OFS. The disease was classified as severe in 29 patients (APACHE II score eight or more). There was a significant reduction in the incidence of organ failure (P = 0.041) and in total OFS (P = 0.048) at the end of medication (72 h). During this time seven of 12 patients with severe acute pancreatitis who had Lexipafant recovered from an organ failure; only two of 11 with severe acute pancreatitis who had placebo recovered from an organ failure and two others developed new organ failure. Lexipafant treatment significantly reduced serum IL-8 (P = 0.038), and IL-6 declined on day 1. Plasma PMNE-alpha 1-AT complexes peaked on day 1; the gradual fall to baseline over 5 days observed in controls did not occur in patients given Lexipafant. No effect was observed on serum CRP. This study provides a rationale for further clinical trials with the potent PAF antagonist Lexipafant in human acute pancreatitis.

Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity

“…This may be particularly important for selecting a pretreatment agent in patients that are at a high risk of developing glucocorticoid-induced osteonecrosis (Vora, 2011). Our results also support the need for a clinically available PAF receptor antagonist for mitigating immune responses (Roberts et al, 1988;Hozawa et al, 1995;Kingsnorth et al, 1995) and emphasize that it may be important to monitor asparaginase activity if pretreatment medications are used. Furthermore, our results indicate that strategies that can lower anti-asparaginase antibodies might be useful to restore enzyme activity in a similar manner as our dose escalation approach.…”

Role of cytokines and their inhibitors in acute pancreatitis.

“…33 In the microvascular ischaemia model of acute pancreatitis, this compound is effective in ameliorating the local pancreatic damage when given after induction of the disease.50 Lexipafant has subsequently undergone a successful randomised double blind Phase II clinical trial in human acute pancreatitis. 13 In this study 83 patients were randomised to receive lexipafant 60 mg intraveneously for three days or placebo. Clinical progression was assessed by daily APACHE II scores and organ failure scores and the magnitude of the inflammatory response was assessed by serial measurements of interleukin 8, interleukin 6, E-selectin, PMN elastase, and C reactive protein.…”

Localization of the Platelet-Activating Factor Receptor to Rat Pancreatic Microvascular Endothelial Cells

“…12 Hence, although it is clear that PAF plays a key role in the course of AP, the precise cellular target for PAF associated with pancreatitis has not been determined.…”