P0627 Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Oral Resolvin E1-based Therapy in Inflammatory Bowel Disease (IBD): Translating Resolvin E1 Activation of BLT1 in Experimental Models to Healthy Volunteers
S Danese, B Siegmund, L Peyrin-Biroulet, B Verstockt, M Dubinsky, R Newman, H Thomas, R Guttendorf, R Lipper, J Steinberg, B Paperiello, T Jennings, D Jordan, J Parkinson, G Mathias, B SandsAbstract
Background
Resolvin E1 (RvE1), an endogenous lipid mediator, shows efficacy in murine colitis models by modulating mucosal immunity and protecting epithelial barrier function. RvE1 and leukotriene B4 (LTB4) are both BLT1 receptor agonists but elicit distinct biological outcomes through biased agonism. LTB4, a pro-inflammatory lipid mediator, initiates and regulates inflammatory responses by stimulating recruitment and activation of immune cells. In contrast, RvE1 selectively engages BLT1 to promote immune homeostasis and repair. TP-317, a stabilized RvE1 molecule, is being investigated as oral therapy for inflammatory bowel disease (IBD). In a sub-chronic murine model of DSS colitis, oral TP-317 (4.0 mg/kg) significantly improved disease activity and histological scores for mucosal inflammation and crypt loss. GLP toxicology studies in rats and dogs support TP-317’s safety profile, with the highest RvE1 doses tested in both preclinical species determined to be the no observed adverse event levels (NOAEL). This Phase 1a clinical study describes the pharmacokinetics (PK), pharmacodynamics (PD) and safety profile of TP-317 given as an enteric-coated tablet to healthy volunteers.
Methods
Twenty-four subjects were randomized 3:1 to single oral doses of TP-317 at 10, 40 and 80 mg (n=8/group). Safety, tolerability and PK/PD were assessed using standard methods. Subjects receiving the 80 mg dose underwent frequent CBC testing to assess short-term fluctuations in circulating neutrophils.
Results
Oral TP-317 was well tolerated, producing peak plasma RvE1 concentrations exceeding the EC50 for BLT1 activation (~10 nM) by 1.2, 2.8, and 6.7 times at 10, 40, and 80 mg doses, respectively. The mean AUC of the 80 mg group met regulatory requirements when compared to NOAEL dose exposures in rats and dogs. All 80 mg subjects experienced transient neutropenia, with neutrophils dropping below 1500/mL near RvE1 peak, followed by complete recovery above normal within ~2 hours. A similar pattern was previously observed without safety concerns in healthy subjects receiving an RvE1 drug at 150 mg twice daily for 10 days.
Conclusion
TP-317 demonstrates good tolerability and achieves adequate systemic RvE1 levels to engage the BLT1 receptor, offering a novel agonist approach to the LTB4-BLT1 pathway. Transient neutropenia observed with TP-317, a known effect of BLT1 activation by LTB4 and RvE1, suggests target engagement in humans. Oral TP-317’s safety profile and unique pro-resolution, barrier-protective mechanism warrant further clinical studies in IBD patients.