THE EFFECT OF NLRX1 ACTIVATION ON EOSINOPHILS IN ULCERATIVE COLITIS AND INFLAMMATION: TRANSLATIONAL LEARNINGS ACROSS DISEASES AND FROM MOUSE TO HUMAN

Background: Although the precise role of eosinophils in IBD is debated, elevated eosinophils may influence response to therapy and clinical outcomes¹. Thus, therapeutic agents which affect both neutrophil and eosinophil recruitment may provide more robust clinical improvement in patients with UC. NLRX1 is an immunometabolic protein which reduces oxidative stress, shifts cellular metabolism, and decreases inflammation in multiple cell types implicated in ulcerative colitis (UC). Studies of NLRX1 agonists (gut-selective NX-13 & systemic LABP-73) in diverse disease models identified novel cellular targets of NLRX1 activation. We compared NLRX1’s effect on eosinophils in two disease states, UC and the more prototypical eosinophilic disease, asthma, and evaluated the findings.
Methods: In the 4-week NX-13 Phase 1b, a double-blind trial of 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) who were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks, histology was assessed using the Geboes score by a blinded pathologist².For allergic asthma models, mice were immunized with ovalbumin or house dust mite followed by antigen challenge concurrent with LABP-73 or vehicle. Cells isolated from the lung were analyzed by flow cytometry using the BD FACS Celesta / Diva system. Data are represented as means (standard error).
Results: In the 1b clinical trial, both the Geboes score and neutrophil subscores were reduced in the IR NX-13 group compared to placebo, consistent with the effects seen in preclinical IBD models. Upon examination, eosinophil infiltration was reduced in both the IR dose cohorts compared to placebo (Fig1A). In the subset of patients with active eosinophil infiltration at baseline (defined as Geboes subscore ≥2A.1), eosinophil reduction was seen in all NX-13 doses (Fig1B). Importantly, a numerically increased clinical response rate (decrease in total Mayo score of ≥3 or ≥30%) was seen in patients that demonstrated effective eosinophil reduction, compared to patients without improvement (75% versus 29%; Fisher’s Exact Test, p=0.08). In two allergic asthma models, NLRX1 activation by LABP-73 significantly reduced the fraction of eosinophils within the lung relative to vehicle control (n=7-8; p< 0.05), confirming NLRX1 activation can regulate eosinophilic inflammation in Th2-mediated responses.
Conclusion: Neutrophil and eosinophil infiltration were reduced in UC patients treated with the gut selective NLRX1 agonist, NX-13, and was coupled with better clinical outcomes. The effect of NX-13 on eosinophils will be evaluated further in the ongoing phase 2 NEXUS trial in patients with UC.
Reference:
¹ A Mookhoek, et al. JCC (16).
² L Peyrin-Biroulet, et al. JCC (17) Supp.