S1169 The Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat Containing X1 Agonist NX-13 Demonstrates Rapid Symptomatic and Biomarkers Improvement in Ulcerative Colitis: Results in a Phase 1b Study

Introduction: Activation of NLRX1 reduces cellular oxidative stress and decreases effector immune responses. NX-13 is a first-in-class, orally active, gut selective NLRX1 agonist with low systemic exposure. In preclinical IBD models, NX-13 reduced inflammatory responses and disease severity. NX-13 was well tolerated in phase 1 trials and topline results were reported previously.1 Herein, we present data supporting rapid improvement in symptoms within 2 weeks of treatment. Methods: In this double-blind, placebo-controlled trial, 36 patients with UC (Total Mayo Score [MCS] 4-10; Mayo endoscopic subscore [MES] 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks. Biologic exposed patients, stable 5-ASA and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. Stool Frequency (SFS), Rectal Bleeding Score (RBS) and FCP were collected using daily diaries and at in-person visits at baseline, week 2 and week 4. Results: Symptom Improvement (SI), Symptom Resolution (SR), and Total Symptom Remission (TSR) rates were calculated and are defined in Table 1. Early Symptom Improvement in RBS or SFS was observed by NX-13 patients within 48 hours with a clear demarcation after just 2 weeks of treatment, vs placebo (Table 1, Figure 1). The greatest response was seen in the 250mg IR group with 9 patients showing Symptom Improvement and 5 in Total Symptomatic Remission at week 2. 500mg IR and DR dosed patients also responded with about half of patients showing Symptom Improvement at 2 weeks. RBS and SFS in the IR groups continued to improve to 4 weeks, with an additional 5 patients reaching SI or TSR. NX-13 IR patients also demonstrated rapid decreases in FCP levels with normalization rates of 20% (500mg IR) and 36% (250mg IR) at 2 weeks increasing to 40% (500mg IR) and 46% (250mg IR) at 4 weeks. Conclusion: In patients with UC, once-daily NX-13 demonstrated rapid onset of action within 48 hours. Distinct Symptom Improvement of RBS, SFS and/or FCP at week 2, and continued to improve to week 4. This novel mechanism of action with the potential to provide fast clinical improvement is under evaluation in a proof-of-concept study (NCT05785715). Table 1. - Symptom and Biomarker Definitions and Outcomes at 2 and 4 weeks Outcome Definition Time Point Placebo (n = 4) NX-13 250mg IR (n=11) NX-13 500mg IR (n=10) NX-13 500mg DR (n=11) Symptom Improvement (SI) Change from Baseline of < 0 in Rectal Bleeding Score AND/OR Stool Frequency Score Week 2 1 (25%) 9 (81.2%) 5 (50.0%) 5 (45.5%) Week 4 2 (50%) 9 (81.2%) 7 (70%) 5 (45.5%) Symptom Resolution (SR) Rectal Bleeding Score OR Stool Frequency Score =0 Week 2 0 (0%) 2 (18.2%) 4 (40.0%) 3 (27.3%) Week 4 0 (0%) 1 (9.1%) 4 (40%) 1 (9.1%) Total Symptom Resolution (TSR) Rectal Bleeding Score AND Stool Frequency Score = 0 Week 2 0 (0%) 5 (45.5%) 0 (0%) 0 (0%) Week 4 0 (0%) 8 (72.8%) 0 (0%) 0 (0%) Fecal Calprotectin (FCP) Normalization FCP level ≤250μg/g Week 2 1 (25%) 4 (36.4%) 2 (20%) 2 (18.2%) Week 4 1 (25%) 5 (45.5%) 4 (40%) 2 (18.2%) Figure 1.: Early onset of improvement in the Rectal Bleeding Score at 2 and 4 weeks in NX-13 treated patients.

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