S1206 Rapid Symptomatic Relief Is Correlated with Early Endoscopic Response to the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat Containing X1 (Nlrx1) Agonist Nx-13 in Ulcerative Colitis in a Phase 1b Study

Introduction: NLRX1 is an immunometabolic mitochondrial protein whose activation reduces oxidative stress to decrease inflammation. NX-13 is a novel, first-in-class, orally active and gut selective NLRX1 agonist with low systemic exposure. In animal studies of IBD, NX-13 reduced inflammatory responses and overall disease severity. A phase 1a study showed NX-13 to be well tolerated. The aim of this analysis was to assess the association between the onset of clinical improvement with early endoscopic response after the 4 weeks of NX-13 treatment. Methods: In this double-blind, placebo-controlled trial, 36 patients with active UC (Total Mayo Score 4-10; Mayo Endoscopic Subscore [MES] 2-3) were randomized to receive NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo QD for 4 weeks. Stable 5-ASAs and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. Stool Frequency (SFS) and Rectal Bleeding Scores (RBS) were collected at baseline, week 2 and week 4. MES was centrally read in a blinded manner at screening and week 4. A blinded pathologist performed Geboes scoring. Results: Symptom Improvement, Endoscopic Response, Endoscopic Remission, and Histologic Remission rates were calculated and are defined in Table 1. No placebo patients achieved Endoscopic Response. More than half of NX-13 dosed patients with Symptom Improvement at week 2 progressed to achieve rapid Endoscopic Response after only 4 weeks, with 26% in complete Endoscopic Remission in this short trial (Table 1). Histologic Remission was also more common in patients with Symptom Improvement. Sub analysis of the Symptom Improvement group highlighted patients with early, isolated SFS improvement (n=4) had the greatest rates of Endoscopic Response (100%), Endoscopic Remission (75%), and Histologic Remission (75%) (Figure 1). Patients with RBS Improvements also responded endoscopically and histologically better than patients without symptom improvement. Conversely, nearly all Endoscopic Responders showed early Symptom Improvement (10/11) at week 2. Further, all 5 of the Endoscopic Remitters had symptomatic improvement at week 2. Conclusion: Patients with active UC starting treatment with NX-13 that achieved fast onset of Symptom Improvement were more likely to achieve associated rapid Endoscopic Response and Remission. This novel MOA with good safety paired with promising efficacy results will be further evaluated in a proof-of-concept study (NCT05785715).Figure 1.: Endoscopic Outcomes at week 4 were Correlated with Symptom Improvement by week 2. Table 1. - Endoscopic Definitions and Outcomes at Week 4 of NX-13 treatment by presence or absence of early Symptom Improvement at Week 2 Outcome Definition Time Point Symptom Improvement at Week 2 No Symptom Improvement◊ (n=13) All Symptom Improvement◊ (n=19) RBS Symptom Improvement◊ (n=10) SFS Symptom Improvement◊ (n=4) RBS+SFS Symptom Improvement◊ (n=5) Endoscopic Response Change from Baseline (CFB) MES of < 0 Week 4 1 (7.6%) 10 (52.6%)¤ 4 (40%) 4 (100%)* 2 (40%) Endoscopic Remission Mayo Endoscopic Score = 0 Week 4 0 (0%) 5 (26.3%)¤ 2 (20%) 3 (75%)* 0 (0%) Histologic Remission Geboes score ≤3.1, no increase in neutrophils in the Lamina Propria Week 4 3 (23.1%) 8 (42.1%) 4 (40%) 3 (75%) 1 (20%) ◊No Symptom Improvement (SI) defined as RBS and SFS CFB ≥0; All SI defined as RBS or SFS CFB < 0; RBS SI defined as RBS CFB of < 0, SFS CFB ≥0; SFS SI defined as SFS CFB of < 0, RBS CFB ≥0; RBS+SFS SI defined as CFB of < 0 in RBS AND SFS; *χ2 p≤0.05; ¤χ2 p≤0.10.

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