Introduction
Targeting mitochondrial function and oxidative stress is successful in animal models of IBD. NLRX1 is a mitochondrial associated protein upregulating mitochondrial metabolism: It reduces oxidative stress and decreases pro-inflammatory cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, once-daily, gut-selective NLRX1 agonist with low systemic exposure in development for Ulcerative Colitis (UC). In three mouse models of IBD, NX-13 effectively activated NLRX1 to reduce inflammatory responses and disease severity. In two phase 1 studies (56 healthy subjects; 38 UC patients) NX-13 was well tolerated. Low systemic drug exposure relative to stool levels suggested a gut-selective drug distribution. Phase 1B topline results were reported previously1. We now present data demonstrating target engagement and downstream effects consistent with the preclinical mechanism of action (MOA).
Aims & Methods
In this double-blind phase 1B trial, 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo to be taken QD for 4 weeks. We report pharmacodynamic results based on expression of NLRX1 and downstream immunometabolic markers in colonic tissue samples collected at screening and week 4 of treatment. NLRX1 protein levels were measured by immunohistochemistry scored by a blinded pathologist, and immunometabolic markers were measured by qRT-PCR.
Results
All NX-13 treated groups showed target engagement through mean positive increases in NLRX1 expression versus placebo at week 4, with more pronounced upregulation observed in responding patients (Table 1A). Gene expression profiles after 4 weeks of treatment showed upregulation of the mitochondrial metabolism gene MT-ND3, with downstream reductions in HIF1α and NLRP3 in the NX-13 IR groups but not in the placebo group (Table 1B). NX-13 250mg IR dosed patients also displayed downstream decreases in IL-17α and IL-1β gene expression, and the 500mg IR group showed reduction in IL-1β. Changes in NLRX1 expression and immunometabolic markers correlated with clinical response to NX-13 and were numerically greater in responding IR-dosed patients compared to non-responding patients (Table 1).
| A. Immunohisto-chemistry | Definition | Subgroup | Placebo
(n=2) | NX-13 250mg IR
(n=8) | NX-13 500mg IR
(n=8) | NX-13 500mg DR (n=8) |
| NLRX1 Composite Score Change from Baseline | Mean (Standard Error) of 4-point score accounting for NLRX1 intensity and number of positive cells in the epithelium and lamina propria | Responder | n/a | n/a | 0.54 | (0.36) | 2.58 | (0.46) | 1.42 | (0.68) |
| Non-responder | -0.38 | (0.38) | 0.25 | (0.25) | 1.35 | (0.84) | 0.7 | (0.76) |
| B. Gene Expression | Definition |
| Placebo (n=1) | NX-13 250mg IR (n=7) | NX-13 500mg IR (n=6) | NX-13 500mg DR (n=5) |
| MT-ND3 | Median (Interquartile Range) fold change over baseline expression | Responder | (n/a) | (n/a) | 1.37 | (1.2-1.54) | 1.52 | (1.14-1.90) | n/a | n/a |
| Non-responder | 0.71 | (n/a) | 0.86 | (0.45-1.28) | 1.04 | (0.96-1.14) | 0.76 | (0.34-1.68) |
| HIF1α | Responder | (n/a) | (n/a) | 0.74 | (0.53-0.81) | 0.83 | (0.80-0.86) | n/a | n/a |
| Non-responder | 1.06 | (n/a) | 2.18 | (1.07-3.29) | 0.95 | (0.55-1.5) | 1.11 | (0.69-2.50) |
| NLRP3 | Responder | (n/a) | (n/a) | 0.65 | (0.58-0.88) | 0.59 | (0.56-0.62) | n/a | n/a |
| Non-responder | 1.26 | (n/a) | 1.89 | (1.28-2.50) | 0.92 | (0.30-2.04) | 1.35 | (0.64-2.34) |
Conclusion
Treatment with NX-13 induced upregulation of its target, NLRX1, as well as downstream immunometabolic signaling consistent with preclinical MOA studies. Most importantly, target engagement parallels clinical benefit. This novel mechanism of action warrants further study and is currently being evaluated in a phase 2 proof of concept study (NCT05785715).
References
1 L Peyrin-Biroulet, S Danese, J F Colombel, F Rieder, A Yarur, B Verstockt, S Lichtiger, R Mosig, F Cataldi, B Feagan, P577 A Phase 1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the Nucleotide-binding oligomerization domain, Leucine rich Repeat containing X1 (NLRX1) agonist NX-13 in Ulcerative Colitis, Journal of Crohn's and Colitis, Volume 17, Issue Supplement_1, February 2023, Pages i705–i706
Disclosure
BV - AbbVie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Guidepont, Inotrem, Ipsos, Janssen, MSD, Mylan, Pfizer, Progenity, R-Biopharm, Sandoz, Sossei Heptares and Takeda, Tillots Pharma, Truvion and Viatris;
SV - grants from: AbbVie, J&J, Pfizer, Takeda and Galapagos, consulting / speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma;
BS - consultant for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Falk, Janssen, Lilly, Pfizer, PredictImmune and Takeda; and received speaker’s fees from AbbVie, BMS, CED Service GmbH, Falk, Ferring, Janssen, Pfizer and Takeda (served as representative of the Charité);
FR - Adnovate, Agomab, Allergan, AbbVie, Arena, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio;
SL – owns Landos Stock;
RM – employee of Landos;
FC – employee of Landos;
SD - AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor;
