P3548 - Target Engagement and Pharmacodynamic Molecular Mechanism Evaluation in a Phase 1b Study of the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat Containing X1 (NLRX1) Agonist NX-13 in Ulcerative Colitis

Tuesday, October 24, 2023

10:30 AM – 4:00 PM PT

Location: Exhibit Hall

Presenting Author(s)

Silvio Danese, MD, PhD

IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University
Milan, Lombardia, Italy

Silvio Danese, MD, PhD¹, Séverine Vermeire, MD, PhD², Britta Siegmund, MD, PhD³, Florian Rieder, MD⁴, Stefan Schreiber, MD⁵, Simon Lichtiger, MD⁶, Rebecca Mosig, PhD⁷, Fabio A. Cataldi, MD⁷, Bram Verstockt, MD, PhD⁸
¹IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Lombardia, Italy; ²UZ Leuven, Leuven, Vlaams-Brabant, Belgium; ³Charité – Universitätsmedizin Berlin, Berlin, Berlin, Germany; ⁴Cleveland Clinic, Cleveland, OH; ⁵University Hospital Schleswig Holstein, Kiel, Schleswig-Holstein, Germany; ⁶Landos Biopharma, Inc., Blacksburg, VA; ⁷Landos Biopharma, Blacksburg, VA; ⁸KU Leuven, Leuven, Vlaams-Brabant, Belgium

Introduction: Targeting mitochondrial function and oxidative stress is successful in models of IBD. NLRX1 is a mitochondria-associated protein which upregulates mitochondrial metabolism, reduces oxidative stress and decreases pro-inflammatory cells and cytokines. 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 3 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, and here we present data to support target engagement and effects consistent with the preclinical mechanism of action (MOA).

Methods: In this double-blind 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 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 (Fig1A). Placebo patients’ NLRX1 levels did not increase (Fig1A). Gene expression profiles after 4 weeks of NX-13 or placebo treatment showed upregulation of the mitochondrial metabolism gene MT-ND3 (Fig1B) with downstream reductions in HIF1α and NLRP3 (Fig1C) expression in the NX-13 IR groups. NX-13 250mg IR patients also displayed decreases in IL-17α and IL-1β expression after 4 weeks and the 500mg IR group showed reduced IL-1β but not in IL-17α. Changes in NLRX1 expression and immunometabolic markers correlated with clinical response to NX-13.

Discussion: NX-13 induced signs of engagement and upregulation of NLRX1 as well as immunometabolic signaling consistent with the preclinical MOA. This novel mechanism of action warrants further study and is currently being evaluated in a phase 2 proof of concept study (NCT05785715).

Figure: Treatment with NX-13 for 4 weeks results in upregulation of NLRX1 protein expression which correlated with clinical response (A), upregulation of the mitochondrial metabolism gene MT-ND3 (B), and decreased expression of the inflammasome-associated NLR, NLRP3 (C), consistent with preclinical molecular MOA studies.

Disclosures:

Silvio Danese: AbbVie – Consultant, personal fees (lecture fees). Alimentiv – Consultant. Allergan – Consultant, personal fees. Amgen – Consultant, lecture fees. Applied Molecular Transport – Consultant. AstraZeneca – Consultant, personal fees. Athos Therapeutics – Consultant, personal fees. Biogen – Consultant, personal fees. Boehringer Ingelheim – Consultant, personal fees. Bristol Myers Squibb – Consultant. Celgene – Consultant, personal fees. Celltrion Healthcare – Consultant, Personal fees. Dr Falk Pharma – Consultant. Eli Lilly – Consultant, personal fees. Enthera – Consultant, personal fees. Ferring Pharmaceuticals – Consultant, lecture fees. Gilead – Consultant, lecture fees. Hospira – Consultant, personal fees. Inotrem – Consultant, personal fees. Janssen Pharmaceuticals – Consultant, lecture fees. Johnson & Johnson – Consultant, personal fees. Morphic – Consultant. MSD – Consultant, personal fees. Mundipharma – Consultant, personal fees. Mylan – Consultant, lecture fees. Pfizer – Consultant, lecture fees. Roche – Consultant, personal fees. Sandoz – Consultant, personal fees. Sublimity Therapeutics – Consultant, personal fees. Takeda – Consultant, lecture fees. Teladoc Health – Consultant. TiGenix – Consultant, personal fees. UCB – Consultant, personal fees. Vial – Consultant. Vifor – Consultant, personal fees.

Séverine Vermeire: AbbVie – Consultant, Grant/Research Support. AbolerIS Pharma – Grant/Research Support. AgomAb – Grant/Research Support. Alimentiv – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. Avaxia Biologics – Consultant. Boehringer Ingelheim – Consultant. Bristol Myers Squibb – Consultant. Celgene – Consultant. CVasThera – Consultant, Speakers Bureau. Cytoki Pharma – Consultant, Speakers Bureau. Dr. Falk Pharma – Consultant, Speakers Bureau. Eli Lilly – Consultant, Speakers Bureau. Ferring Pharmaceuticals – Consultant, Speakers Bureau. Galapagos – Consultant, Grant/Research Support, Speakers Bureau. Genentech/Roche – Consultant, Speakers Bureau. Gilead – Consultant, Speakers Bureau. GSK – Consultant, Speakers Bureau. Hospira – Consultant, Speakers Bureau. IMIDomics – Consultant, Speakers Bureau. Janssen Pharmaceuticals – Consultant, Speakers Bureau. Johnson & Johnson – Consultant, Grant/Research Support, Speakers Bureau. Materia Prima – Consultant, Speakers Bureau. MiroBio – Consultant, Speakers Bureau. Morphic – Consultant, Speakers Bureau. MRM Health – Consultant, Speakers Bureau. MSD – Consultant, Speakers Bureau. Mundipharma – Consultant, Speakers Bureau. Pfizer – Consultant, Grant/Research Support, Speakers Bureau. ProDigest – Consultant, Speakers Bureau. Progenity – Consultant, Speakers Bureau. Prometheus – Consultant, Speakers Bureau. Robarts Clinical Trials – Consultant, Speakers Bureau. Second Genome – Consultant, Speakers Bureau. Shire – Consultant, Speakers Bureau. Surrozen – Consultant, Speakers Bureau. Takeda – Consultant, Grant/Research Support, Speakers Bureau. Theravance Biopharma – Consultant, Speakers Bureau. Tillotts Pharma – Consultant, Speakers Bureau. Zealand Pharma – Consultant, Speakers Bureau.

Britta Siegmund: Abbvie – Consultant, Speakers Bureau. Arena – Consultant. Boehringer Ingelheim – Consultant. Bristol Myers Squibb – Consultant. CED Service GmbH – Speakers Bureau. Celgene – Consultant. Eli Lilly – Consultant. Endpoint Health – Consultant. Falk Pharma – Consultant, Speakers Bureau. Ferring – Speakers Bureau. Galapagos – Consultant, Speakers Bureau. Janssen – Consultant, Speakers Bureau. Pfizer – Consultant, Speakers Bureau. PredictImmune – Consultant. Prometheus – Consultant. Takeda – Consultant, Speakers Bureau.

Florian Rieder: 89Bio – Advisory Committee/Board Member, Consultant. Abbvie – Advisory Committee/Board Member, Consultant. Adnovate – Advisory Committee/Board Member, Consultant. Agomab – Advisory Committee/Board Member, Consultant. Allergan – Advisory Committee/Board Member, Consultant. Arena – Advisory Committee/Board Member, Consultant. Boehringer Ingelheim – Advisory Committee/Board Member, Consultant. CDISC – Advisory Committee/Board Member, Consultant. Celgene/Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Ferring – Advisory Committee/Board Member, Consultant. Galapagos – Advisory Committee/Board Member, Consultant. Galmed Pharmaceuticals – Advisory Committee/Board Member, Consultant. Genentech – Advisory Committee/Board Member, Consultant. Gilead – Advisory Committee/Board Member, Consultant. Gossamer – Advisory Committee/Board Member, Consultant. Guidepoint – Advisory Committee/Board Member, Consultant. Helmsley – Advisory Committee/Board Member, Consultant. Horizon Therapeutics – Advisory Committee/Board Member, Consultant. Image Analysis Limited – Advisory Committee/Board Member, Consultant. Index Pharmaceuticals – Advisory Committee/Board Member, Consultant. Janssen – Advisory Committee/Board Member, Consultant. Koutif Therapeutics – Advisory Committee/Board Member, Consultant. Mestag Therapeutics – Advisory Committee/Board Member, Consultant. Metacrine – Advisory Committee/Board Member, Consultant. Morphic Therapeutic – Advisory Committee/Board Member, Consultant. Organovo – Advisory Committee/Board Member, Consultant. Origo – Advisory Committee/Board Member, Consultant. Pfizer – Advisory Committee/Board Member, Consultant. Pliant – Advisory Committee/Board Member, Consultant. Prometheus Biosciences – Advisory Committee/Board Member, Consultant. Receptos – Advisory Committee/Board Member, Consultant. REDX – Advisory Committee/Board Member, Consultant. Roche – Advisory Committee/Board Member, Consultant. Samsung – Advisory Committee/Board Member, Consultant. Surmodics – Advisory Committee/Board Member, Consultant. Surrozen – Advisory Committee/Board Member, Consultant. Takeda – Advisory Committee/Board Member, Consultant. TD Cowen – Advisory Committee/Board Member, Consultant. Techlab – Advisory Committee/Board Member, Consultant. Theravance – Advisory Committee/Board Member, Consultant. Thetis Pharmaceuticals – Advisory Committee/Board Member, Consultant. UCB – Advisory Committee/Board Member, Consultant. Ysios Capital – Advisory Committee/Board Member, Consultant.

Stefan Schreiber: AbbVie – Consultant, Speakers Bureau. Arena – Consultant. Biogen – Advisory Committee/Board Member, Consultant. Bristol Myers Squibb, – Consultant, Speakers Bureau. Celgene – Consultant. Celltrion – Advisory Committee/Board Member, Consultant. Eli Lilly – Consultant, Speakers Bureau. Falk Pharma – Consultant, Speakers Bureau. Fresenius – Consultant. Galapagos/Gilead – Consultant, Speakers Bureau. Hikma – Consultant, Speakers Bureau. IMAB – Advisory Committee/Board Member, Consultant. Janssen – Consultant, Speakers Bureau. MSD – Consultant, Speakers Bureau. Mylan – Advisory Committee/Board Member, Consultant. Pfizer – Consultant, Speakers Bureau. Protagonist – Consultant. Provention Bio – Consultant. Takeda – Consultant, Speakers Bureau. Theravance – Consultant.

Simon Lichtiger: Landos Biopharma – Consultant, Employee, Stock-publicly held company(excluding mutual/index funds).

Rebecca Mosig: Landos Biopharma – Employee, Stock Options.

Fabio Cataldi: Landos Biopharma – Employee, Stock-publicly held company(excluding mutual/index funds).

Bram Verstockt: Abbvie – Consultant, Grant/Research Support, Speakers Bureau. Alimentiv – Consultant. Applied Strategic – Consultant. Atheneum – Consultant. Biogen – Speakers Bureau. Biora Therapeutics – Consultant, Grant/Research Support. BMS – Consultant, Speakers Bureau. Celltrion – Speakers Bureau. Chiesi – Speakers Bureau. Dr. Falk Pharma – Speakers Bureau. Ferring – Speakers Bureau. Galapagos – Consultant, Speakers Bureau. Guidepoint – Consultant. Inotrem – Consultant. Ipsos – Consultant. Janssen – Consultant, Speakers Bureau. MSD – Speakers Bureau. Mylan – Consultant. Pfizer – Grant/Research Support, Speakers Bureau. Progenity – Consultant. R-Biopharma – Speakers Bureau. Sandoz – Consultant. Sossei Heptares – Consultant, Grant/Research Support. Takeda – Consultant, Grant/Research Support, Speakers Bureau. Tillots – Consultant. Viatris – Consultant, Speakers Bureau.

Silvio Danese, MD, PhD¹, Séverine Vermeire, MD, PhD², Britta Siegmund, MD, PhD³, Florian Rieder, MD⁴, Stefan Schreiber, MD⁵, Simon Lichtiger, MD⁶, Rebecca Mosig, PhD⁷, Fabio A. Cataldi, MD⁷, Bram Verstockt, MD, PhD⁸. P3548 - Target Engagement and Pharmacodynamic Molecular Mechanism Evaluation in a Phase 1b Study of the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat Containing X1 (NLRX1) Agonist NX-13 in Ulcerative Colitis, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.