NIMML Announces Publication of New Mechanistic Insights on the Metabolic Control of Inflammation and Infection in Scientific Reports
This study provides a use case for applying the TITAN-X platform and its advanced M2 Pipeline metabolic modeling capabilities to analyzing host responses to infection and inflammation
Clostridiodes difficile infection (CDI) induces a biphasic host metabolic response at the colon that shifts from a glycolytic dominance during peak of inflammation to enhanced mitochondrial metabolism during disease recovery and tissue healing phase
Inhibition of glycolysis ameliorates disease severity and colitis in a mouse model of CDI while protecting the epithelial barrier from the deleterious effects of toxins
These new mechanistic insights postulate novel host-targeted, broad-based therapeutic approaches that modulate host metabolic responses for treating infection and inflammation
Blacksburg VA, September 12, 2023 – The NIMML Institute (“NIMML”), a 501 (c) (3) nonprofit foundation dedicated to the discovery of novel precision medicines for infectious and autoimmune diseases, today announced the publication of a seminal article that reports the therapeutic potential of immunometabolic reprograming of the mucosal host responses to Clostridioides difficile infection (CDI). These novel findings were published in Scientific Reports.
“The high recurrence rates associated with the current standard of care for CDI highlight the urgent unmet medical need to develop more effective, antimicrobial-free therapeutic alternatives,” said Dr. Raquel Hontecillas, Chief Scientific Officer and corresponding author of the study. “Our recent publication highlights the potential of host-centered therapeutics that modulate the mucosal response to treat a broad range of infections by supporting novel pharmacological strategies targeting mechanisms at the intersection of immunity and metabolism.”
The study was conducted with a comprehensive, systems-wide bioinformatics analysis and computational modeling of metabolic host responses to infection, while leveraging NIMML’s advanced M2 pipeline and TITAN-X precision medicine platform. The subsequent analysis unveiled details on the host metabolic profile, characterized by increased activity of glycolytic pathways during the acute phase of infection, when the effector immune mechanisms are activated. Mitochondrial metabolism was favored during the tissue healing and resolution phase.
“This publication builds upon NIMML’s mission of conducting innovative, cutting-edge research aimed at developing innovative precision medicines for infectious and autoimmune diseases,” continued Dr. Hontecillas. “At NIMML, we remain dedicated to applying our first-in-class computational models, proprietary tools and scientific approaches to accelerate the development of safe and effective clinical countermeasures.”
The computational predictions were validated in vivo through pharmacological modulation of host metabolism. Indeed, inhibition of glycolysis via oral 2-Deogy-D-glcuose (2-DG) administration decreased disease severity, protected from mortality, and reduced inflammation during infection with a toxin-producing bacteria. At the colonic level, inhibition of glycolysis reduced the infiltration of inflammatory immune cell subsets while downregulating the production of inflammatory mediators and antimicrobial peptides. Notably, the pharmacological downregulation of host glycolytic metabolism also protected epithelial cells from toxin-induced damage, preventing loss of epithelial barrier function and reducing the production of proinflammatory cytokines.
The NIMML Institute has an extensive track record for leading analysis on host responses against enteric pathogens, and in particular C. difficile, as one of four Nationwide NIH Research Centers for Modeling Immunity for Biodefense, as well as under the ongoing research support from the Defense Threat Reduction Agency. A publication in Artificial Intelligence in Medicine details an advanced computational pipeline that combines mechanistic models with stochastic simulation and machine-learning methods to predict efficacy of treatments against CDI. This study proposed for the first time the therapeutic potential of Lanthionine synthetase C-like protein 2 (LANCL2) as a target during CDI. In a paper published in Nature Systems Biology and Applications, the NIMML team characterized the CD4+ T cells response during CDI, using a computational model of CD4+ T cell immune signaling and metabolism. A proceedings paper presented during the 11th International Conference on Bioinformatics and Computational Biology (ICBCB) described how NIMML’s Modeling Metabolism (M2) Pipeline, a novel, disease-agnostic tool, capable to rapidly analyze host metabolic profiles from global transcriptomic datasets was successfully utilized to analyze the host metabolic profile against four viral respiratory infections. In a recent publication in Inflammatory Bowel Diseases, the NIMML team demonstrated for the first time the therapeutic efficacy of oral omilancor, a first-in-class, gut-restricted, oral, once-daily immunoregulatory therapeutic in late stage clinical development for inflammatory bowel disease (IBD) that binds and activates LANCL2, in recurrent CDI plus concomitant CDI and IBD. Additional LANCL2 therapeutics such as NIM-1324 are currently in development for treating rheumatic diseases. The NIMML Institute is partnering with NImmune Biopharma to advance precision medicine research.
NIM-1324 is an oral, systemically distributed, small-molecule therapeutic candidate which activates LANCL2, a surface membrane-associated receptor that is responsible for modulating key cellular and molecular changes tied to autoimmune diseases. By activating the LANCL2 pathway, NIM-1324 increases the anti-inflammatory capacity and stability of regulatory CD4+ T cells while also supporting the metabolic demands of autophagy in phagocytes. To date, treatment with NIM-1324 has reduced the production of interferon alpha in human peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and provided protection from clinical disease and tissue pathology in mouse models of lupus, rheumatoid arthritis and multiple sclerosis. Phase 2-ready NIM-1324 completed Phase 1 clinical testing where it met all endpoints and demonstrated a dose proportional change in plasma exposure within the therapeutic range with no accumulation. NIM-1324 target U.S. market size is expected to be valued at $226.0 billion 2021-2030, of which a peak annual market size of $23.1 billion is expected to occur in 2030. NImmune expects unadjusted revenue estimates from all NIM-1324 therapeutics to be valued at $2.3 billion from the 2028-2030 projections.
By activating the LANCL2 pathway and modulating the interactions between immunological and metabolic signals in immune and epithelial cells, omilancor is a first-in-class, oral, once-daily, gut restricted therapeutic designed to create a favorable regulatory microenvironment in the gut, decreasing the production of key inflammatory mediators and increasing anti-inflammatory functions in regulatory T cells (Treg) within the site of inflammation. Omilancor has completed Phase 2 clinical testing in UC patients showing a clinical remission of 30.4% with a placebo-adjusted 12-week clinical remission rate of 26.7% (p=0.01) for the 440 mg dose. Following demonstration of a statistically significant approvable primary endpoint for clinical remission in an active disease patient population, NImmune expects to initiate a global pivotal Phase 3 program (PACIFY I and PACIFY II trials) in UC patients in the second half of 2023. Omilancor’s target U.S. market size is expected to be valued at $394.9 billion 2021-2030, of which a peak annual market size of $49.5 billion is expected to occur in 2030. NImmune expects peak unadjusted revenue of $12.5 billion in 2030.
About NImmune Biopharma
NImmune is a late-stage precision immunology biopharmaceutical company that develops novel best-in-class biomarker-driven immunoregulatory therapeutics. Underpinned by a discovery platform that utilizes advanced computational modeling, A.I. and bioinformatics coupled with biomedical research capabilities to pioneer innovation in immunoregulatory drug development, NImmune’s business model enables the rapid and capital-efficient clinical development of high conviction drug candidates into New Drug Application (NDA) filing and commercialization. The lead product candidate from NImmune’s internal discovery platform is omilancor, a wholly-owned Phase 3 oral, once-daily, gut-restricted, first-in-class therapeutic targeting LANCL2 for Ulcerative Colitis, with fast follower potential in Crohn’s disease, Psoriasis and other autoimmune diseases. Phase 2 first-in-patient data for omilancor in UC show potential best in class efficacy and safety. Additional information: www.NIMMUNEBIO.COM or contact firstname.lastname@example.org.
The NIMML Institute is a 501 (c) (3) non-profit foundation focused on applying transdisciplinary, team-science approaches to precision medicine. The NIMML Institute applies its TITAN-X advanced A.I. platform to large-scale transdisciplinary projects aimed at solving important public health problems through precision medicine. NIMML combines the expertise of immunologists, computational biologists, toxicologists, computational modelers, translational and clinical researchers, and molecular biologists to translate novel scientific discoveries into medicines for human diseases. The Institute is headquartered in Blacksburg, VA. For more information, please visit www.nimml.org or contact email@example.com.
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