eritoran (E5564) / Eisai - LARVOL DELTA

Taking its TOLL: the role of toll-like receptor 4 in human health and disease, and its potential as a therapeutic target. (PubMed, Front Immunol) - "Several TLR4 targeted therapeutics have been developed and studied in animal models, however many of these therapeutics including Eritoran and TAK-242 did not prove to be effective in clinical trials. Overall, TLR4 exhibits context-dependent protective and pathogenic roles across infectious and non-infectious diseases, reflecting the complexity of its signaling in human health and disease."

Journal • Review • Cardiovascular • Infectious Disease • Inflammation • IFNA1 • IFNB1 • IL1B • IL6 • TLR4 • TNFA

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P3 | N=10000 | Recruiting | Sponsor: UMC Utrecht | Phase classification: P4 ➔ P3 | N=7100 ➔ 10000 | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Dec 2021 ➔ Dec 2023

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P4 | N=6800 | Recruiting | Sponsor: MJM Bonten | N=4000 ➔ 6800 | Trial completion date: Feb 2019 ➔ Jun 2022 | Trial primary completion date: Feb 2019 ➔ Dec 2021 | Initiation date: Dec 2015 ➔ Apr 2016

Enrollment change • Trial completion date • Trial initiation date • Trial primary completion date • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P4 | N=7100 | Recruiting | Sponsor: MJM Bonten | Trial completion date: Jun 2022 ➔ Dec 2023

Trial completion date • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P4 | N=4000 | Recruiting | Sponsor: UMC Utrecht

New P4 trial • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P3 | N=10000 | Recruiting | Sponsor: UMC Utrecht | Trial completion date: Dec 2025 ➔ Feb 2028 | Trial primary completion date: Dec 2023 ➔ Feb 2026

Trial completion date • Trial primary completion date • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (clinicaltrials.gov) - P3 | N=20000 | Recruiting | Sponsor: UMC Utrecht | N=10000 ➔ 20000

Enrollment change • Infectious Disease • Influenza • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

On the right TRACK: Providing comprehensive genomic profiling (CGP) and molecular tumor board (MTB) for patients (pts) with rare cancers. (ASCO 2024) - P=N/A | " Pts with rare cancers (incidence<6/100,000) were enrolled and consented remotely (WCG IRB 1287011)... A fully remote, advocacy driven, national precision genomics trial is feasible for managing rare cancers. CGP with expert MTB review can identify potentially targetable alterations and inform therapeutic options."

Clinical • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hematological Disorders • Microsatellite Instability • Oncology • Solid Tumor • CDKN2A • CDKN2B • CHEK2 • DNMT3A • IDH1 • KRAS • MSI • MTAP • TMB • TP53

The Therapeutic Targeting Effect of Toll-Like Receptors and Their Related Signaling Pathways in Cardiomyopathy. (PubMed, Immunol Invest) - "Preclinical investigations demonstrate favorable outcomes from selective pathway modulation, including TLR4 antagonists (such as TAK-242 and eritoran), MyD88 pathway inhibitors, and nucleic-acid-directed TLR9 strategies. Targeting TLR signaling has strong potential to limit inflammation, curb fibrotic remodeling, and preserve cardiac function across diverse cardiomyopathies. The most promising therapeutic direction involves developing subtype-specific and cell- or pathway-targeted interventions, supported by translational research to bridge preclinical findings with clinical application."

IO biomarker • Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Genetic Disorders • Heart Failure • Immunology • Inflammation • Obesity • MYD88 • TLR2 • TLR3 • TLR4 • TLR7 • TLR9

Synthesis and Docking Studies of Glycolipids Inspired by Bacteroides fragilis Lipid A. (PubMed, Molecules) - "Docking results reveal that Tetra C-1 exhibits more favorable antagonist binding characteristics compared to the well-studied TLR4 antagonist Eritoran. This work highlights a microbiota-informed strategy for the development of novel TLR4 antagonists, potentially enabling targeted modulation of innate immunity for therapeutic applications in inflammatory diseases and as vaccine adjuvants."

Journal • Immunology • Inflammation • Septic Shock • TLR4

IG A DEFICIENCY IS NOT ASSOCIATED WITH HIGHER LIVER-RELATED EVENTS IN MASLD/MASH PATIENTS: A MULTI-CENTER ANALYSIS (UEGW 2025) - "No patients from our study developed cirrhosis.Clinical Outcomes MASLD/MASH with IgA Deficiency vs MASLD/MASH controlOutcomesMASLD/MASH with IgA DeficiencyMASLD/MASH controlHR (95% CI)IncludedEventsIncludedEventsHCC67310674101.01 (0.14, 7.19)Hepatic decompensation64614653160.87 (0.42, 1.78)Mortality67229673251.15 (0.67, 1.96)MACE55643550241.79 (1.09, 2.96)CKD51548527540.90 (0.61, 1.33)Abbreviations: MASLD metabolic dysfunction-associated steatotic liver disease; MASH metabolic dysfunction-associated steatohepatitis; HCC hepatocellular carcinoma; MACE major adverse cardiovascular events; CKD chronic kidney disease; HR, hazard ratio; CI, confidence interval; AE, adverse events... Conversely to the expected increase in the liver-related outcomes, IgA deficient patients had no significant risk. Normally, IgA promotes fibrosis through the IgA-FcR signaling axis, and given that IgA is deficient, this condition can theoretically alter the immune landscape in MASLD. Contrarily,..."

Clinical • Addiction (Opioid and Alcohol) • Cardiovascular • Chronic Kidney Disease • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Renal Disease • Solid Tumor

Dietary emulsifier carboxymethylcellulose-induced gut dysbiosis and SCFA reduction aggravate acute pancreatitis through classical monocyte activation. (PubMed, Microbiome) - "This study reveals the detrimental impact of CMC on AP due to gut dysbiosis, with Akkermansia muciniphila or butyrate offering potential therapeutic avenues for counteracting CMC-induced AP exacerbation. Video Abstract."

Journal • Inflammation • Pancreatitis • Transplantation

Population dynamics of sympatric Phortica spp. and first record of stable presence of Phortica oldenbergi in a Thelazia callipaeda-endemic area of Italy. (PubMed, Parasit Vectors) - "For the first time, this study analysed several ecological aspects of Phortica species coexisting in a T. callipeada endemic area, highlighting different behaviors in the same environment and their vectorial role. Notably, this is also the first report of the presence of P. oldenbergi in Italy and P. okadai in Europe, underscoring the importance of extensive sampling for detecting potential vectors and alien species with direct implications for vector-borne disease epidemiology."

Journal • Infectious Disease

THE EFFECT OF TLR4 INHIBITOR AGENTS ON SIZE OF INFARCTION VOLUME AND NEUROLOGICAL FUNCTIONS IN THE RODENT ISCHEMIC STROKE MODELS: A SYSTEMATIC REVIEW (WSC 2024) - "Administration of MTS510 as an anti-TLR4 antibody, miR-542-3p as a TLR4 expression inhibitor, ApTLR#4F and ApTLR#4FT as TLR4-blocking DNA aptamers, TAK-242 and Eritoran (E5564) as TLR4 antagonists, and intracerebroventricular injection of Resatorvid as a TLR4-NOX4 signal inhibitor on the MCAO mice model showed a significant reduction in infarction volume and improvement in neurological function. Conclusions These findings indicate to potential strategies for employing anti-TLR4 agents in various inhibitory categories to cure cerebral ischemic injury along with reperfusion therapy."

IO biomarker • Preclinical • Review • Cardiovascular • Ischemic stroke • Reperfusion Injury • MIR542 • NOX4 • TLR4

Optimization of a Lethal, Combat-Relevant Model of Sterile Inflammation in Mice for Drug Candidate Screening. (PubMed, Mil Med) - "We optimized a TBX mouse model of SIRS/MODS for the purpose of evaluating novel therapeutic interventions to prevent trauma-related pathophysiologies in wounded Service Members. Negative effects of K/X on lethality of TBX should be further evaluated, particularly in the light of widespread use of ketamine in treatment of pain. By mimicking muscle crush, bone fracture, and necrosis, the TBX model has pleiotropic effects on physiology and immunology that make it uniquely valuable as a screening tool for the evaluation of novel therapeutics against trauma-induced SIRS/MODS."

Journal • Preclinical • Anesthesia • Immunology • Inflammation • Musculoskeletal Diseases • Orthopedics • Pain • Systemic Inflammatory Response Syndrome • TLR4

Copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to testicular damage and impaired spermatogenesis in Wilson disease. (PubMed, Chem Biol Interact) - "Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods...PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD."

IO biomarker • Journal • Genetic Disorders • Hepatology • Inflammation • Metabolic Disorders • Movement Disorders • TLR4

Neuroenhancement and mental health in students from four faculties - a cross-sectional questionnaire study. (PubMed, GMS J Med Educ) - "Of the 5564 students who were invited to participate, 1010 completed the questionnaire (18.2%)...NE was used in particular during preparations for exams, to enhance performance, and/or to regulate emotions, most commonly through caffeine tablets, cannabis, and methylphenidate. NE was associated with risky use of alcohol or tobacco, and to a lesser extent with ADHD symptoms and stress experience. Students are at risk of substance abuse and NE. Effective stress management and prevention approaches as well as low-threshold services are needed to identify and support students with risk profiles."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • Substance Abuse

Quality of life (QoL) and toxicity in patients (pts) with hormone receptor-positive, HER2-negative early breast cancer (HR+, HER2– eBC) treated with adjuvant (adj) endocrine therapy (ET) in the CANcer TOxicities (CANTO) study (ESMO 2023) - P=N/A | "Results Of the 5564 pts who met the inclusion criteria (median age: 57 yrs), 63% were post-menopausal and 52% had stage I eBC at diagnosis...This study confirmed long-term toxicity of ET, particularly pain. Better management of symptoms and supportive interventional strategies are needed to further improve QoL in eBC."

Clinical • HEOR • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The TLR4/NF-κB signaling pathway-mediated type 2 skewing of T helper cell in cough variant asthma was counteracted by ethanol extract of Anacyclus pyrethrum root. (PubMed, Immunobiology) - "Subsequently, we proved that TLR4 antagonist E5564 played a similar improvement role to EEAP in Th1/Th2 imbalance, while combination of TLR4 agonist LPS and EEAP abolished the inhibitory effect of EEAP on Th2 polarization in Th2-induced CD4T cells...In a word, EEAP restores Th1/Th2 balance in CVA through restraining the TLR4/NF-кB signaling pathway. This study may contribute to the clinical application of EEAP in CVA-related disease."

Journal • Asthma • Cough • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IFNG • IL13 • IL2 • IL4 • IL5 • IL6 • NF-κβ • TLR4

Quantitative Proteomic Screening Uncovers Diagnostic and Monitoring Serum Biomarkers of Ankylosing Spondylitis (ACR Convergence 2022) - "Figure 1... We identified multiple candidate AS diagnostic and disease activity monitoring serum biomarkers using a comprehensive proteomic screen. Enrichment analysis identified key pathways in AS diagnosis and monitoring. Lasso regression identified candidate diagnostic serum biomarker panels with modest predictive ability."

Biomarker • Ankylosing Spondylitis • Immunology • Inflammatory Arthritis • Rheumatology • Seronegative Spondyloarthropathies • IL10

Increasing Incidence of Large Artery Manifestations in Patients with Giant Cell Arteritis, a Population-based Cohort over 70 Years (ACR Convergence 2022) - "Incidence of large artery manifestations (mainly large artery stenosis) has increased over time likely from increased awareness and greater use of imaging studies. The incidence of aortic aneurysm/dissection has not changed over the last 7 decades. Mortality improvements may be due to earlier detection and identification of large artery manifestations.Figure 1: Cumulative incidence for time to any large artery manifestation in patients with incident GCA 1950-2016 (i.e., earliest of large artery stenosis or aortic aneurysm or aortic dissection) adjusted for the competing risk of death."

Clinical • Cardiovascular • Fatigue • Giant Cell Arteritis • Immunology

Increasing Incidence of Large Artery Manifestations in Patients with Giant Cell Arteritis, a Population-based Cohort over 70 Years (ACR Convergence 2022) - "Incidence of large artery manifestations (mainly large artery stenosis) has increased over time likely from increased awareness and greater use of imaging studies. The incidence of aortic aneurysm/dissection has not changed over the last 7 decades. Mortality improvements may be due to earlier detection and identification of large artery manifestations.Figure 1: Cumulative incidence for time to any large artery manifestation in patients with incident GCA 1950-2016 (i.e., earliest of large artery stenosis or aortic aneurysm or aortic dissection) adjusted for the competing risk of death."

Clinical • Cardiovascular • Fatigue • Giant Cell Arteritis • Immunology

Is SARS-CoV-2 Associated with Worse Outcomes After Total Knee Arthroplasty? (ACR Convergence 2022) - "Previous SARS-CoV-2 infection was not associated with worse pain or function 6 months after TKA. However, a shorter time between TKA and clinical COVID19 was correlated with worse pain and function 6 months after TKA. Larger studies are needed to evaluate whether high-risk patients may benefit from delaying elective TKA 10-12 months after COVID19."

Fatigue • Immunology • Infectious Disease • Neuralgia • Novel Coronavirus Disease • Orthopedics • Osteoarthritis • Pain • Pulmonary Disease • Respiratory Diseases • Rheumatology

Responsiveness of the Patient Reported Outcomes Measurement Information System (PROMIS) Computerized Adaptive Test (CAT) Measures in a Single Canadian Lupus Cohort (ACR Convergence 2022) - "PROMIS CAT detected improvement and worsening over time in most domains in patients with SLE in concordance with the external anchors, supporting its responsiveness in this population for most but not all types of change.Table 1. Cohort Characteristics at Baseline (n=108)Table 2. Results of Responsiveness at 6 MonthsSpearman correlation: *moderate: 0.3-0.7; **strong: >0.7"

Clinical • Patient reported outcomes • CNS Disorders • Depression • Fatigue • Immunology • Inflammatory Arthritis • Lupus • Mood Disorders • Pain • Psychiatry • Sleep Disorder • Systemic Lupus Erythematosus

Unsupervised Cluster Analysis of Clinical and Ultrasound Features Reveals Unique Gout Subtypes: Results from the Egyptian College of Rheumatology (ECR) (ACR Convergence 2022) - "SD: standard deviation; WBCs, PLT, ESR, SUA *Cluster 2 vs cluster 1, ** Cluster 3 vs cluster 1, *** Cluster 2 vs cluster 3.Definition: Obesity was defined as body mass index ≥30 kg/m2... Cluster combined clinical and ultrasound findings from adults with gout identified three differentiated subgroups. Ultrasound may help in identifying different disease phenotypes and could support more tailoring of treatments at various stages of gout. Thus, we should pay attention to the musculoskeletal ultrasound findings when treating patients with gout.Acknowledgment: We would like to thank Rasha Fawzy, and Doaa Mosaad."

Clinical • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Genetic Disorders • Gout • Hepatology • Hypertension • Hypertriglyceridemia • Immunology • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Obesity • Renal Disease • Rheumatology