Elaspol (sivelestat) / Ono Pharma - LARVOL DELTA

Lipid nanoparticles carrying neutrophil extracellular trap inhibitors specifically target lung neutrophils and prevent COVID-19-associated lung injury in mice (IMMUNOLOGY 2025) - "In this study, we designed a lipid nanoparticle (LNP) platform to deliver two established neutrophil extracellular trap (NET) inhibitors, DNase I and Sivelestat, referred to as DPNLNPs, specifically to lung neutrophils...Together, this study serves as proof-of-concept for adapting the LNP platform to deliver NET-targeted drugs to lung neutrophils. This preclinical evaluation highlights the potential of targeting neutrophils as an alternative strategy to reduce inflammation and fibrosis in COVID-19."

Late-breaking abstract • Preclinical • Fibrosis • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Lipid nanoparticles target neutrophils to reduce SARS-CoV-2-induced lung injury and inflammation. (PubMed, J Control Release) - "This study presents a lipid nanoparticle (LNP) platform designed to deliver two established NET inhibitors, DNase I and Sivelestat (Siv) referred to as DPNLNPs, specifically to lung neutrophils...Importantly, DPNLNP treatment only during the symptomatic phase of infection improved SARS-CoV-2 outcome revealing the complex role of NETs in COVID-19 pathogenesis. Together, this study serves as a proof-of-concept for adapting the LNP platform to deliver more than one immunomodulatory drug in a cell-specific manner to manage NET-associated complications in COVID-19 and other respiratory diseases."

Journal • Fibrosis • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

DSS-induced colitis exacerbates Alzheimer's pathology via neutrophil elastase and cathepsin B activation. (PubMed, Int Immunopharmacol) - "Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CTSB • ELANE

Neutrophil extracellular traps associated RNA impedes CD4+ Treg differentiation by TLR7-IRF7 axis in ankylosing spondylitis. (PubMed, Arthritis Rheumatol) - "Elevated NETs impeded CD4+ Treg differentiation by activating the TLR7-IRF7 axis via their associated RNA in AS, and targeting NETs may be a novel treatment strategy for AS and related inflammatory disorders."

Journal • Ankylosing Spondylitis • Immunology • Inflammation • Inflammatory Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CD4 • ELANE • IRF7 • TLR7

Sivelestat sodium regulates cellular inflammatory factors and immune markers in the treatment of acute severe pancreatitis (ChiCTR) - P=N/A | N=60 | Recruiting | Sponsor: Dazhou Central Hospital; Dazhou Central Hospital

New trial • Pancreatitis

Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) on Oxygenation in Patients with Sepsis-Induced Acute Respiratory Distress Syndrome. (PubMed, J Inflamm Res) - "The Kaplan-Meier curves showed a significantly improved 28-day survival rate in patients receiving sivelestat than those not (hazard ratio, 0.32; 95% CI, 0.11 to 0.95; p=0.041). In patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first five days and may be associated with decreased 28-day mortality."

Clinical • Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Septic Shock • ELANE

A single-center, prospective, open-label study of the efficacy of sivelestat sodium in patients with post-surgical acute lung injury (ChiCTR) - P=N/A | N=60 | Not yet recruiting | Sponsor: Shaoxing People's Hospital; Shaoxing People's Hospital

New trial • Acute Lung Injury • Respiratory Diseases

Cohort Study on the Effectiveness and Safety of Sivelestat Sodium in the Treatment of Respiratory Failure Caused by Community-Acquired Pneumonia (ChiCTR) - P=N/A | N=1000 | Not yet recruiting | Sponsor: The First Affiliated Hospital of China Medical University; The First Affiliated Hospital of China Medical University

New trial • Infectious Disease • Pneumonia • Respiratory Diseases

Lipid Nanoparticles Targeting Neutrophil and NETs to Mitigate Lung Injury in SARS-CoV-2 Mice (CROI 2025) - "Methods The lipid nanoparticle (LNP) platform designed to deliver two NET inhibitors, DNase I and Sivelestat (Siv), referred to as DPNLNPs, specifically to lung neutrophils...Importantly, DPNLNP treatment only during the symptomatic phase of infection improved SARS-CoV-2 outcome revealing the complex role of NETs in COVID-19 pathogenesis. Conclusions Together, this study serves as a proof-of-concept for adapting the LNP platform to deliver more than one immunomodulatory drug in a cell-specific manner to manage NET-associated complications in COVID-19 and other respiratory diseases."

Late-breaking abstract • Lipid Nanoparticle • Preclinical • Fibrosis • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Acute Respiratory Distress Syndrome Following Minimally Invasive Cardiac Surgery. (PubMed, Cureus) - "Inhalation of nitric oxide, methylprednisolone, and Sivelestat were initiated...She remained stable in the general ward and was transferred for rehabilitation. Early diagnosis and intervention are key for favorable outcomes in these cases."

Journal • Acute Respiratory Distress Syndrome • Cardiovascular • Pulmonary Disease • Respiratory Diseases

Efficacy of sivelestat in alleviating postoperative pulmonary injury in patients with acute aortic dissection undergoing total arch replacement: a retrospective cohort study. (PubMed, BMC Cardiovasc Disord) - "Among patients with AAD with mild or moderate preoperative lung injury, defined by a low P/F ratio, sivelestat significantly improved the postoperative P/F ratio and attenuated inflammatory responses after TAR. These findings suggest an important avenue for further research."

Journal • Retrospective data • Inflammation • Pulmonary Disease • Respiratory Diseases • CRP

The Protective Effects of Sivelestat Sodium on the Basis of Corticosteroid Therapy in Patients With Moderate-to-Severe Acute Respiratory Distress Syndrome. (PubMed, Emerg Med Int) - "It might be advisable to avoid CTSSS in moderate-to-severe ARDS patients aged 80 years or older. Prospective studies involving larger sample sizes are needed to verify these findings."

Journal • Acute Respiratory Distress Syndrome • Critical care • Pulmonary Disease • Respiratory Diseases

A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis. (PubMed, Exp Mol Med) - "Strategies to correct A1AT dysregulation, such as A1AT supplementation or PR3 inhibition with sivelestat, may offer protection against the development and progression of MASH and fibrosis...PR3 cleaves IL-32γ, transforming it from an anti-inflammatory and antifibrogenic cytokine into a potent activator of KCs and failing to prevent HSC activation. This cascade amplifies liver inflammation and fibrosis, suggesting that targeting the A1AT/PR3/IL-32γ axis could be a strategy for treating MASH."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • CCR2 • IL1B • IL32 • SERPINA1

Population pharmacokinetics of sivelestat in Chinese patients with severe pneumonia. (PubMed, Fundam Clin Pharmacol) - "In conclusion, our findings suggest that the CL/F in patients with severe pneumonia is similar to that in healthy individuals. TBIL can affect CL/F of sivelestat; therefore, TBIL-based dosing regimens provide a practical strategy for achieving sivelestat therapy."

Journal • PK/PD data • Infectious Disease • Pneumonia • Respiratory Diseases • ELANE • STAT3

Elastase Mediated White Matter Damage in Cerebral Small Vessel Disease: Microglia - Neutrophils Pas De Deux (ISC 2025) - "This study provides new insights into the pathogenetic mechanism of microglia-derived ELANE acting in conjunction with neutrophil elastase to induce oligodendrocyte damage and the development of WMLs, identifying ELANE as a promising therapeutic target for managing small vessel disease and vascular dementia."

Late-breaking abstract • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Solid Tumor • Vascular Neurology • ELANE • OLIG2

Lung-homing nanoliposomes for early intervention in NETosis and inflammation during acute lung injury. (PubMed, Nano Converg) - "Here we report a pulmonary targeting lung-homing nanoliposome (LHN) designed to attenuate excessive Neutrophil Extracellular Trap formation (NETosis) through sivelestat and DNase-1, coupled with an anti-inflammatory effect mediated by 25-hydroxycholesterol (25-HC), offering a promising intervention for the acute phase of ALI...Also, attenuation of systemic inflammatory response syndrome (SIRS), with notable reductions in NETosis and neutrophil trafficking was investigated. This presents a targeted therapeutic approach that can be applied in early stages of high-risk patients to prevent severe pulmonary disease progression."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Systemic Inflammatory Response Syndrome

Anti-IL-5 treatment, but not neutrophil interference, attenuates inflammation in a mixed granulocytic asthma mouse model, elicited by air pollution. (PubMed, Respir Res) - "Inhibition of IL-5 signalling, but not neutrophil interventions, significantly attenuates eosinophilic inflammation in a mouse model of mixed granulocytic asthma, elicited by air pollution exposure."

Journal • Preclinical • Asthma • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE • IL5

Evaluation of Neutrophil Elastase Inhibitors as Potential Therapies for ELANE Associated Neutropenia. (PubMed, J Cell Immunol) - "In contrast, other NE inhibitors, i.e., sivelestat, BAY-678, and GW311616 and the DPP1 inhibitor, brensocatib, showed no effect on neutrophil differentiation. Molecular docking studies showed that MK0339 binds to an alternative site on the NE protein compared to other inhibitors with greater inhibitor-NE protein stability, suggesting a unique mechanism of action and supporting further investigation of MK0339 as a therapy for ELANE associated neutropenia."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Musculoskeletal Pain • Myelodysplastic Syndrome • Neutropenia • Oncology • Pain • Transplantation • CD14 • CD34 • CEACAM8 • ELANE • ITGAM

Sivelestat sodium protects against renal ischemia/reperfusion injury by reduction of NETs formation. (PubMed, Arch Biochem Biophys) - "Sivelestat sodium ameliorates renal IRI by downregulating neutrophil NETs, reducing inflammation, oxidative stress, and apoptosis, thereby enhancing renal function."

Journal • Acute Kidney Injury • Cardiovascular • Nephrology • Oncology • Renal Disease • Reperfusion Injury • ELANE • IL6 • KIM1 • LCN2 • TNFA

The impact of perioperative administration of sivelestat sodium on liver and kidney function in patients undergoing cardiac surgery in the early postoperative period (ChiCTR) - P4 | N=84 | Sponsor: The First Affiliated Hospital of Guangxi Medical University; The First Affiliated Hospital of Guangxi Medical University

New P4 trial • Cardiovascular • Heart Failure • IL6

A multicenter, prospective, double-blind, randomized controlled trial of sivelestat sodium in patients with brain injury and ARDS (ChiCTR) - P4 | N=54 | Sponsor: The First Affiliated Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital, Zhejiang University School of Medicine

New P4 trial • Acute Respiratory Distress Syndrome • CNS Disorders • Pulmonary Disease • Respiratory Diseases • Vascular Neurology

Neutrophil elastase inhibitor (Sivelestat) in the treatment of acute respiratory distress syndrome induced by COVID-19: a multicenter retrospective cohort study. (PubMed, Respir Res) - "Among patients with ARDS induce by COVID-19, sivelestat administration is associated with improved clinical outcomes."

Journal • Retrospective data • Acute Respiratory Distress Syndrome • Critical care • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • ELANE

Neutrophil Elastase as A Potential Target in Ischemia-Reperfusion Injury. (PubMed, Curr Vasc Pharmacol) - "Furthermore, we highlight the key question, the balance of NE and NE inhibitors, and propose new research directions. This review is useful for understanding the intrinsic interplay between NE and I/R injury-related diseases and expects to facilitate the development of effective NE inhibitors applied for I/R injury."

Journal • Cardiovascular • Inflammation • Myocardial Infarction • Reperfusion Injury • ELANE

A novel biomarker of COVI-19: MMP8 emerged by integrated bulk RNAseq and single-cell sequencing. (PubMed, Sci Rep) - "Sivelestat sodium (SS) is indicated as an effective cure for lung dysfunction, a characteristic symptom of COVID-19 infection, but its pharmacological target is still unclear...MMP8-positive myelocytes interacted with other cell types through RETN-TLR4 and RETN-CAP1 ligand-receptor patterns. These findings emphasize the important role of MMP8 in COVID-19 progression and provide a potential therapeutic target for COVID-19 patients."

Biomarker • Journal • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • MMP8 • RETN • TLR4

Deciphering Genotype-Phenotype Correlations and the Mechanism of the Action of Neutrophil Elastase Inhibitors during ELANE Associated Neutropenia Utilizing Molecular Modeling Software (ASH 2024) - "Molecular docking analysis of 4 small molecule, cell permeable NE inhibitors (MK0339, sivelestat, GW311616, BAY-678) and inactive control, BAY-677, revealed an alternative binding site for MK0339 inhibitor compared to all others. Conclusions : Molecular modeling software analysis of the effect of high- and low-risk mutations on NE protein structure may be key for understanding genotype-phenotype correlations for ELANE associated neutropenia. The current results of molecular docking and inhibitor-protein complex analysis via molecular modeling software correlates with our previous studies and suggests that MK0339 forms a much more stable complex with w-type and mutant NE protein compared to the other inhibitors tested, a valuable insight for developing a therapeutic agent for ELANE associated neutropenia."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • ELANE