reparixin (DF 1681Y) / Dompe - LARVOL DELTA

Megakaryocytes engage in emperipolesis with neutrophils and emperipolesis by the immune MK subset leads to efferocytosis and is exacerbated by CXCR1/2 activation in myelofibrosis (ASH 2025) - "In selected experiments, thecocultures were performed with Reparixin (10μM), the inhibitor of CXCR1/CXCR2, or the CD41pos cellswere also labeled with CD53-647 which recognizes the immune-subpopulation...In summary, we conclude that 1) all MK subpopulations engage inemperipolesis with neutrophils but only the immune-MK engage in emperipolesis associated withefferocytosis; 2) due to CXCR1/CXCR2 activation, Gata1low immune-MK are more likely to engage inefferocytosis than the wild-type ones, and this susceptibility decrease with age. In future studies we willinvestigate whether, in contrast to conventional models, MK efferocytosis protects Gata1low mice fromthe development of fibrosis in the bone marrow."

Fibrosis • Immunology • Myelofibrosis • CD53 • CXCL1 • CXCR1 • ITGA2B • ITGAM

Phase II study of reparixin in patients with myelofibrosis. myeloproliferative neoplasms research consortium (MPN-RC) 120 trial (ASH 2025) - P2 | "MPN Research Consortium (MPN-RC) 120 is currently enrolling patients through the MPN-RC clinical sitesthroughout the United States. Clinical Trial Identifier: NCT05835466"

Clinical • P2 data • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • CD34 • CXCL8 • CXCR1

Interleukin-8 inhibition by reparixin protects megakaryocytes and alleviates thrombocytopenia in Acute Myeloid Leukemia (ASH 2025) - "Leukemia was validated by bi-daily complete blood count and marrow GFP⁺ blast quantification.The mice then received azacitidine+venetoclax±reparixin until chemotherapy completion andhematologic recovery, with analyses mirroring those in model 1.ResultsIn wild-type C57BL/6 mice, flow cytometric analysis of bone marrow-derived cells revealed that,compared with vehicle control treatment, IL-8 administration markedly reduced the number of CD41⁺MKs (P = 0.0079). This increaseextended to total MK counts and the fraction of terminally differentiated CD41⁺CD42b⁺ MKs, displaying aprotective effect of reparixin on megakaryocytic development and highlighting its potential therapeuticvalue in mitigating thrombocytopenia.ConclusionsThe findings suggest that systemic IL-8 suppresses megakaryocytopoiesis and platelet production,prolonging the bleeding time, similar to AML pathology. In a humanized AML model, reparixin added toazacitidine/venetoclax preserved MK maturation during..."

Acute Myelogenous Leukemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Primary Immunodeficiency • Thrombocytopenia • CXCL8 • CXCR1 • CXCR2 • ITGA2B

NRAS mutation drives excessive netosis and differentiation syndrome in acute promyelocytic leukemia (ASH 2025) - "Background Acute promyelocytic leukemia (APL) is highly curable with all-trans retinoic acid (ATRA) and arsenictrioxide (ATO)...Inhibitors targeting CXCR1/2 (Reparixin), NE(Sivelestat), MEK(Trametinib), PAD4(GSK484), and JAK1/2 (Ruxolitinib) were applied to evaluate their inhibitory effects onNETosis and differentiation...Targeting this pathway with reparixin or sivelestatattenuates NET formation without compromising cell differentiation, offering a promising therapeuticstrategy to mitigate DS-induced tissue damage while preserving anti-leukemic efficacy. These findingsprovide mechanistic insights into NRAS-driven inflammation in APL and support NETs-targeted therapyfor prophylaxis of DS."

Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Thrombosis • ANXA5 • CXCL8 • CXCR1 • ICAM1 • ITGAM • JAK1 • JAK2 • NRAS • VCAM1

Primary Amine-Catalyzed Enantioselective Fluorination of α-Branched Aldehydes with Low Catalyst Loadings. (PubMed, J Org Chem) - "Furthermore, as a synthetic application, the enantioselective syntheses of fluorine-containing biologically active pharmaceuticals─such as LY50340, α-fluorinated NSAIDs, and α-fluorinated reparixin─were successfully demonstrated. DFT calculations revealed that cumulative steric repulsions among the phenyl groups of NFSI, the enamine, and the catalyst are critical for achieving high enantioselectivity."

Journal

IL-8-Induced Tumor Self-Rampart Spatially Confines Oncolytic Virotherapy in Glioblastoma. (PubMed, Neuro Oncol) - "Glioblastoma mounts a spatial self-protective defense through IL-8-driven TSR formation that restricts oncolytic virus spread. IL-8 functions as both a pharmacodynamic biomarker and a therapeutic target, and its inhibition provides a rational strategy to overcome resistance and optimize GBM virotherapy."

IO biomarker • Journal • Brain Cancer • Fibrosis • Glioblastoma • Infectious Disease • Oncology • Solid Tumor • CXCL8

Fusobacterium nucleatum drives gastric cancer metastasis via Gbp-CypA-NF-κB-mediated CXCL8 crosstalk between tumor cells and mast cells. (PubMed, Cell Commun Signal) - "In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn."

Journal • Gastric Cancer • Oncology • Solid Tumor • CXCL8

Distinctive Alterations in the Emperipolesis between Neutrophils and Megakaryocytes from the Bone Marrow of Gata1low Mice Documented By Time-Lapse Observations (ASH 2024) - "The discovery that the MK from these patients express an IL-8 (CXCL1 in the mouse) signature3, a potent chemo-attractant for Neu4, lead us to discovery that treatment of the Gata1low mouse model with Reparixin, an inhibitor of CXCR1/CXCR2 (the CXCL1 receptors), rescues both fibrosis and pathological MK-Neu emperipolesis in their bone marrow5...6.Huang FY et al. Blood Adv 2022; 6 : 2081."

Preclinical • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ATG3 • ATG7 • CLEC7A • CXCL1 • CXCL8 • CXCR1 • FPR2 • IL1B • ITGA2B • PTEN • RAB27A • SIRPA • SLC11A1 • TLR2

Integrated multi-omics identifies a CD54+ iCAF-ITGAL+ macrophage niche driving immunosuppression via CXCL8-PDL1 axis in cervical cancer. (PubMed, Mol Cancer) - "Therapeutic intervention using the CXCL8-CXCR1/2 inhibitor reparixin disrupted the CXCL8-PD-L1 axis, reduced PD-L1+ macrophage abundance and enhanced CD8+ T cell cytotoxicity. Notably, combination therapy with PD-L1 blockade demonstrated synergistic efficacy. Collectively, our findings reveal a stromal-immune checkpoint axis orchestrated by CD54⁺ iCAFs and ITGAL⁺ macrophages that underpins immunosuppression in CC, thereby providing a translational rationale for stroma-directed combination therapies that may overcome resistance to current immunotherapies."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • CAFs • CCL2 • CD8 • CXCL8 • CXCR1 • ICAM1

Mechanistic pathway analysis of PD-L1 upregulation in Glioblastoma cells following hypofractionated Irradiation (EANO 2025) - "Standard treatment schemes, including surgical resection, temozolomide and radiotherapy, have yielded only modest clinical benefit...This study seeks to identify the signaling pathways responsible for PD-L1 upregulation in GBM after irradiation.Material and We investigated the impact of hypofractionated radiotherapy (2x5Gy) combined with various signaling pathway Inhibitors (Akt-Inhibitor VIII, c-Met-Inhibitor 1, Cobimetinib, Encorafenib, Erlotinib, m-TOR-Inhibitor 3, Vemurafenib and SC79) on the expression profile of the immune checkpoint molecules PD-L1/2 in the murine GBM cell line GL261-luc2 using flow cytometry...Based on the transcriptomic findings, further flow cytometric analyses were conducted to assess the effects of CXCR2 inhibition with Reparixin on PD-L1 regulation... Modulating these pathways post-irradiation may reduce GBM cell radioresistance, necessitating further investigation into potential molecular targets."

IO biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CXCR2 • EGFR

Cytokine Blockade Attenuates Inflammation and Improves Depressive Psychopathology After COVID-19: A Naturalistic Observational Study. (PubMed, J Neuroimmune Pharmacol) - "In the present naturalistic observational study we evaluated the possible effect of the cytokine-blocking agents in preventing the development of post-COVID depression in a large sample of survivors also exploring the relationship between post-COVID depressive risk, treatment with cytokine-blocking agents, and innate immune response markers. 588 COVID-19 survivors were included, of them 374 received the best available treatment at the time and 131 received standard treatment combined with cytokine-blocking agents (anakinra, tocilizumab, sarilumab, reparixin and mavrilimumab). Finally, we observed that cytokine-blocking agents' impact on depression was mediated by lowering of systemic inflammation. Our findings indicate potential efficacy of cytokine-blocking agent treatment during the early stages of COVID-19, mitigating post-COVID depressive symptoms by attenuating systemic inflammation. Further investigation through preclinical and clinical studies is..."

Journal • Observational data • CNS Disorders • Depression • Infectious Disease • Inflammation • Novel Coronavirus Disease • Psychiatry

Reparixin in Patients With Myelofibrosis Myeloproliferative Neoplasms Research Consortium (MPN-RC 120) (clinicaltrials.gov) - P2 | N=26 | Recruiting | Sponsor: Icahn School of Medicine at Mount Sinai | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytosis

IMMUNE-MEGAKARYOCYTES ARE RESPONSIBLE FOR THE PATHOLOGICAL INTERLEUKIN-8 DEPENDENT EMPERIPOLESIS WITH NEUTROPHILS ASSOCIATED WITH MYELOFIBROSIS IN GATA1LOW MICE (EHA 2025) - "Selected experiments were performed with Reparixin (10µM), the inhibitor of CXCR1/CXCR2 (expressed at high levels by malignant MK) or the CD53 antibody which recognize the immune MK subpopulation... These data indicate that in the myelofibrosis Gata1low mouse model, MK are enriched for the immune subpopulation which is responsible to activate the CXCL1-dependent pathological emperipolesis which leads to their dead and release of pro-inflammatory cytokines in the microenvironment."

Preclinical • Myelofibrosis • CD53 • CXCL1 • CXCR1 • ITGA2B

The CXCL1-CXCR2 Axis as a Component of Therapy Resistance, a Source of Side Effects in Cancer Treatment, and a Therapeutic Target. (PubMed, Cancers (Basel)) - "It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions."

Adverse events • IO biomarker • Journal • Review • Cardiovascular • Oncology • Pain • CXCL1 • CXCL8 • CXCR2

Downstream Signaling Mediators of CXCL6-driven Synthesis of Collagen in Human Fibroblasts (ATS 2025) - "Doxycycline was used to induce CXCL6 expression and secretion in BJ13 cells. A panel of specific pathway inhibitors were added to cells, including SR11302 (AP1), MK2206 (AKT), SB203850 (p38), SP600125 (JNK), PD184352 (MEK), FASUDIL (ROCK/RHO), SLV2436 (MNK1/2), Omipalisib (mTOR/PI3K), Torin (mTOR), and Reparixin (CXCR1/2)... We identified that CXCL6 induces collagen production through multiple pathways including mTOR, p38, JNK and MEK. Targeting a combination of these pathways may be a potential therapeutic direction for IPF treatment."

Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CXCL6 • CXCR1 • SMAD3 • TGFB1

Add-on Reparixin in Adult Patients With ARDS (clinicaltrials.gov) - P2 | N=66 | Completed | Sponsor: Dompé Farmaceutici S.p.A | Recruiting ➔ Completed | Trial completion date: Aug 2025 ➔ Apr 2025 | Trial primary completion date: Aug 2025 ➔ Mar 2025

Trial completion • Trial completion date • Trial primary completion date • Acute Respiratory Distress Syndrome • Pulmonary Disease • Respiratory Diseases • CXCL8 • ICAM1

Interleukin-8 expression inversely predicts the therapeutic effectiveness of doxorubicin and paclitaxel on triple-negative breast cancer (AACR 2025) - "These findings demonstrated that IL-8 expression could be a useful indicator to predict the responsiveness of TNBC patients who are deciding to receive doxorubicin or paclitaxel therapy."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL8

Reparixin as a Potential Antiepileptogenic Agent: Modulation of the CXCL1-CXCR1/2 Axis and Seizure Activity in a Kindling Rat Model of Temporal Lobe Epilepsy. (PubMed, Int J Mol Sci) - "Levetiracetam, a broad-spectrum antiseizure drug, was administered intraperitoneally (i.p.) as positive control 1 h before each stimulation. Reparixin exhibited antiepileptogenic and partial antiseizure effects by modulating the CXCL1-CXCR1/2 axis and reducing ERK signaling. Already in clinical trials on respiratory diseases, reparixin could be repurposed for epilepsy therapy."

Journal • Preclinical • CNS Disorders • Epilepsy • Inflammation • Respiratory Diseases • CXCL1 • CXCL8 • CXCR1

Inhibition of IL-8/CXCR2 signaling axis prevents tumor growth and metastasis in triple negative breast cancer cells. (PubMed, Pharmacology) - "Our results underscore the significant role of the IL-8/CXCR2 signaling axis in the metastasis of TNBC and suggest that CXCR2 inhibitors such as SB225002 may be promising therapeutic agents for TNBC patients."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • BIRC5 • CXCL8 • CXCR1 • CXCR2 • HER-2 • HIF1A • XIAP

Enhanced Expression of TRIM46 in Ovarian Cancer Cells Induced by Tumor-Associated Macrophages Promotes Invasion via the Wnt/β-Catenin Pathway. (PubMed, Cells) - "Notably, pre-treatment with reparixin, a CXCR1/2 inhibitor, blocked OC-MQ-induced TRIM46 expression and cell invasion. These results suggest that CXCL8 derived from TAMs promotes human ovarian cancer cell invasion via the Wnt/β-catenin pathway by upregulating TRIM46."

Journal • Oncology • Ovarian Cancer • Solid Tumor • CXCL8 • CXCR1 • TRIM4 • TRIM46

Targeting CXCL8 signaling sensitizes HNSCC to anlotinib by reducing tumor-associated macrophage-derived CLU. (PubMed, J Exp Clin Cancer Res) - "Our results provide novel evidence of a feedback loop between cancer cells and TAMs in glucose-deficient regions. HNSCC-derived CXCL8 favors endogenous antioxidative processes and confers therapeutic resistance to nutrient-starvation therapies in HNSCC."

Journal • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • CXCL8

Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. (PubMed, J Diabetes Res) - P, P1/2, P2, P2/3, P3, P4 | "FDA-approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti-CD3 monoclonal antibody), daclizumab (an anti-CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG)...Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA-approved for other uses...This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481,..."

Journal • Review • Diabetes • Immunology • Metabolic Disorders • Transplantation • Type 1 Diabetes Mellitus • CXCR1

Monocyte adhesion to and transmigration through endothelium following cardiopulmonary bypass shearing is mediated by IL-8 signaling. (PubMed, Front Cardiovasc Med) - "Finally, inhibition of HNDMVECs CXCR2/IL-8 receptor with Reparixin and of IL-8 expression with siRNA blocked sheared THP-1 cell adhesion to the endothelial monolayer. These results suggest that CPB-like sheared monocytes promote IL-8 production followed by increased endothelium permeability, and monocyte adhesion and transmigration. This study revealed a novel mechanism of post-CPB inflammation and will contribute to the development of targeted therapeutics to prevent and repair the damage to neonatal patients."

Journal • Inflammation • CDH5 • CXCL8 • ICAM1 • VCAM1

Pilot Study of Reparixin for Early Allograft Dysfunction Prevention in Liver Transplantation (clinicaltrials.gov) - P2 | N=40 | Terminated | Sponsor: Dompé Farmaceutici S.p.A | Completed ➔ Terminated; Taking into account that 5 out of 22 patients in the Reparixin group experienced EAD during the first stage of the study, according to the Protocol and the DMC conclusion, it was decided on the early termination of the study

Trial termination • Cardiovascular • Hepatology • Liver Failure • Reperfusion Injury • Transplantation

Blockade of the Platelet-Driven CXCL7-CXCR1/2 Inflammatory Axis Prevents Murine Cerebral Aneurysm Formation and Rupture. (PubMed, Transl Stroke Res) - "Mice treated with 1 mg/kg clopidogrel develop significantly less aneurysms than controls (18% vs 73%, n = 11 and 11, respectively, p = 0.03)...Targeting CXCL7-CXCR1/2 axis with 10 mg/kg reparixin (CXCR1/2 antagonist) significantly decreases cerebral aneurysm formation (11% vs 73%, n = 9 and 11, p = 0.0098) while treatment with 10 mg/kg SB225002 tends to decrease aneurysm formation (36% vs 73%, n = 11 vs n = 7, p = 0.11)...Platelet inflammation has an important role in cerebral aneurysm formation. Small molecule inhibitors targeting platelet CXCL7-CXCR1/2 inflammatory axis could be used to prevent cerebral aneurysm formation or progression."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertension • Inflammation • Thrombosis • Vascular Neurology • CD31 • CXCR1 • ELANE • PECAM1 • PPBP