nibrozetone (RRx-001) / EpicentRx, SciClone - LARVOL DELTA

Validation of the clinical stage therapeutic agent RRx-001 as a novel disease-modifying treatment for Amyotrophic Lateral Sclerosis (Neuroscience 2025) - "Together, our results suggest that RRx-001 could be effective in slowing disease progression by blocking both pathological inflammasome activation, and independently, by increasing protective NRF2 in skeletal muscle, blood, and the central nervous system. Given that RRx-001 has been tested in over 300 patients to date, with no dose limiting toxicities or related serious adverse events, our results highlight the prospect of RRx-001 as a new disease-modifying therapeutic for ALS with the potential for rapid clinical translation."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • NLRP3

Dual STING activation and CD47/SIRPα blockade via chitooligosaccharide-based nanoparticles to amplify antitumor immunity. (PubMed, J Control Release) - "To further counter immune evasion, we encapsulated the CD47/SIRPα inhibitor RRX-001 into reactive oxygen species (ROS)-responsive carriers, yielding RRX@RCD...In CT26 tumor-bearing mice, RRX@RCD achieved superior tumor regression, doubled median survival. Overall, RRX@RCD synchronizes innate and adaptive immune activation, offering a safe and potent nanomedicine strategy for durable antitumor immunity."

IO biomarker • Journal • Oncology • CD8 • CXCL10 • SIRPA • STING

Enhancement of Targeted and Antitumor Effects of M1 Macrophages Based on Bioorthogonal Reactions. (PubMed, Mol Pharm) - "Addition of the small-molecule inhibitor RRx-001 further improved the synergistic effect on phagocytosis and immune cell phenotypes in tumors. In summary, our study highlights the metabolic labeling strategy as a potent approach to promote M1 macrophage-mediated antitumor responses within the tumor environment, providing a novel means for the development of therapeutic strategies tailored for solid tumors."

Journal • Oncology • Solid Tumor

Signal Transducer Nanoparticles Enable Siglec-10/G Blockade Immunotherapy for Breast Cancer Treatment. (PubMed, Adv Mater) - "The therapeutic effects can be further improved through encapsulation of RRx-001, a small molecule inhibitor of the CD47-SIRPα signaling. Compared to the antibody approach, the synthetic nanoparticle approach offers greater efficacy with lower side effects and enables combination therapy through a simple formulation. Moreover, the approach is versatile and could be adapted for targeting other ICB signaling, advancing the next generation of cancer immunotherapy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD24 • SIRPA

Biomimetic Delivery of Cisplatin for Efficient Immunotherapy of Gasdermin E-Positive Hepatocellular Carcinoma via a Pt Concentration-Dependent Minimalist Pyroptosis Strategy. (PubMed, Adv Healthc Mater) - "Compared to the classical Gasdermin D (GSDMD)-mediated pyroptosis that has been extensively explored for cancer immunotherapy, the direct induction of Gasdermin E (GSDME) pyroptosis has been rarely reported, likely due to the well-recognized reduced GSDME levels in solid tumors. This nanoplatform, CDDP/1-bromoacetyl-3,3-dinitroazetidine (RRx-001) @iRGD-Pla-Exo nanoparticles (CRRPE NPs) leads to almost complete tumor eradication in a Hepa1-6-luc orthotopic liver cancer model by activating macrophages, and can be combined with the commercially available programmed death ligand 1 (PD-L1) antibody immunomodulator to maintain T cells' effector function for a prolonged survival lifetime. Overall, this study provides a conceptual advance in revealing the role of chemotherapy in mediating tumor cell pyroptosis and immune cell activation."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • GSDME

RRx-001, A Specific Macrophage-Targeted Immunotherapeutic, Orchestrates a Cd45+ Anti-Endometriosis Impact (WCE 2025) - "RRx-001 minimally impacts the endometrium, supporting our previous findings of unaffected fertility. Taken together, RRx-001 represents a promising new therapy for endometriosis and is soon to enter a clinical trial."

IO biomarker • Endometriosis • Gynecology • Pain • Women's Health • PTPRC

Therapeutic Hypothermia and Recombinant Erythropoietin Mitigate Brain Microvascular Endothelial Cell Dysfunction via Modulating the Pentose Phosphate Pathway. (PubMed, J Mol Neurosci) - "Human brain microvascular endothelial cells (HBMECs) underwent oxygen-glucose deprivation (OGD) and were treated with TH and G6PD inhibitor RRx-001...Inhibition of G6PD disrupted the protective effects of TH and EPO on the patency of the PPP and the function of HBMECs, and barrier integrity was further broken. This study reveals that the combination of TH and EPO mitigates microvascular endothelial cell dysfunction via partially modulating the PPP, thus preserving barrier integrity."

Journal • CNS Disorders • Inflammation • Vascular Neurology

Innate immune checkpoint SIRPα/CD47 blockade ameliorates silica-induced pulmonary fibrosis by modulating macrophage immunity. (PubMed, Int Immunopharmacol) - "Using RRx-001 to block SIRPα/CD47 signaling in mice, we observed a marked reduction in lung injury, decreased collagen deposition, and improved pulmonary function...Additionally, levels of soluble SIRPα and CD47 in the peripheral blood of silicosis patients were significantly higher than those in healthy controls. In summary, this study demonstrates that SIRPα/CD47-mediated immunomodulatory signaling is the driving factor for the progression of silicosis, and this pathway might serve as a therapeutic target for silicosis treatment."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CD47 • SIRPA

Nitro-group π system drives the interaction of RRx-001 with solvated electrons in solution. (PubMed, Chemistry) - "Surprisingly, no Br dissociation is observed despite its high electron affinity. We assign this behavior to the "inaccessibility" of sigma virtual states for electrons in the solvent, which can be of a general nature."

Journal

Increased antitumor activity and reduced organ toxicity of doxorubicin administered using RRx-001 modified RBCs (AACR 2025) - "For reference, a typical blood donation is approximately 450 mL. In conclusion, this describes the pre-clinical rationale and establishes a clinical procedure for administering RBCs loaded with doxorubicin and treated with RRx-001 as a way to improve its activity and reduce side effects."

Colorectal Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Rational design of alternative treatment options for radioresistant rectal cancer using patient-derived organoids. (PubMed, Br J Cancer) - "Combining RRx-001 with the inhibition of GCLC may be a promising alternative treatment strategy in radioresistant rectal cancer."

Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor

Orphan Drug Designations and Approvals (FDA) - "Generic Name: N-(bromoacetyl)-3,3-dinitroazetidine; Date Designated: 06/15/2017; Orphan Designation: Treatment of neuroendocrine tumors; Orphan Designation Status: Designated"

Orphan drug • Neuroendocrine Tumor

EpicentRx and Texas Children's Cancer Center Announce the Initiation of a Phase 1 Clinical Trial with RRx-001 for Pediatric CNS Tumors (PRNewswire) - "EpicentRx, Inc...today announced the start of a Phase 1 study to examine the safety and benefit of its lead small molecule, RRx-001, plus irinotecan and temozolomide for pediatric patients with recurrent or progressive malignant solid and central nervous system tumors. The study, PIRATE (NCT04525014) was conceived and developed by doctors Holly Lindsay and Patricia Baxter at the Texas Children's Cancer Center and will enroll patients 1 to 21 years of age with recurrent or progressive malignant primary brain or spinal cord tumors and solid tumors, excluding lymphomas."

New P1 trial • Brain Cancer • CNS Tumor • Oncology • Solid Tumor

Chimeric Peptide Functionalized Immunostimulant to Orchestrate Photodynamic Immunotherapeutic Effect by PD-L1 Deglycosylation and CD47 Inhibition. (PubMed, ACS Appl Mater Interfaces) - "Concurrently, the release of RRx-001 blocks the CD47 pathway, disrupting the antiphagocytic signaling of breast cancer cells and activating innate immune responses. This synergistic immunomodulatory approach effectively reverses the complex immunosuppressive factors, significantly enhancing the immunotherapeutic effects of conventional treatments."

Journal • Breast Cancer • Oncology • Solid Tumor

Promotion of Triple Negative Breast Cancer Immunotherapy by Combining Bioactive Radicals with Immune Checkpoint Blockade. (PubMed, Acta Biomater) - "STATEMENT OF SIGNIFICANCE: Significance 1: The significance of the work with respect to the existing literature This study introduces a nano-system that leverages ozone and RRx-001 in the presence of X-ray irradiation to generate reactive nitrogen species, enhancing immunogenic cell death and promoting T-lymphocyte infiltration in triple-negative breast cancer, addressing a significant unmet need in the field. Significance 2: The scientific impact and interest to our readership The scientific contribution is the development of a clinically translatable nano-system that not only induces ICD but also reshapes the tumor microenvironment, which is expected to have a profound impact on the readership in pharmaceutics, material science, and nano-bio interaction, particularly for those interested in advanced immune therapy approaches."

Checkpoint inhibition • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Anti-tumor and anti-metastatic effects of RRx-001 on hepatocellular carcinoma: mechanisms of action and therapeutic potential. (PubMed, Front Pharmacol) - "RRx-001 reduces the viability of HCC cells and induces apoptosis. This effect may be due to the downregulation of CD47 expression and the alteration of the TP53 protein regulatory pathway."

Journal • Metastases • Hepatocellular Cancer • Oncology • Solid Tumor • CD47

Anti-tumor and anti-metastatic effects of RRx-001 on hepatocellular carcinoma: mechanisms of action and therapeutic potential (Front Pharmacol) - "RRx-001 inhibits HCC cell viability, migration, and invasion while inducing apoptosis, These effects are potentially mediated by the downregulation of CD47 and the upregulation of TP53, both of which modulate key signaling pathways. In vivo experiments demonstrated that RRx-001 effectively inhibits tumor growth."

Preclinical • Hepatocellular Cancer

PREVLAR: Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for the Treatment of Oral Cancers (clinicaltrials.gov) - P2 | N=53 | Completed | Sponsor: EpicentRx, Inc. | Phase classification: P2a ➔ P2

Metastases • Phase classification • Mucositis • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Stomatitis

REPLATINUM: A Phase 3, Controlled, Open-label, Global Randomized Study of RRx-001 With a Platinum Doublet or a Platinum Doublet in Small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=292 | Active, not recruiting | Sponsor: EpicentRx, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Preclinical development of a CNS-permeable dual NLRP3 inhibitor and NRF2 activator for disease modification in Amyotrophic Lateral Sclerosis (Neuroscience 2024) - "Once weekly dosing with RRx-001 at 2 to 5 mg/kg also improved exercise intolerance and markers of muscle injury such as malonaldehyde. Moreover, RRx-001 therapy improved motor deficits and increased median survival in SOD1 G93A ALS model.Together, our initial results suggest that RRx-001 could be effective in slowing disease progression by blocking inflammasome activation which occurs in ALS, and, independently, by increasing protective NRF2 in muscle, blood, and the central nervous system.Given that RRx-001 has been tested in almost 400 patients to date, with no dose limiting toxicities or related serious adverse events, our early results highlight the prospect of RRx-001 as a new disease-modifying therapeutic for ALS with the potential for rapid clinical translation."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • NLRP3

Validating the clinical stage NLRP3 inflammasome inhibitor nibrozetone as a disease-modifying therapeutic for Parkinson's disease (MDS Congress 2024) - "Given the excellent clinical safety record of RRx-001 in human studies to date, our results suggest that RRx-001 could be an attractive neuroprotective strategy for disease modification of PD, with the potential for rapid clinical translation."

Clinical • CNS Disorders • Parkinson's Disease • NLRP3

Orphan Drug Designations and Approvals (FDA) - "Generic Name: N-(bromoacetyl)-3,3-dinitroazetidine; Date Designated: 06/15/2017; Orphan Designation: Treatment of small cell lung cancer; Orphan Designation Status: Designated"

Orphan drug • Small Cell Lung Cancer

Orphan Drug Designations and Approvals (FDA) - "Generic Name: N-(bromoacetyl)-3,3-dinitroazetidine; Date Designated: 01/16/2019; Orphan Designation: Treatment of glioblastoma multiforme; Orphan Designation Status: Designated"

Orphan drug • Glioblastoma

EU/3/17/1966 - orphan designation for treatment of small cell lung cancer (European Medicines Agency) - "On 17 January 2018, orphan designation (EU/3/17/1966) was granted by the European Commission to Sirius Regulatory Consulting Limited, United Kingdom, for N-(bromoacetyl)-3,3-dinitroazetidine (also known as RRx-001) for the treatment of small cell lung cancer."

Orphan drug • Small Cell Lung Cancer

PIRATE: RRx-001 Given With Irinotecan and Temozolomide for Pediatric Patients With Recurrent or Progressive Malignant Solid and Central Nervous System Tumors (clinicaltrials.gov) - P1 | N=2 | Terminated | Sponsor: EpicentRx, Inc. | N=24 ➔ 2 | Trial completion date: Dec 2024 ➔ Jul 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Jul 2024; Low Enrollment

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • CNS Tumor • Oncology • Pediatrics • Solid Tumor