Cu(II)ATSM / Collaborative Medicinal Development - LARVOL DELTA

In vivo evaluation of local theranostic approach to high-grade glioma with hypoxia-targeting radiopharmaceutical 64Cu-ATSM (SNMMI 2025) - "Our clinical PET study has demonstrated that Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) highly accumulated in the HGGs generally expressing hypoxia marker HIF-1α... The MTD of 64Cu-ATSM local treatment in mice was 3.7 MBq. After the local treatment with MTD, Imaging and autoradiography analyses demonstrated high tumor penetration, distribution, and retention of64Cu-ATSM within HGG PDX tumors, with highly expressed hypoxic markers of HIF-1α and BNIP3. A single 64Cu-ATSM local treatment significantly prolonged overall survival as well as potently induced DNA double-strand breaks and apoptosis in tumors."

Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • HIF1A

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

In vivo evaluation of local theranostic approach to high-grade glioma with hypoxia-targeting radiopharmaceutical 64Cu-ATSM (SNMMI 2025) - "Our clinical PET study has demonstrated that Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) highly accumulated in the HGGs generally expressing hypoxia marker HIF-1α... The MTD of 64Cu-ATSM local treatment in mice was 3.7 MBq. After the local treatment with MTD, Imaging and autoradiography analyses demonstrated high tumor penetration, distribution, and retention of64Cu-ATSM within HGG PDX tumors, with highly expressed hypoxic markers of HIF-1α and BNIP3. A single 64Cu-ATSM local treatment significantly prolonged overall survival as well as potently induced DNA double-strand breaks and apoptosis in tumors."

Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • HIF1A

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Cardiovascular • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model. (PubMed, Acta Neuropathol Commun) - "We evaluated whether the blood-brain-barrier-permeable copper delivery drug, CuATSM, attenuated the misfolding and deposition of wild-type disSOD1 and associated neuron death in a novel mouse model that expresses this pathology...These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. Our data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • SOD1

CuATSM Enhances Wound Repair Without Scarring via Hippo/YAP Signalling Pathway to Reduce Ferroptosis and Macrophage Polarisation. (PubMed, J Cell Mol Med) - "Furthermore, our findings suggest that this effect is mediated through the ferroptosis-induced Hippo/YAP signalling pathway and macrophage polarisation. These findings highlight CuATSM as a promising therapeutic candidate for achieving scarless wound repair in clinical applications."

Journal • Inflammation

CuII-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases. (PubMed, Semin Nucl Med) - "Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • TNFA

A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis. (PubMed, EBioMedicine) - "These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Effect of Cu(ATSM) on the expression and activity of ABC export proteins in killifish (Fundulus heteroclitus) kidney tubules. (PubMed, Environ Toxicol Pharmacol) - "Cu(ATSM)-induced activation was further suppressed by phosphatidylinositol 3-kinase inhibitor LY-294002 and mTOR inhibitor rapamycin. Activation was also inhibited by GSK650394, an inhibitor of serum-and-glucocorticoid-inducible-kinase-1 being a subsequent target. Given the parallelism with other metals, this ABC transporter regulation appears to be a general defense mechanism of teleosts to react on metallic pollutants."

Journal

Clinical characterization of IRF2BPL mutation: Case series and review of the literature. (PubMed, Medicine (Baltimore)) - "We have come across a case of recurrent seizures of epilepsy and dystonia due to a mutation in the IFR2BPL gene for which no definitive treatment has been found. Recently, several studies have led to the discovery of a new drug for the treatment of NEDAMSS. CuII (atsm) (copper II diacetylbis(4-methylaminouracil)) (CuATSM) is a small-molecular-weight drug that can be administered orally and then used in the human body. The literature suggests that the underlying mechanism of CuATSM involves the restoration of mitochondrial function, including correction of the mitochondrial differentiation and mislocalization observed in cells from NEDAMSS patients, but extensive trials are needed to demonstrate its efficacy in IFR2BPL-related diseases."

Journal • Review • CNS Disorders • Developmental Disorders • Dystonia • Epilepsy • Movement Disorders • Psychiatry • IRF2

Measurement of Airborne Radioactivity in the Inpatient Room after Administering [64Cu]Cu-ATSM to Patients (PubMed, Kaku Igaku) - "The results of this study confirmed that the airborne concentration of [64Cu]Cu-ATSM after administration to patients was below the legally permitted level."

Journal • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants. (PubMed, J Am Chem Soc) - "CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells. (PubMed, Radiat Res) - "Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • CAT

Evaluations for quality management of metal impurities in [64Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) as a radiopharmaceutical (EANM 2024) - "This study showed that trace amounts of Ni2+, Fe2+, and Zn2+ had little effect on the quality of [64Cu] Cu-ATSM. However, it was concluded that the concentration of Cu2+ should be controlled. These results would provide useful information for the quality management of [64Cu]Cu-ATSM."

Brain Cancer • Oncology • Solid Tumor

Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis. (PubMed, Neurotherapeutics) - "Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise."

Journal • CNS Disorders • Immunology • Multiple Sclerosis

Phase I clinical trial of 64 Cu-ATSM for malignant brain tumors. (ASCO 2024) - "Intravenous administration of 64 Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options."

Clinical • P1 data • Brain Cancer • CNS Lymphoma • Glioblastoma • Glioma • Hematological Disorders • Hematological Malignancies • Lymphoma • Meningioma • Oncology • Solid Tumor

Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS. (PubMed, Sci Rep) - "Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer's Disease. (PubMed, ACS Chem Neurosci) - "To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders...Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • IFNG • TNFA

Copper's dual role: unravelling the link between copper homeostasis, cuproptosis, and cardiovascular diseases. (PubMed, Hypertens Res) - "Therapeutic interventions include copper chelators (e.g., ammonium tetrathiomolybdate), and oxidative phosphorylation inhibitors like elesclomol and copper ionophores (CuII(atsm), CuII(gtsm), and disulfiram). These interventions modulate intracellular copper, elevate NO, and reduce inflammatory cytokines, contributing to decreased cardiovascular diseases."

Journal • Atherosclerosis • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Myocardial Ischemia • Reperfusion Injury • FDX1 • LIAS

Microglial ferroptotic stress causes non-cell autonomous neuronal death. (PubMed, Mol Neurodegener) - "By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Infectious Disease • Oncology

Trace Metal Impurities Effects on the Formation of [Cu]Cu-diacetyl-bis(N-methylthiosemicarbazone) ([Cu]Cu-ATSM). (PubMed, Pharmaceuticals (Basel)) - "Trace amounts of Ni, Zn, and Fe showed little effect on [Cu]Cu-ATSM' quality, while the concentration of impurity Cu must be controlled. These results can provide process management tools for radiopharmaceuticals."

Journal • Brain Cancer • Oncology • Solid Tumor

Evidence for decreased copper associated with demyelination in the corpus callosum of cuprizone treated mice. (PubMed, Metallomics) - "Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum...These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed."

Journal • Preclinical • CNS Disorders • Multiple Sclerosis

Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [Cu][Cu(ATSM)] PET and proteomic studies. (PubMed, EJNMMI Res) - "Overall, [Cu][Cu(ATSM)] imaging and proteomic results showed the presence of hypoxia and protein expression changes linked to hypoxia and oxidative stress in BM, which are more pronounced in cortical BM compared to striatal BM. Moreover, it emphasized the interest of [Cu][Cu(ATSM)] PET to characterize TME of BM and depict inter-metastasis heterogeneity that could be useful to guide treatments."

Journal • Brain Cancer • Lung Cancer • Oncology • Solid Tumor • CA9 • DMRT1 • EPAS1 • GFAP • HIF1A

A polytherapy approach demonstrates therapeutic efficacy in familial SOD1 ALS models (ALS-MND 2023) - "We have identified two additional FDA-approved small molecules, ebselen and telbivudine that may aid in reducing the accumulation of mutant misfolded SOD1. CuATSM treatment was shown to dose dependently improve the survival of cultured NSC-34 cells expressing SOD1G93A-GFP compared to the vehicle control (p < 0.05). Furthermore, multiple different ratios of the CET treatment) were found to significantly improve survival compared to the highest concentration of CuATSM alone tested (0.5 mM) (p < 0.05), despite using less than half the concentration of CuATSM. In addition, CET treatment significantly reduced the percentage of cells containing inclusions compared to the highest concentration of CuATSM alone."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Hematological Disorders • SOD1