Pixuvri (pixantrone) / Servier - LARVOL DELTA

Search for acetylcholinesterase inhibitors by computerized screening of approved drug compounds. (PubMed, SAR QSAR Environ Res) - "Notable candidates include Pixantrone, Guanfacine and Hydroxystilbamidine. These compounds, although not previously known as AChE inhibitors, represent diverse chemical classes including substituted thiophenes, pyridines, and fused nitrogen-containing heterocycles, showing high potential for treating neurodegenerative diseases such as Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Histidinol dehydrogenase (HisD): a critical regulator of Staphylococcus aureus virulence and a promising target for antivirulence therapy. (PubMed, Microbiol Spectr) - "HisD inhibition by pixantrone was further evaluated...By uncovering HisD's role in connecting metabolism to virulence through the saeR/S system, we reveal a druggable target for fighting multidrug-resistant infections. This work addresses the urgent need for innovative solutions to the global antibiotic resistance crisis, paving the way for therapies that outsmart evolving superbugs."

Journal • Hematological Disorders • Infectious Disease • Inflammation • GLS2 • IL6 • TNFA

Mechanism-informed identification of FDA-approved topoisomerase inhibitors disrupting SARS-CoV-2 nucleocapsid-RNA interactions. (PubMed, BMC Chem) - "Inspired by adenosine triphosphate (ATP)'s competitive inhibition of NP-RNA binding, we screened 121 FDA-approved ATP-competitive kinase inhibitors, identifying mitoxantrone (IC₅₀ = 1.22 µM) as a potent inhibitor. Considering its known topoisomerase inhibitory activity, we further screened 23 additional topoisomerase inhibitors, uncovering four active compounds-pixantrone (IC₅₀ = 5.67 µM), doxorubicin (IC₅₀ = 20.19 µM), epirubicin (IC₅₀ = 7.23 µM), and suramin (IC₅₀ = 0.44 µM)...Our findings demonstrate the feasibility of a mechanism-informed repurposing strategy and identify FDA-approved topoisomerase inhibitors and suramin as valuable chemical starting points. Although these compounds are not directly suitable as antivirals due to toxicity concerns, they provide promising scaffolds for further optimization aimed at selective disruption of SARS-CoV-2 NP-RNA interactions."

FDA event • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Nanoscopy Reveals Heparan Sulfate Clusters as Docking Sites for SARS-CoV-2 Attachment and Entry. (PubMed, bioRxiv) - "Blocking HS binding with the clinically used HS- binding agent pixantrone strongly inhibited the clinically relevant SARS-CoV-2 Omicron JN.1 subvariant from attaching to and infecting human airway cells...This new model suggests perturbation of HS binding as a more effective anti-COVID-19 strategy than previously recognized. It may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Evaluating the multitargeted potency of Pixuvri against cell cycle regulation proteins in cervical cancer. (PubMed, Front Oncol) - "Molecular dynamics (100 ns, NVT ensemble at 300K) validated stability by deviation and fluctuation studies and found many interactions to stabilize the complex, with binding free energy computations confirming its affinity. While the results support Pixuvri's repurposing for cervical cancer, experimental validation is essential for clinical application."

Journal • Cardiovascular • Cervical Cancer • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

PIXBRIDGE: Pixantrone as Bridging Therapy to Allogenic Transplant or CAR-T Cell Therapy in DLBCL Patients (clinicaltrials.gov) - P=N/A | N=15 | Active, not recruiting | Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna

New trial • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Characterization of pixantrone regioisomeric conjugates arising from AP sites in DNA by NMR spectroscopy (ACS-Fall 2024) - "AP sites are reactive and recent studies showed they may form Schiff base conjugates with exocyclic amines on the anthracycline-class drugs pixantrone and mitoxantrone, analogs of the anti-tumor antibiotic doxorubicin. The two regioisomers are distinguished by NOESY NMR data. The NMR data also differential rates of formation of the two isomers favoring regioisomer A."

Oncology

Pixantrone as a novel MCM2 inhibitor for ovarian cancer treatment. (PubMed, Eur J Pharmacol) - "These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic."

Journal • Oncology • Ovarian Cancer • Solid Tumor • MCM2

Interactions of pixantrone with apurinic/apyrimidinic sites in DNA. (PubMed, MicroPubl Biol) - "Here, pixantrone was demonstrated to have similar properties, but relative to mitoxantrone, it was significantly less potent in both DNA incision and APE1 inhibition. Consistent with these observations, pixantrone had ~ 15-fold lower affinity for DNA containing an AP site analogue, tetrahydrofuran, as measured by a Thiazole Orange (ThO) displacement assay."

Journal • Oncology

Oncogenic functions and therapeutic potentials of targeted inhibition of SMARCAL1 in small cell lung cancer. (PubMed, Cancer Lett) - "Pixantrone caused DNA damage and exhibited inhibitory effects on SCLC cells in vitro and in a patient-derived xenograft mouse model. These results indicated that SMARCAL1 functions as an oncogene in SCLC, and pixantrone as a SMARCAL1 inhibitor bears therapeutic potentials in this deadly disease."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SMARCA2

Delineating Pixantrone Maleate's adroit activity against cervical cancer proteins through multitargeted docking-based MMGBSA, QM-DFT and MD simulation. (PubMed, PLoS One) - "We also explore the stability of the multitargeted potential of Pixantrone Maleate through 100ns MD simulations and investigate the RMSD, RMSF and intermolecular interactions between all three proteins-ligand complexes. All computational studies favour Pixantrone Maleate as a multitargeted inhibitor of the TBK1, DNA polymerase epsilon, and integrin α-V β-8 and can be validated experimentally before use."

Journal • Cervical Cancer • Oncology • Solid Tumor

Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for hepatocellular carcinoma. (PubMed, Hepatology) - "HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • NOTCH1

PIVeR: Study of Pixantrone in CD20+ Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma (clinicaltrials.gov) - P2 | N=74 | Active, not recruiting | Sponsor: The Lymphoma Academic Research Organisation | Recruiting ➔ Active, not recruiting

Enrollment closed • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Pharmacokinetic and Safety Study of Pixantrone in Patients With Metastatic Cancer and Hepatic Impairment (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: CTI BioPharma | N=32 ➔ 0 | Unknown status ➔ Withdrawn

Enrollment change • Metastases • Trial withdrawal • Hepatology • Oncology

Pixantrone (BBR 2778) in Patients With Refractory Acute Myelogenous Leukemia (AML) (clinicaltrials.gov) - P1/2 | N=12 | Completed | Sponsor: CTI BioPharma | N=119 ➔ 12

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Epcoritamab (Epkinly) for diffuse large B-cell lymphoma (DLBCL). (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Pixantrone as bridging therapy to allogeneic transplantation or in CAR T-cell pathway in patients with diffuse large B-cell lymphoma. (PubMed, Hematol Oncol) - No abstract available

CAR T-Cell Therapy • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Insight into the structural effects of anthracycline drugs, pixantrone and mitoxantrone, in duplex DNA (ACS-Fall 2023) - "AP sites are reactive and recent studies showed they may form Schiff base conjugates with exocyclic amines on the anthracycline-class drugs pixantrone and mitoxantrone, analogs of the anti-tumor antibiotic doxorubicin. The hydroquinone moiety of mitoxantrone features two hydrogen bond donors, which may form two hydrogen bonds in the DNA duplex. The pixantrone, hydroquinone moiety features a nitrogen atom, which may only form one hydrogen bond as a hydrogen bond acceptor."

Oncology

LONG-TERM FOLLOW-UP AND GENE EXPRESSION PROFILES ASSOCIATED WITH OUTCOME IN PATIENTS WITH RELAPSED AGGRESSIVE B- OR T-CELL LYMPHOMAS TREATED IN THE NORDIC P[R]EBEN TRIAL (ICML 2023) - "The research was funded by: Servier Laboratoires Introduction: The Nordic Lymphoma Group (NLG) performed a dose-finding/expansion trial evaluating pixantrone, etoposide, bendamustine and, in CD20+ lymphomas, rituximab (P[R]EBEN) in patients (pts) with relapsed diffuse large B-cell (DLBCL) or peripheral T-cell (PTCL) lymphomas. The P[R]EBEN regimen is feasible on an out-pt basis and shows encouraging response rates and DoR. In PTCL, we observed an overrepresentation of AML/MDS, possibly related to the use of etoposide in multiple treatment lines. Gene expression analysis identified signatures and single genes predictive of long-term response."

Clinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CD20 • NCF4 • NCOA3 • PLA2G2A

Pixantrone containing R-CPOP as firstline treatment in elderly DLBCL patients with congestive heart failure or high risk of anthracycline induced cardiotoxicity (ICML 2023) - "(Ann Oncol, 2013, 24:2618) comparing first line R-CHOP with R-CPOP (substituting doxorubicin with pixantrone, 88 mg/m2) in patients with DLBCL resulted in similar PFS with reduced grade 3 CHF rates in R-CPOP patients. With this trial we could show feasibility and encouraging efficacy of R-CPOP in elderly DLBCL patients with CHF and/or high risk of anthracycline induced cardiotoxicity which invites further trials to establish R-CPOP as standard first line treatment in this patient cohort."

Clinical • Diffuse Large B Cell Lymphoma • Oncology

Combination of pixantrone with rituximab, ifosfamide and etoposide in relapsed/refractory aggressive non-Hodgkin lymphoma. Results from a phase II LYSA study (PIVeR) (ICML 2023) - "The primary objective of this trial was met with a high OMR rate of 59.5% after 2 cycles of the PIVeR regimen. The safety profile appeared manageable with few grade 3–4 cardiac AEs. Based on these results, the use of pixantrone in salvage treatment of R/R aNHL should be further evaluated, in particular in the context of bridging therapy before CAR T-Cells."

P2 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy. (PubMed, J Oncol Pharm Pract) - "Viability of the selected pathogenic microorganisms was retained in most of the tested biological and small molecule preparations used to treat cancer patients. Therefore, in pharmacy departments strict aseptic conditions should be regarded and the lack of antimicrobial activity should be considered when assigning shelf life to RTA parenteral preparations."

Journal • Oncology

Long-term efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma achieving a complete response with pixantrone. (PubMed, Eur J Haematol) - "In this real-life experience, pixantrone demonstrated long-term efficacy in a cohort of R/R DLBCL cases who had previously received at least two prior regimens; many of whom had characteristics associated with poor prognosis."

Journal • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Clonal Evolution of a Mutation in Ptpra As a Potential Cause for Resistance Against Anti-CD19 Directed Chimeric Antigen Receptor T-Cell (CAR-T) Therapy with CTL019 in DLBCL Patients (ASH 2018) - "Results :The first analyzed patient, #UKK2, is a 67 year old male patient, who had chemotherapy refractory disease after treatment with R-CHOP, R-DHAP and Pixantrone. We hypothesize that this PTPRA mutation contributes to an invasive phenotype and extranodal lymphoma growth pattern allowing the lymphoma to escape from the pattern allowing the lymphoma to escape from the CAR-T cell attack. Genomic workup of patients with pre- and posttreatment biopsies and functional investigation of this hypothesis is ongoing and will be presented."

CAR T-Cell Therapy • Clinical • IO biomarker • Acute Lymphocytic Leukemia • Biosimilar • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Topoisomerase II as a Novel Antiviral Target against Panarenaviral Diseases. (PubMed, Viruses) - "Although many arenaviruses cause severe diseases with high fatality rates each year, treatment options are limited to off-label use of ribavirin, and a Food and Drug Administration (FDA)-approved vaccine is not available...Using this system, we screened 2595 FDA-approved compounds for inhibitors of LASV genome replication and identified multiple compounds including pixantrone maleate, a topoisomerase II inhibitor, as hits...These topoisomerase II inhibitors also inhibited Junin virus (JUNV) MG activity and effectively limited infection by the JUNV Candid #1 strain, and siRNA knockdown of both topoisomerases (IIα and IIβ) restricted JUNV replication. These results suggest that topoisomerases II regulate arenavirus replication and can serve as molecular targets for panarenaviral replication inhibitors."

Journal • Infectious Disease