sotuletinib (BLZ-945) / Novartis, BMS - LARVOL DELTA

Evaluation of in vivo and in vitro binding property of a novel candidate PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, EJNMMI Radiopharm Chem) - "These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

Microglia endotoxin tolerance is retained after enforced repopulation. (PubMed, Brain Behav Immun) - "Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced endotoxin tolerance in mice...Nonetheless the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications."

Journal • CNS Disorders • Infectious Disease • Inflammation • CSF1R

Evaluation of in-vivo and in-vitro binding property of a novel PET tracer for CSF1R imaging and comparison with two currently-used CSF1R-PET tracers. (PubMed, Res Sq) - "Addition of cold CPPC partially blocked in - vitro [ 11 C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Conclusions These results suggest [ 11 C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [ 11 C]CPPC and [ 11 C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging."

Journal • Preclinical • Oncology • CSF1R

ENHANCING MICROGLIAL TARGETING IN PRECLINICAL DRUG DISCOVERY VIA HUMAN MICROGLIA CHIMERIC MICE (ADPD 2025) - "Endogenous murine microglia were depleted using BLZ945 treatment, after which human microglial precur sors were engrafted... This humanized microglia -engrafted APP knock -in model closely mimics human neuroinflammatory responses and represents a valuable tool for investigating microglial function and therapeutic targets in neurodegenerative diseases. The robust human microglial e ngraftment and amyloid pathology observed underscore the model's potential for preclinical drug development. Ongoing refinements a im to further enhance the utility of this platform, accelerating the discovery of novel therapies that modulate microglial activity and mitigate disease progression."

Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • CD9 • CSF1 • PTPRC

Discovery of Novel Pyrrolo[2,3-b]pyridine-Based CSF-1R Inhibitors with Demonstrated Efficacy against Patient-Derived Colorectal Cancer Organoids. (PubMed, J Med Chem) - "In this work, a series of novel CSF-1R inhibitors were designed and synthesized through rational molecular hybridization strategy and step by step structural optimization based on PLX3397 and BLZ945. Mechanically, III-1 efficiently repolarized M2-like TAMs into M1-phenotype, and inhibited the proliferation and promoted apoptosis of tumor cells through immunoregulation. More importantly, III-1 showed demonstrated efficacy against patient-derived colorectal cancer organoids and exhibited stronger anticolorectal cancer efficacy in vivo compared to PLX3397, highlighting its potential in the immunotherapy of colorectal cancer."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Repopulating Microglia in the Auditory Brainstem Recapitulate Developmental Properties following Cessation of CSF1R Inhibitor Treatment (ARO 2025) - "After temporary microglial ablation with the CSF1R inhibitor, BLZ945, repopulating microglia reinstate some active characteristics as they rapidly recover damage from their depletion."

CD68 • CX3CR1 • FAP • GFAP

Modulating tumor-associated macrophages through CSF1R inhibition: a potential therapeutic strategy for HNSCC. (PubMed, J Transl Med) - "Targeting TAMs via CSF1R inhibition enhances the therapeutic efficacy of cisplatin in HNSCC. These findings suggest that CSF1R inhibitors hold promise as a component of combination therapy for HNSCC."

Journal • Head and Neck Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD68 • CD8 • IL10 • MRC1

Ionizable cationic lipid nanoparticles loaded with miRNA-125b/BLZ945 for pancreatic cancer treatment. (PubMed, Biotechnol Appl Biochem) - "(ii) miRNA-125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Proguanil inhibits proliferation and migration in glioblastoma development through targeting CSF1R receptor. (PubMed, Cell Signal) - "More importantly, we found that Proguanil's inhibitory effect on U87MG cell growth and migration was positively correlated with CSF1R expression, and this effect diminished following CSF1R knockdown and Proguanil demonstrated synergistic effects with CSF1R-targeting positive drugs (BLZ945 and GW2580). Meanwhile, Proguanil targeted CSF1R to inhibit M2-type polarization of tumor-associated macrophages (TAMs) and their proliferation, thus altering the tumor microenvironment while indirectly suppressing the proliferation and migration of U87MG cells. Taken together, these findings suggest that Proguanil may serve as a promising CSF1R antagonist for GBM treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCND1 • CDK4 • CDKN1A • CSF1R • MAP2K1 • MMP3 • PTEN

Targeting brain metastasis from triple-negative breast cancer by blocking CSF1R signaling in the tumor microenvironment (EORTC-NCI-AACR 2024) - "Our data have demonstrated the efficacy of BLZ945 on the burden of brain metastases in animal models of TNBC. In addition, our findings support a role for microglia and macrophages in regulating the development of breast cancer brain metastases. Together, these findings provide a potential therapeutic approach for the prevention and/or treatment of brain metastases."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CSF1R • GFAP • IL1B • IL6 • TNFA

Enhancing Microglial Targeting in Preclinical Drug Discovery via Human Microglia Chimeric Mice (Neuroscience 2024) - "Immunodeficient (RAG2-/-) newborn mice expressing human CSF1 (to enhance human microglia survival) and three familial APP mutations (APPSAA) were depleted of endogenous microglia using BLZ945 treatment and subsequently engrafted with human microglial precursors...Currently efforts are being made to refine the process of generating chimeric pups, aiming to enhance adherence to study protocols. This innovative platform will represent a valuable tool for expediting the development of novel therapeutics aimed at modulating microglial function and mitigating disease progression."

Preclinical • Alzheimer's Disease • CNS Disorders • CD9 • CSF1 • PTPRC

Tracking changes in functionality and morphology of repopulated microglia in young and old mice. (PubMed, J Neuroinflammation) - "A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry...We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age."

Journal • Preclinical • Inflammation

CSF1R inhibition depletes brain macrophages and reduces brain virus burden in SIV-infected macaques. (PubMed, Brain) - "Our results indicate that doses as low as 10 mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance."

Journal • CNS Disorders • Human Immunodeficiency Virus • Infectious Disease • CD163 • IGFBP7 • MRC1

Study of Safety and of the Mechanism of BLZ945 in ALS Patients (clinicaltrials.gov) - P2 | N=28 | Terminated | Sponsor: Novartis Pharmaceuticals | N=56 ➔ 28 | Trial completion date: Jun 2026 ➔ Feb 2024 | Recruiting ➔ Terminated | Trial primary completion date: Mar 2025 ➔ Feb 2024; Study terminated after assessment of potential benefit-risk from available data

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Amyotrophic Lateral Sclerosis • CNS Disorders

Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine. (PubMed, bioRxiv) - "Further, the CSF1R inhibitor BLZ945 reduced restitution in scratch wounded IPEC-J2 cells...These studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for medical management of patients with ischemia-mediated intestinal injury."

Journal • Cardiovascular • Gastrointestinal Disorder • Infectious Disease • Septic Shock

Study of Safety and of the Mechanism of BLZ945 in ALS Patients (clinicaltrials.gov) - P2 | N=56 | Recruiting | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders

Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy through Immunogenic Tumor Induction and Tumor Associated Macrophage Depletion. (PubMed, Adv Healthc Mater) - "Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior anti-tumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management."

Journal • Oncology

Targeting CSF-1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors (AACR 2024) - P1/2 | "Given the potential effects of BLZ945 on effector T-cell activity, a combination of BLZ945 with the programmed death 1 (PD-1) inhibitor spartalizumab was investigated in 1) a dose escalation phase I clinical trial with advanced solid tumor patients; and 2) an expansion phase II clinical trial in adult patients with relapsed/refractory glioblastoma (GBM) after standard of care and other lines of therapy (NCT02829723). This suggests that non-mesenchymal GBM, for which PDGFRA is part of the defining signature, are more sensitive to the treatment. DNA-sequencing of these archival samples also revealed mutations in p53 in the tumors with partial responses but no mutations in EGFR or TERT."

IO biomarker • Metastases • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CSF1R • EGFR • PDGFRA • TERT • TP53

Therapeutic effects and underlying mechanism of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol)/combretastatin A4/BLZ945 nanoparticles on Renca renal carcinoma. (PubMed, Front Bioeng Biotechnol) - "Results suggested that CB-NPs can induce necrosis in renal carcinoma cells and tissues, downregulate VEGFA expression, promote renal carcinoma cell apoptosis, and reduce the polarization of M2 macrophages. These findings offer innovative perspectives for the treatment of advanced renal carcinoma."

Journal • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Study of Safety and of the Mechanism of BLZ945 in ALS Patients (clinicaltrials.gov) - P2 | N=56 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy. (PubMed, Acta Biomater) - "Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues...As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80% of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur)...The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mn and curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CSF1R

Preparation and Characterization Evaluation of Poly(L-Glutamic Acid)-g-Methoxy Poly(Ethylene Glycol)/Combretastatin A4/BLZ945 Nanoparticles for Cervical Cancer Therapy. (PubMed, Int J Nanomedicine) - "FS2 has provided significant insights for cervical cancer therapy. It is also crucial to develop a comprehensive evaluation strategy for the formulation of nanomedicine, which has the potential to serve as a guideline for future clinical trials."

Journal • Cervical Cancer • Oncology • Solid Tumor

A proof of mechanism study toevaluate the effect of sotuletinib(BLZ945) on neuroinflammation asmeasured by [11C]-PBR28 PETimaging in participants withamyotrophic lateral sclerosis (ALS-MND 2023) - P2 | "Selective inhibition of CSF-1R resulted in areduction of TSPO PET Vt in the precentral gyrus of partici-pants with ALS, indicating a depletion of microglia. Theobserved reduction in Vt persisted for up to 15 days off-drugsuggesting that repeated dosing cycles could have an addi-tive effect. A new cohort (Cohort 5) is currently being enrolled in thestudy to evaluate the safety, tolerability and pharmacody-namic effect of repeated dosing cycles of sotuletinib, usingtwo different dosing regimens."

Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • CSF1R

Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580. (PubMed, Clin Cancer Res) - "This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CSF1R • IL10 • IL6 • ITGAM

"Dominolike" Barriers Elimination with an Intratumoral Adenosine-Triphosphate-Supersensitive Nanogel to Enhance Cancer Chemoimmunotherapy. (PubMed, ACS Nano) - "Once it has reached the tumor site, B@PAC-PTX nanogel undergoes supersensitive collapse triggered by adenosine triphosphate (ATP) in perivascular regions and releases BLZ-945 conjugated albumin (B) to deplete tumor-associated macrophages (TAMs). Deeper spatial penetration of shrunk nanogel (PAC-PTX) could not only block CXCR4 on the cell membrane to decrease immunosuppressive cell recruitment but also internalize into tumor cells for tumor-killing and T cell priming. The strategy of "dominolike" barriers elimination in tumors enables immune cell infiltration for a potentiated immune response and offers a high-responsive treatment opinion for chemoimmunotherapy."

Journal • Oncology