edicotinib (PRV-6527) / Sanofi - LARVOL DELTA

A Novel Small Molecule Screening Assay Using Normal Human Chondrocytes Toward Osteoarthritis Drug Discovery (ACR Convergence 2024) - "This included lorecivivint, used as a positive control...Staurosporine inhibited MMP-13 in chondrocytes but was cytotoxic in synovial fibroblasts while edicotinib inhibited MMP-13 and IL-6 but with considerable variability between donors. We have successfully tested a novel HTS for OA drug discovery. We have successfully tested a novel HTS for OA drug discovery. Potential targets for OA therapeutic development were identified including CDK1 which inhibited MMP-13 and IL-6 production by OA chondrocytes and synovial fibroblasts. Given the lack of effective drugs on the market, the discovery of novel OA therapeutics that eliminate catabolic and inflammatory signaling in multiple joint tissue cell types would be a tremendous benefit to public health."

Immunology • Osteoarthritis • Pain • Rheumatology • CDK1 • IL6 • MAP2K1 • MMP13

A novel small molecule screening assay using normal human chondrocytes toward osteoarthritis drug discovery. (PubMed, PLoS One) - "These included RO-3306 (CDK1 inhibitor (i)), staurosporine (PKCi), trametinib (MEK1 and MEK2i), GSK-626616 (DYRK3i), and edicotinib (CSF-1Ri). Secondary testing using immunoblots and cells derived from OA joint tissues confirmed the ability of selected compounds to inhibit chondrocyte MMP-13 production and FN-f stimulated IL-6 production by synovial fibroblasts. These findings support the use of this high throughput screening assay for discovery of disease-modifying osteoarthritis drugs."

Journal • Preclinical • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • CDK1 • CSF1R • IL6 • MAP2K1 • MMP13

The colony-stimulating factor-1 receptor inhibitor edicotinib counteracts multidrug resistance in cancer cells by inhibiting ABCG2-mediated drug efflux. (PubMed, Biomed Pharmacother) - "These results underscore an additional pharmacological benefit of edicotinib against ABCG2 activity, suggesting its potential incorporation into combination therapies for patients with ABCG2-overexpressing tumors. Further research is warranted to validate these findings and explore their clinical implications."

Journal • Oncology • ABCB1 • ABCG2

MICAD: MIcroglial Colony Stimulating Factor-1 Receptor (CSF1R) in Alzheimer's Disease (clinicaltrials.gov) - P1 | N=2 | Terminated | Sponsor: University of Oxford | N=54 ➔ 2 | Not yet recruiting ➔ Terminated; Delayed due to COVID19. Study drug expired before could be used.

Enrollment change • Trial termination • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Daratumumab or FMS Inhibitor JNJ-40346527 Before Surgery in Treating Patients With High-Risk, Resectable Localized or Locally Advanced Prostate Cancer (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Daratumumab or FMS Inhibitor JNJ-40346527 Before Surgery in Treating Patients With High-Risk, Resectable Localized or Locally Advanced Prostate Cancer (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2023 ➔ Jul 2024 | Trial primary completion date: Dec 2023 ➔ Jul 2024

Metastases • Surgery • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Daratumumab or FMS Inhibitor JNJ-40346527 Before Surgery in Treating Patients With High-Risk, Resectable Localized or Locally Advanced Prostate Cancer (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Jun 2023 ➔ Dec 2023

Metastases • Surgery • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer. (PubMed, Explor Target Antitumor Ther) - "The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity."

IO biomarker • Journal • Oncology • CSF1R

Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease. (PubMed, J Neuroinflammation) - "Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process."

Biomarker • Journal • CNS Disorders • Inflammation • GFAP

Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor). (PubMed, J Immunother Cancer) - "Daratumumab and edicotinib treatment was safe and well-tolerated in patients with localized prostate cancer but did not induce pCRs. Decreases in CD38 immune cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, but changes in CSF-1R immune cells were not consistently observed with edicotinib. Neither myeloid-targeted agent alone was sufficient to generate antitumor responses in prostate cancer; thus, combinations with agents to induce T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive prostate TME."

Journal • Genito-urinary Cancer • Hematological Malignancies • Immune Modulation • Immunology • Oncology • Prostate Cancer • Solid Tumor

Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor) (J Immunother Cancer) - P1 | N=33 | NCT03177460 | "Twenty-five patients were treated (daratumumab, n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 treatment-related AEs with daratumumab occurred in 3 patients (12%), and no ≥grade 3 treatment-related AEs occurred with edicotinib. No changes in serum prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to a decreased frequency of CD38+ T cells, natural killer cells, and myeloid cells in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in CSF-1R+ immune cells in prostate, bone marrow, or PBMCs with edicotinib. Neither treatment induced T cell infiltration into the prostate TME."

P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Target Modulation within the Tumor Microenvironment (TME) by Daratumumab (anti-CD38) but not Edicotinib (CSF-1R inhibitor) in Men with High-Risk Localized Prostate Cancer (SITC 2021) - P1 | "Myeloid-targeted agents such as daratumumab alone are insufficient to generate anti-tumor responses in prostate cancer. Trial Registration NCT03177460"

Biomarker • Tumor microenvironment • Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor

Daratumumab (anti-CD38) but not edicotinib (CSF-1R inhibitor) demonstrates target engagement within the primary prostate cancer, bone marrow and systemic circulation of patients with localized disease (CRI-ENCI-AACR ICIC 2022) - "Daratumumab and edicotinib were safe in patients with high-risk localized prostate cancer but did not induce pCRs or declines in serum PSA levels. Target modulation was consistently observed in prostate tumors, bone marrow, and PBMCs following daratumumab treatment, but not with edicotinib. Agents targeting immunosuppressive molecular pathways within the TME such as daratumumab alone are insufficient to generate clinically meaningful anti-tumor responses in localized prostate cancer. Combinations with therapies that promote T cell infiltration are likely to be needed to improve clinical outcomes."

Daratumumab or FMS Inhibitor JNJ-40346527 Before Surgery in Treating Patients With High-Risk, Resectable Localized or Locally Advanced Prostate Cancer (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jun 2020 ➔ Jun 2023 | Trial primary completion date: Jun 2020 ➔ Jun 2023

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Inhibiting CSF1 receptor signaling dampens microglial proliferation and reduces Tau deposition in mice (Neuroscience 2021) - "Here we tested selective brain penetrant small molecule CSF1R antagonist: JNJ-40346527 (JNJ527) to inhibit microglia proliferation...These ligands can potentially serve as target engagement biomarkers for clinical investigation of CSF1R inhibitors. Overall, these findings strongly support the inhibition of CSF1R to reduce microglial proliferation as a promising immunomodulatory strategy for the treatment of AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • CSF1R • CTNNB1 • TNFA

PRINCE: Phase 2a Study of PRV-6527 in Subjects With Moderately to Severely Active Crohn's Disease (clinicaltrials.gov) - P2a; N=93; Completed; Sponsor: Provention Bio, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

JNJ-40346527 in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P2; N=3; Terminated; Sponsor: OHSU Knight Cancer Institute; N=28 ➔ 3; Trial completion date: Dec 2023 ➔ Sep 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2022 ➔ Sep 2020; Not enough enrollment to determine efficacy

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MICAD: MIcroglial Colony Stimulating Factor-1 Receptor (CSF1R) in Alzheimer's Disease (clinicaltrials.gov) - P1; N=54; Not yet recruiting; Sponsor: University of Oxford; Trial primary completion date: Nov 2020 ➔ Dec 2021

Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CSF1

JNJ-40346527 in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P2; N=28; Active, not recruiting; Sponsor: OHSU Knight Cancer Institute; Recruiting ➔ Active, not recruiting; N=100 ➔ 28

Clinical • Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. (PubMed, Brain) - "Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases."

Biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology

MICAD: MIcroglial Colony Stimulating Factor-1 Receptor (CSF1R) in Alzheimer's Disease (clinicaltrials.gov) - P1; N=54; Not yet recruiting; Sponsor: University of Oxford; Initiation date: Nov 2019 ➔ May 2020

Trial initiation date

Daratumumab or FMS Inhibitor JNJ-40346527 Before Surgery in Treating Patients With High-Risk, Resectable Localized or Locally Advanced Prostate Cancer (clinicaltrials.gov) - P1; N=33; Active, not recruiting; Sponsor: M.D. Anderson Cancer Center; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

The CSF-1-receptor inhibitor, JNJ-40346527 (PRV-6527), reduced inflammatory macrophage recruitment to the intestinal mucosa and suppressed murine T cell mediated colitis. (PubMed, PLoS One) - "CSF-1 biology is activated in Crohn's disease and in murine T cell transfer colitis. Inhibition of CSF-1R by JNJ-40346527 was associated with attenuated clinical disease scores and reduced inflammatory gene expression in mice. These data provide rationale for testing JNJ-40346527 (PRV-6527) in human inflammatory bowel disease."

Journal • Preclinical

Janssen does not want Crohn’s disease asset back from Provention following trial failure (BioSpace) - "Janssen said it will 'support and expand the field' of the agreement between the two companies to allow continued development of the asset...According to the filing, Janssen will assist Provention in transferring the manufacturing rights of PRV-6527 to either Provention for continued development or assist in the transference of rights to a third party. Additionally, Janssen said it will 'irrevocably waive its rights to assume distribution and pricing decision making authority' of PRV-6527....Provention said it has no real intention of attempting to develop the asset any longer and could explore sublicensing the compound to a third party."

Licensing / partnership

MICAD: MIcroglial Colony Stimulating Factor-1 Receptor (CSF1R) in Alzheimer's Disease (clinicaltrials.gov) - P1; N=54; Not yet recruiting; Sponsor: University of Oxford

New P1 trial