Abstract 1324: NMS-P088, a novel FLT3, KIT and CSF1R inhibitor, is a promising clinical candidate for AML and CMML treatment
Authors: Ciomei Marina , Ardini Elena , Gianellini Laura , Borleri GianMaria , Romero Gemma Texido , Ceruti Roberta , Pastori Wilma , Avanzi Nilla , Casero Daniele , Gnocchi Paola , Borgia Andrea Lombardi , Lussana Federico , Rambaldi Alessandro , Galvani Arturo , Isacchi Antonella 
Published: August 2019

Abstract
NMS-P088 is a potent and selective inhibitor of FLT3 and KIT kinases, including variants with both primary as well as secondary resistance mutations, in particular retaining potent activity against residue 691 gatekeeper mutation which still represents an unmet medical need. Different form most clinically advanced selective FLT3 inhibitors, NMS-P088 was also shown to strongly inhibit CSF1R in biochemical assays (Ki= 4.5 nM; Kd 0.88nM). FLT3, KIT and CSF1R are members of the class III receptor tyrosine kinase family. Activating rearrangements of the JM domain of FLT3 (FLT3 ITD) occur in 20-25% of Acute Myeloid Leukemia (AML) and represent a driver of disease and a negative prognostic factor. Another 5-7% of AML cases harbor an activating D835 mutation in the activation loop of the kinase domain. KIT is also found mutated in circa 8.0% of AML, primarily in core binding factor (CBF) AML. CSF1R has been shown to polarize macrophages towards an immunosuppressive and tumor-promoting phenotype. CSF1 and/or CSF1R genes are expressed in AML blasts and CSF1R mediates supportive interactions between AML and stromal cells in the AML microenvironment. CSF1R has also been found to be highly expressed in blast samples from chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disorder with poor survival rates post- blast transformation. Hypomethylating agents or standard induction with chemotherapy are the most commonly used therapeutic intervention for CMML and no targeted therapy is currently approved. We found that in vitro NMS-P088 has potent activity on CSF1-dependent macrophages, inhibiting CSF1-stimulated proliferation and cell signalling. In mice NMS-P088 efficiently and dose-dependently decreased tissue infiltration of CSF1R expressing macrophages in liver, consistent with potent in vivo inhibition of this kinase. Furthermore, it showed single agent efficacy in a syngeneic mouse tumor model, with robust reduction of CSF-1R positive intratumoral macrophages. Importantly, we observed high expression of CSF1R in blast samples derived from CMML patients, and the compound was able to inhibit their proliferation and CSF1R signalling. It has been reported that treatment with CSF1R inhibitors induces upregulation of circulating CSF1 ligand as compensatory feedback modulation. Accordingly, during preclinical studies of NMS-088 conducted in non-human primates, a dose-related increase of circulating CSF1 levels was consistently observed. These data confirm in vivo CSF1R inhibition by NMS-P088 and support the opportunity to monitor CSF1 levels as a pharmacodynamic biomarker of CSF1R modulation in the clinical setting. Based on its original kinase targets profile, including FLT3 and KIT gatekeeper resistance mutations as well as CSF1R, preclinical efficacy and safety NMS-P088 was selected to initiate in a clinical trial to potentially address unmet medical needs in AML and CMML.
Citation Format: Marina Ciomei, Elena Ardini, Laura Gianellini, GianMaria Borleri, Gemma Texido Romero, Roberta Ceruti, Wilma Pastori, Nilla Avanzi, Daniele Casero, Paola Gnocchi, Andrea Lombardi Borgia, Federico Lussana, Alessandro Rambaldi, Arturo Galvani, Antonella Isacchi. NMS-P088, a novel FLT3, KIT and CSF1R inhibitor, is a promising clinical candidate for AML and CMML treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1324.