On December 3, 2018 Oregon Health & Science University (OHSU) and Aptose Biosciences Inc. (NASDAQ: APTO, TSX: APS) reported the presentation of preclinical data demonstrating that CG-806, a first-in-class pan-FLT3/pan-BTK inhibitor, exhibits broad ex vivo potency on bone marrow cells from patients with diverse hematologic malignancies and superior potency relative to ibrutinib on those bone marrow cells from patients with CLL or other B-cell cancers (Press release, Aptose Biosciences, DEC 3, 2018, View Source [SID1234531814]). In addition, bioinformatic analyses revealed an unexpected ex vivo potency of CG-806 on bone marrow cells from AML patients with IDH1 mutations or with FLT3-ITD mutations. Plus, CG-806 demonstrated a favorable safety profile in GLP toxicology and safety studies. The data were highlighted in a poster presentation on Sunday, December 2, 2018 at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held December 1-4, 2018 in San Diego, CA. Separately, Aptose and The University of Texas MD Anderson Cancer Center researchers also presented new data on CG-806 at ASH (Free ASH Whitepaper) (see press release here).
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Studies have shown that more than 50% of patients with CLL and mantle cell lymphoma (MCL) discontinue ibrutinib treatment due to intolerance or emergence of resistant disease. "Our data indicate that CG-806 clearly addresses ibrutinib’s shortcomings, inhibiting driver and rescue pathways to directly and potently kill a broad range of malignant B-cells. CG-806 has potential to be an important part of our future armamentarium against hematologic malignancies that are resistant, refractory or intolerant to other therapies," said Jeffrey W. Tyner, Ph.D., Associate Professor in the OHSU School of Medicine department of Cell, Developmental & Cancer Biology.
The poster, CG-806, a First-in-Class Pan-FLT3/Pan-BTK Inhibitor, Exhibits Broader and Greater Potency than Ibrutinib Against Primary and Cultured Malignant B Cells, evaluated the activity of CG-806 on various hematologic malignancy cell lines and patient primary bone marrow specimens. CG-806 inhibited cell proliferation and induced apoptosis with a potency that was 50-6,000 times greater than that of ibrutinib when tested against 14 established malignant B-cell lines in vitro. When tested against 124 samples freshly isolated from the bone marrow of chronic lymphocytic leukemia (CLL) patients, the median IC50 for CG-806 was 0.11 µM and the median for ibrutinib was 4.09 µM, respectively, p<0.001. Since stromal mediated signaling plays an important role in malignant B-cell survival and chemoresistance, the apoptotic effect of CG-806 was further analyzed on cultured and primary malignant B-cells in the presence of stromal cells, and its potency was not impaired. CG-806 was shown to be significantly more potent than Ibrutinib at inhibiting malignant B-cell colony formation, migration, and inducing apoptosis in the presence of stromal cells.
Primary cells from patients with diverse hematologic malignancies are highly sensitive to CG-806, including cells with the FLT3-ITD mutation, found in approximately 30% of acute myeloid leukemia (AML) patients. The data presented at ASH (Free ASH Whitepaper) showed that primary cells from AML patients with the IDH-1 mutation similarly demonstrated high sensitivity to CG-806. Aptose also reported new results from the 28-day GLP toxicity and toxicokinetic studies of CG-806, which continue to demonstrate a highly favorable safety profile with no adverse findings to date.
"CG-806’s activity against IDH-1 mutant AML patient bone marrow cells is an unexpected new finding that further broadens its potential use and potential paths for rapid development," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "In addition, CG-806 has continued to perform well in all toxicology and safety studies, and we look forward to filing an IND in early 2019."
About CG-806
CG-806 is a preclinical stage oral, first-in-class pan-FLT3/pan-BTK multi-cluster kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and all mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG-806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG-806 may be developed for various B-cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. It is in development for acute myeloid leukemia (AML) and B cell lymphoma.