Aptose Biosciences is a science-driven biotechnology company advancing first-in-class agents to treat life-threatening hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), as well as various non-Hodgkin’s lymphomas (NHL). Based on insights into the genetic and epigenetic profiles of certain cancers and patient populations, Aptose is building a pipeline of novel targeted oncology medicines directed at dysregulated processes and signaling pathways. This strategy is intended to optimize anti-tumor efficacy, while maintaining quality of life by minimizing the cytotoxic side effects associated with conventional therapies.
CG-806 (also known as CG026806, CG’806 or CG806) is a highly potent first-in-class pan-FLT3/pan-BTK mutation-agnostic kinase inhibitor in development as a next generation agent for the treatment of myeloid and lymphoid malignancies. To date, CG-806 displays a superior preclinical profile relative to other FLT3 inhibitors and BTK inhibitors and may become a transformational agent in certain myeloid and lymphoid malignancies that are refractory, resistant or intolerant to other agents. CG-806 inhibits FLT3-ITD and all other known mutant forms of FLT3 with IC50’s in the pM to low-nM range, and potently inhibits other oncogenic signaling pathways (“rescue” pathways) operative in AML. In models of myeloid malignancy, CG-806 is more potent than other FLT3 inhibitors, including midostaurin, sorafenib, gilteritinib, quizartinib, and crenolanib and is active in a mutation-agnostic way against primary samples from AML patients with both wild-type as well as mutated FLT3. In addition, CG-806 targets the ATP-binding pocket of BTK, a driver of B-cell malignancy, through a reversible, non-covalent mechanism, thereby allowing CG-806 to retain low nM potency against the BTK-C481S mutant enzyme and to exert superior potency relative to ibrutinib against primary samples from the bone marrow of patients with B-cell cancers. Oral CG-806 has a desirable safety profile in GLP toxicology studies of rodents and dogs, and in rodent respiratory and central nervous safety studies, dog cardiovascular studies, and in the bacterial reverse mutagenesis assay. CG-806 is currently in a Phase 1a/1b clinical trial for the treatment of patients with CLL/SLL and non-Hodgkin’s lymphomas (NHL) that have failed other therapies due to drug resistance or intolerance, or refractory disease. In addition, a second clinical trial with CG-806 for the treatment of patients with relapsed/refractory AML and MDS is in the planning stage.
APTO-253, currently in a Phase 1b dose-escalating trial in patients with relapsed/refractory AML or high-risk MDS, is a small molecule therapeutic agent that inhibits expression of the MYC oncogene, yet does not cause general myelosuppression. The MYC oncogene, which regulates cell growth, proliferation, differentiation and apoptosis, is overexpressed in hematologic cancers, including AML, and overexpressed MYC amplifies new sets of genes to promote oncogenesis. APTO-253 does not target directly the MYC protein, but rather binds to a regulatory motif in the promoter of the MYC oncogene and dramatically downregulates expression of the gene, thereby depleting cells of the MYC oncoprotein and leading to apoptotic cell death. Analysis of MYC expression in PBMCs of the initial patients treated with APTO-253 has demonstrated significant reductions in MYC expression during the 28-day cycle of dosing. Thus, APTO-253 may serve as safe and effective MYC inhibitor for the treatment of AML broadly that combines well with other agents.