PF203 CG‐806, PRECLINICAL IN VIVO EFFICACY AND SAFETY PROFILE AS A PAN‐FLT3/PAN‐BTK INHIBITOR
Authors: H. Zhang, K. Benbatoul, S. Sheng, C.‐Y. Tsai, S. Howell, W. Rice
Journal: HemaSphere (2019)

Background: CG‐806, a non‐covalent pan‐FLT3/pan‐BTK inhibitor, is being developed for treatment of non‐Hodgkin's lymphomas and myeloid malignancies including those are resistant, refractory, or intolerant to covalent or non‐covalent BTK inhibitors, Bcl‐2 inhibitors, chemotherapy, or immunotherapies, and the emerging populations resistant to FLT3 inhibitors. CG‐806 was previously shown to be more potent than ibrutinib against malignant B cells in vitro (EHA23 Abstract #PF337) and to have very efficient anti‐leukemic activity in a patient‐derived xenograft model of FLT3 ITD plus D835 dual‐mutant AML (ASH2018 Abstract #2635). Aims: To characterize the in vivo anti‐leukemic efficacy, pharmacokinetics (PK) and pharmacodynamics of CG‐806 and its GLP toxicology and toxicokinetic profile. Methods: CG‐806 was evaluated in a xenograft model of human AML (FLT3 ITD‐mutated MV4–11) in which mice were dosed orally BID with 0, 10, 30, 100 or 300 mg/kg for 28 consecutive days. GLP 28‐day repeat‐dose oral toxicology and toxicokinetic (TK) studies were conducted in CD‐1 mice (0, 30, 100, or 300 mg/kg BID) and in Beagle dogs (0, 30, 60 or 120 mg/kg BID). Receptors, enzymes, channels, and transporters were screened to identify potential off‐target activities. Genotoxicity was evaluated with a GLP in vitro bacterial reverse mutation (Ames) assay. Platelet aggregation studies were performed using fresh human whole blood from healthy donors. Metabolism and the metabolite profiles were evaluated using mouse, rat, dog and human hepatic microsomes. Results: In the subcutaneous MV4–11 xenograft model, CG‐806 suppressed leukemia growth at all doses tested throughout the 28‐day period of dosing. After dosing was stopped, tumors treated with 10 and 30 mg/kg resumed growth but responded again when CG‐806 dosing was resumed. Tumors in mice treated with either 100 or 300 mg/kg did not regrow during a period of 60 days after treatment was stopped. GLP 28‐day toxicology and TK studies in CD1 mice and Beagle dogs showed no adverse CG‐806‐related effects on body weight, ophthalmic, respiratory or neurological examinations, clinical pathology (coagulation, clinical chemistry, or urinalysis), organ weight or macroscopic evaluations. No CG‐806‐related cardiovascular effects were noted by ECGs in the 28‐day GLP toxicology study or in a separate dog cardiovascular safety study. Decreased absolute neutrophil count in 2 female dogs was observed after 28 days at the 120 mg/kg BID but was reversible and not considered adverse. CG‐806 produced micromolar plasma levels without significant drug accumulation over the 28‐day period of dosing. CG‐806 was not mutagenic in the Ames assay, did not inhibit collagen‐ or ADP‐mediated platelet aggregation, and screening of 72 receptors, enzymes, channels, and transporters suggested low risk for off‐target pharmacological effects. CG‐806 was metabolized in a time‐dependent manner likely by CYP3A4 and CYP3A5, but did not inhibit hepatic CYP enzymes, and was not a substrate or inhibitor for P‐glycoprotein (P‐gp) or breast cancer resistance protein (BCRP). Summary/Conclusion: CG‐806 is a potent, non‐covalent, oral inhibitor of wild type and mutated BTK and FLT3 with favorable efficacy and safety profiles. The data support clinical development of CG‐806 in patients with both B‐cell and myeloid malignancies including non‐Hodgkin's lymphomas and AML.