A contender against AML
July 2017
by Lori Lesko  |  Email the author

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TORONTO—Aimed at fighting acute myeloid leukemia (AML), a debilitating disease that will strike more than 20,000 Americans this year, Aptose Biosciences—with leading hematology researchers from Oregon Health & Science University (OHSU) and the University of Texas MD Anderson Cancer Center—has revealed preclinical data on CG’806, a highly potent pan-FLT3/BTK inhibitor, which could translate to a novel therapy. Researchers made this data public at the 2017 American Association for Cancer Research (AACR) Hematologic Malignancies conference.
 
Preclinical data indicated that CG’806 beat competitive agents against AML driven by diverse mutated forms of FLT3 and eradicated AML tumors in a murine xenograft model.
 
“AML represents an extremely heterogeneous and difficult-to-treat cancer of the blood and bone marrow,” Dr. William Rice, chairman and CEO of Aptose, tells DDNews. “CG’806 inhibits multiple abnormal kinase enzymes that contribute to the transformation and maintenance of the malignant state of AML cells.”
 
“[Clinical] demonstration of the ability of CG’806 as a single agent to deliver meaningful and durable responses (including complete and incomplete responses) to improve overall survival, and to do so with an improved safety profile relative to standard chemotherapy, would symbolize success for AML patients and for CG’806,” he says, adding that “Such findings with CG’806 would represent a major advancement in AML therapy and would deliver a new tool to the arsenal for physicians as they seek to deliver cures for AML.”
 
AML’s symptoms result from a shortage of normal blood cells, which happens when the leukemia cells crowd out the normal blood-making cells in the bone marrow, according to the American Cancer Society. A shortage of red blood cells can cause fatigue, weakness, feeling cold, dizzy, lightheaded, headaches and shortness of breath. Patients with AML also can get infections that don’t seem to go away or may get one infection after another, often accompanied by fever.
 
The American Cancer Society estimates that in 2017, there will be about 21,380 new cases of AML and about 10,590 deaths from AML in the United States, with the average patient age at 67.
 
Researchers presented some of the results of the preclinical data at the AACR conference, in a poster entitled “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.” The results demonstrated the superior potency of CG’806, relative to competitive agents, against hematologic malignancy cell lines driven by various WT or mutant forms of FLT3. The data also indicated that once-daily oral dosing of CG’806 in a murine model achieved sustained micromolar plasma concentration over a 24-hour period and was accompanied by complete elimination of AML FLT3-ITD tumors in the absence of toxicity.
 
“Given the potency of CG’806 against all of the mutant forms of FLT3 AML and the ability to eradicate AML tumors in murine xenograft models, CG’806 has demonstrated the potential to be superior to other FLT3 inhibitors and is beginning to differentiate itself as a targeted treatment for AML,” Rice stated in a press release. “We believe CG’806 has the potential to become the best-in-class FLT3 inhibitor, and our internal efforts now are focused on delivering CG’806 to AML patients as soon as practicable.”
 
In a second poster, OHSU and Aptose Biosciences announced the presentation of preclinical data demonstrating that CG’806 kills malignant cells in samples from patients with various hematologic malignancies. This poster, entitled “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes,” also demonstrated the broad potency of CG’806 against various hematologic malignancy cell lines and patient primary bone marrow specimens.
 
In addition, data for CG’806 indicated its greater potency when compared to other non-proprietary competitive agents in AML and chronic lymphocytic leukemia (CLL), including the bromodomain inhibitors OTX-015 and JQ-1 and the FLT3 inhibitor quizartinib.
 
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Stephen E. Kurtz, lead author and a research assistant professor at the OHSU Knight Cancer Institute, commented in a press release.
 
Through the Beat AML Initiative, primary patient mononuclear cells were derived from 82 patients diagnosed with AML. Primary samples were also collected from patients with myelodysplastic syndrome/myeloproliferative neoplasms, acute lymphoblastic leukemia and CLL. Sensitivity to CG’806 was evaluated across a range of concentrations after a 72-hour treatment. The IC50 values were calculated as a measure of drug sensitivity and compared to other agents.
 
Rice reports that “The goal of Aptose Biosciences is to submit an IND to the U.S. Food and Drug Administration during 2018 and to initiate in 2018 the Phase 1 dose escalation trial in patients with AML, B cell malignancies and other hematologic malignancies.”
 
“The purpose of the Phase 1 trial would be to determine safety, tolerability and pharmacokinetic properties of CG’806 in the indicated patient populations, to identify the recommended Phase 2 dose, and to seek therapeutic responses,” he says.
Code: E071712

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