On December 12, 2024 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated targeted agents to treat hematologic malignancies, reported the publication of preclinical data for Aptose’s lead hematology compound tuspetinib (TUS) in Cancer Research Communications, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Aptose Biosciences, DEC 12, 2024, View Source [SID1234649068]).
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The publication, entitled "Preclinical development of tuspetinib for the treatment of acute myeloid leukemia," is the first preclinical profiling of tuspetinib, a well-tolerated, once daily, oral kinase inhibitor currently in clinical development for treatment of acute myeloid leukemia (AML). The publication defines TUS activities on select oncogenic signaling targets, demonstrates enhanced activity and safety of TUS when combined with other agents, and illustrates synthetic lethality when combined with venetoclax (VEN). Pharmacokinetic and toxicology studies revealed that TUS is readily absorbed and achieves plasma concentrations sufficient to inhibit the target kinases, it has a plasma half-life that supports once daily dosing, and it demonstrates a favorable safety profile.
Aptose is now enrolling newly diagnosed AML patients in a Phase 1/2 clinical study to receive the tuspetinib + venetoclax + azacitidine (TUS+VEN+AZA) triplet combination (NCT03850574). Clinical studies in patients with relapsed or refractory AML receiving TUS single agent or the TUS+VEN combination have been completed.
"The non-clinical findings presented in the publication suggest that TUS will demonstrate favorable safety and a breadth of antileukemic activity across AML patient populations with a diversity of adverse mutations, and the initial clinical data is bearing that out," said William G. Rice, Chairman, President and Chief Executive Officer. "We are eager for the next set of data in our triplet combination trial of TUS+VEN+AZA."
Key findings:
Tuspetinib inhibits a defined cluster of oncogenic signaling kinases operative in AML
TUS inhibits SYK, JAK1/2, RSK2, mutant KIT, and wild type and mutant forms of FLT3
TUS potently killed AML lines (GI50 = 1.3 to 5.2 nM) and Ba/F3 cells expressing wildtype (GI50 = 9.1 nM) or various mutant forms of FLT3 (GI50 = 2.5 – 56 nM)
TUS dampens stroma-induced activation of FLT3-ITD signaling in AML cells
TUS prolongs survival in multiple AML models
Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3 mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax or 5-azacytidine
TUS combines effectively with other classes of agents to kill AML cells with mutations in RAS and other difficult-to-treat adverse mutations
TUS was 2.1-15-fold and a 4.5-13-fold more potent than gilteritinib at blocking fibrinogen and immunoglobulin-mediated activation of SYK in KG-1a cells
The most notable observation was the marked and unexpected synthetic lethal vulnerability to venetoclax and two MCL1 inhibitors in the TUS-resistant cells