Finally, we demonstrated the efficacy of TUS plus PMB therapy in a mouse model of pulmonary infection with a clinical PMB-resistant K. pneumoniae isolate. In all, this work discovers a promising drug combination strategy based on PMB and TUS and underlies the special mode of action that involves inhibiting the activity of NagA.

P1, N=45, Terminated, Aptose Biosciences Inc. | N=80 --> 45 | Trial completion date: May 2025 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Apr 2024; Change in corporate strategy

P1, N=36, Terminated, Aptose Biosciences Inc. | N=160 --> 36 | Trial completion date: May 2025 --> May 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> May 2024; Change in corporate strategy

P1/2, N=240, Recruiting, Aptose Biosciences Inc. | Trial completion date: Dec 2026 --> Apr 2027 | Trial primary completion date: May 2026 --> Nov 2026

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...Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to venetoclax (1900-fold), navitoclax and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to venetoclax (VEN), yet the TUS/VEN combination exhibited synergy in NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.

P1/2, N=260, Recruiting, Aptose Biosciences Inc. | Trial completion date: Aug 2024 --> Dec 2026 | Trial primary completion date: Feb 2024 --> May 2026

P1, N=160, Active, not recruiting, Aptose Biosciences Inc. | Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P1, N=80, Active, not recruiting, Aptose Biosciences Inc. | Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemic efficacy regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).Key pointsThe multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status.CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases.Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells.

P1, N=160, Active, not recruiting, Aptose Biosciences Inc. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

P1, N=80, Active, not recruiting, Aptose Biosciences Inc. | Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

Introduction: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.