Aptose Biosciences Inc.

Pipeline

Product	Mechanism	Ownership	Indication	Preclinical	Clinical Stage Phase 1/2	Registrational Trial
Luxeptinib**	Myeloid Kinase	Aptose: WW Crystal Genomics: Korea	AML & MDS	complete AML & MDS Preclinical Phase complete	in progress Clinical Stage Phase 1/2 Phase in progress	not started Registrational Trial Phase not started

The Story Behind Luxeptinib in Myeloid Tumors

We believe that luxeptinib truly represents an entirely new class of drug. It is a genotype-agnostic and mutation agnostic agent that targets clusters of related kinases, yet with a precision that avoids known targets typically associated with toxicity.

The role of FLT3 in Acute Leukemia

Approximately one third of AML patients harbor a constitutively activating internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase 3 (FLT3), which is associated with poor prognosis. Additional point mutations occur in FLT3, commonly in the activation loop residue D835 and the “gatekeeper” residue F691, which can result in drug resistance to existing therapies and disease relapse. As demonstrated by the success of FLT3 inhibitors approved by the FDA or in late-stage development, the inhibition of FLT3 is a validated strategy in this patient populations. Yet, the clinical benefit of dirty agents is limited due to the challenges of titration due to their toxicity, while the clinical benefit of more selective agents is not overarchingly durable due to the emergence of resistance.

Luxeptinib: A Potent Mutation-Agnostic Inhibitor of FLT3

Luxeptinib inhibits FLT3-ITD and all other known mutant forms of FLT3 with IC50’s in the pM to low-nM range. Luxeptinib is more potent than other FLT3 inhibitors, including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib, crenolanib and gilteritinib against primary samples from patients with AML containing wildtype or mutated FLT3. In murine xenograft models of AML, including a PDX model with cells from the bone marrow of an AML patient with dual FLT3/D835 mutations, luxeptinib demonstrated highly potent anti-leukemic efficacy and cures, and was well tolerated with no toxicities. Importantly, luxeptinib targets other oncogenic kinases which may also be operative in FLT3-ITD AML, thereby potentially allowing the agent to become an important therapeutic option for difficult-to-treat patient populations. Importantly, oral luxeptinib has a desirable safety profile in GLP toxicology studies of rodents and dogs, in rodent respiratory and central nervous safety studies, and in dog cardiovascular studies, and has exhibited no myelotoxicity in animals or humans to date.

Clinical Development

We are currently enrolling and treating patients in a Phase 1a/b multicenter, open-label, dose-escalation clinical trial of luxeptinib in patients with relapsed or refractory AML and high risk MDS. The study is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic responses, and preliminary efficacy of luxeptinib, and establish the recommended Phase 2 dose.

Of note, Aptose received allowance from the FDA to begin treating AML patients in this Phase 1 a/b study at a starting dose of 450mg BID. Since relapsed or refractory AML patients are acutely ill, we did not wish to dose this patient population with a sub-therapeutic dose that likely would not provide clinical benefit. Therefore, we collected and evaluated safety and PK data from the initial cohorts of our study of luxeptinib in patients with B-cell malignancies in order to identify a starting dose with the potential to deliver therapeutic benefit to AML patients.

This Phase 1 a/b study includes AML patients having the ITD mutation in FLT3 (typically referred to as FLT3 positive patients), patients having mutations within the tyrosine kinase or gatekeeper domains of FLT3, as well as AML patients that have wild type FLT3 status. Moreover, the study will include AML patients who are resistant to other FLT3 inhibitors or venetoclax, or those having mutations in IDH1 or IDH2 and other relevant genotypes.

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Posters & Presentations

Our robust library includes numerous publications, including presentations, posters, and other media that provide additional information on our drug candidates, pre-clinical and clinical studies.