Aptose Biosciences Inc.

Luxeptinib for B-cell Tumors

Pipeline

Product Mechanism Ownership Indication Preclinical Clinical Stage Phase 1/2 Registrational Trial
Luxeptinib** Lymphoid Kinase Aptose: WW
Crystal Genomics: Korea		 CLL & NHL
complete
CLL & NHL Preclinical Phase complete
in progress
Clinical Stage Phase 1/2 Phase in progress
not started
Registrational Trial Phase not started
Key Highlights

Key Highlights

Luxeptinib is a New Type of Drug Poised to Overcome the Shortcomings of Current Therapies

  • Non-covalent kinase inhibitor with potent activity against both wildtype and mutant forms of the BTK enzyme
  • Inhibits additional oncogenic rescue pathways and directly kills CLL and other B-cell cancer cells
  • Spares kinase targets typically associated with toxicity and to date retains a desirable safety profile

The Story Behind Luxeptinib in B-cell 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.

Role of BTK in B-cell Signaling and Disease

BTK is an essential element for B-cell receptor (BCR) signaling, which is required for B-cell maturation, survival, and proliferation. It is an upstream activator of multiple pro-survival/anti-apoptotic pathways, including the NF-KB, mTOR-AKT and ERK pathways. BTK is overexpressed in malignant cells from patients with various B-cell malignancies, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). As demonstrated by the success of covalent BTK inhibitors approved by the FDA or in late-stage development, the inhibition of BTK is a validated strategy in these patient populations.

Luxeptinib: A Non-covalent Mutation-Agnostic Inhibitor of BTK

Luxeptinib targets the ATP-binding pocket of Bruton’s tyrosine kinase (BTK), a driver of B-cell malignancy, through a reversible, non-covalent mechanism, thereby allowing luxeptinib to retain low nM potency against both wildtype as well as mutant (e.g. Cys481Ser) forms of the enzyme and to exert superior potency relative to ibrutinib against primary samples from the bone marrow of patients with B-cell cancers. Of note, luxeptinib inhibits phosphorylation of BTK, as well as BLK, ITK, LCK, LYN and SRC of the BCR pathway, and this allows luxeptinib to hit the pathway at multiple critical nodes and to kill the B-cell cancer cells. Importantly, luxeptinib does not inhibit TEC, EGFR or ErbB2 kinases which are implicated in the toxicities of other BTK inhibitors, including bleeding disorders, gut and skin toxicity, and atrial fibrillation, respectively. As a result, in tandem with its anti-tumor potency, 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.

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 B-cell malignancies, including CLL and NHL that have failed other therapies due to drug resistance, intolerance, or refractory disease. 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.

We have completed escalation through the first five dose levels (150, 300, 450, 600, 750 mg BID). Now, we are dosing patients in the sixth cohort (900 mg BID). Once an MTD or a safe-and-biologically-active-dose has been selected as our recommended Phase 2 dose, up to 100 patients may be enrolled in an expansion phase.

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Posters & Presentations

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.

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