Aptose Biosciences Inc.

Pipeline

Product	Trial	Ownership	Indication	Preclinical	Clinical Stage Phase 1/2	Registrational Trial
Tuspetinib Triplet	TUSCANY (TUS/VEN/AZA)	Aptose: WW	Frontline in Newly Diagnosed AML 1L AML	complete Frontline in Newly Diagnosed AML 1L AML Preclinical Phase complete	in progress Clinical Stage Phase 1/2 Phase in progress	not started Registrational Trial Phase not started
Tuspetinib Doublet	APTIVATE (TUS/VEN)	Aptose: WW	R/R AML	complete R/R AML Preclinical Phase complete	complete Clinical Stage Phase 1/2 Phase complete	in progress Registrational Trial Phase in progress
Tuspetinib*	APTIVATE (TUS)	Aptose: WW	R/R AML	complete R/R AML Preclinical Phase complete	in progress Clinical Stage Phase 1/2 Phase in progress	not started Registrational Trial Phase not started
Tuspetinib	APTIVATE (TUS); APTIVATE (TUS/VEN)	Aptose: WW	HR-MDS and CMML	complete HR-MDS and CMML Preclinical Phase complete	in progress Clinical Stage Phase 1/2 Phase in progress	not started Registrational Trial Phase not started

The Story Behind Tuspetinib

Tuspetinib, formerly HM43239, is a potent oral Myeloid Kinome Inhibitor (MKI) being developed for the treatment of patients with AML

The History of Tuspetinib

Tuspetinib (HM43239) was originally discovered by Hanmi Pharmaceutical. Initial in vitro and in vivo work suggested that tuspetinib specifically targets mutations commonly found in AML patients, while overcoming drug resistance observed with currently approved drugs. Based on its unique and promising preclinical profile, Hanmi advanced tuspetinib to a Phase 1 clinical study enrolling patients initially in South Korea and later also in the United States. In October 2018, tuspetinib was granted Orphan Drug Designation (ODD) in AML in the US. On November 4, 2021, Aptose and Hanmi entered into an exclusive worldwide license agreement for the development and commercialization of tuspetinib, and on January 1, 2022, Aptose took over the management of the ongoing study and clinical program. The dose escalation portion of the ongoing study thus far has delivered multiple complete responses in a diverse set of patients with various AML genotypes, and no toxicity trends that prevent further dose escalation to date.

The Profile of Tuspetinib

Tuspetinib is an oral genotype-agnostic small molecule inhibitor of a constellation of kinases operative in myeloid malignancies and known to be involved in tumor proliferation, resistance to therapy, and differentiation. Specifically, tuspetinib is a potent inhibitor of FLT3, SYK, cKIT^MUT, JAK, and other kinases. Regarding FLT3, tuspetinib is highly active in vivo against FLT3 internal tandem duplication (ITD), as well as resistance-conferring D835 and gatekeeper (F691) tyrosine kinase domain (TKD) mutations. In vivo murine xenograft models suggest superior antitumor activity and favorable tolerability relative to established kinase inhibitor in AML, including gilteritinib (FLT3 inhibitor) and entospletinib (SYK inhibitor). Additionally, in vivo xenograft models suggest synergy with inhibitors of DNMT, BCL-2, and other key therapeutic targets, highlighting the combinatorial optionality of tuspetinib in AML.

Clinical Development

Phase 1/2 Clinical Study of Tuspetinib (HM43239)

The international Phase 1/2 open-label dose-escalation clinical trial of tuspetinib (the APTIVATE trial) was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamic responses of tuspetinib in patients with relapsed or refractory AML. In the APTIVATE trial, Aptose completed Phase 1/2 dose escalation and dose exploration of tuspetinib (formerly HM43239), as a single agent and in combination with venetoclax (TUS+VEN), demonstrating favorable safety and broad activity in diverse relapsed or refractory (R/R) AML populations include those with adverse mutations. Responses to TUS were also observed in subjects with prior-VEN and prior-FLT3 inhibitor (FLT3i) treatment, those with highly adverse TP53 and RAS mutations, and subjects with mutated, or unmutated (wildtype), FLT3 genes. Tuspetinib is a convenient once daily oral agent, and the TUS+VEN+AZA triplet has the potential to treat the larger AML population in a mutation agnostic manner, not just narrowly defined subpopulations.

TUSCANY: TUS+VEN+AZA Triplet Phase 1/2 Study

The TUSCANY triplet Phase 1/2 study is designed to test various doses and schedules of TUS in combination with standard dosing of azacitidine and venetoclax for patients with AML who are ineligible to receive induction chemotherapy. The goal of the TUSCANY trial is to create an improved frontline therapy for newly diagnosed AML patients that is active across diverse AML populations, durable, and well tolerated.

TUS is being administered in 28-day cycles, beginning at 40mg once daily, with dose escalations planned after a safety review of each dose level. Multiple U.S. sites are enrolling in the TUSCANY trial with anticipated enrollment of up to 18-24 patients by mid-late 2025.

More information on the TUSCANY Phase 1/2 study can be found on www.clinicaltrials.gov (here).

Future trials examining the use of TUS and TUS combinations to treat AML and related disorders are planned, including as part of the National Cancer Institute (NCI) MyeloMATCH study.

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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.

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