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DRUG:

tuspetinib (HM43239)

i
Other names: HM43239, HM 43239, HM-43239
Company:
Aptose Biosci, Hanmi
Drug class:
FLT3 inhibitor, SYK inhibitor, Myeloid kinome inhibitor
Related drugs:
2ms
APTIVATE: Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tuspetinib (HM43239) in Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)
P1/2, N=260, Recruiting, Aptose Biosciences Inc. | Trial completion date: Aug 2024 --> Dec 2026 | Trial primary completion date: Feb 2024 --> May 2026
Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3)
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Venclexta (venetoclax) • azacitidine • tuspetinib (HM43239)
1year
PHI-101 As a Potent Next-Generation FLT3 Inhibitor, Overcome Resistances in Previously Treated Patients with FLT3-ITD or TKD Acute Myeloid Leukemia: Results of a Phase Ia/Ib Clinical Trial (ASH 2023)
Ten pts were R/R following previous treatment with other FLT3 inhibitors (gilteritinib, quizartinib, midostaurin, or HM43239). In dose-escalating phase Ia clinical trials, PHI-101 was well tolerated at all dose levels with no DLTs. Phase Ib dose-expansion trials with 160 mg daily dosing are currently ongoing. PHI-101 has delivered CRcs at 120 mg and 160 mg.
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835 • FLT3 N676K • FLT3 wild-type • FLT3 D835E
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Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • PHI-101 • tuspetinib (HM43239)
1year
Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) (ASH 2023)
In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib was well-tolerated and delivered single agent clinical responses across four dose levels among diverse AML genotypes; with a RP2D of 80 mg chosen for future single agent studies. Although early, the VEN/TUS combination has been well tolerated with preliminary objective responses noted.
Clinical • P1/2 data
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
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TP53 mutation • FLT3 mutation • NPM1 mutation • FLT3 mutation + NPM1 mutation • FLT3 wild-type
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • entospletinib (GS-9973) • tuspetinib (HM43239)
over1year
Deciphering the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FMS-like tyrosine kinase 3. (PubMed, J Biomol Struct Dyn)
The F691L mutation had relatively larger effect on gilteritinib than HM43239, which showed as the changed and fixed conformation, respectively. These observations rationalized that the binding affinity of gilteritinib decreased more than that of HM43239 in the F691L mutant.Communicated by Ramaswamy H. Sarma.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 F691L
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Xospata (gilteritinib) • tuspetinib (HM43239)
over1year
IN VITRO ACQUIRED RESISTANCE TO THE ORAL MYELOID KINASE INHIBITOR TUSPETINIB CREATES SYNTHETIC LETHAL VULNERABILITY TO VENETOCLAX (EHA 2023)
TUS-resistant cells (TUS/R) were 60-fold resistant to gilteritinib (FLT3 inhibitor) but not to quizartinib (FLT3 inhibitor). There was no observed resistance to azacitidine, luxeptinib (lymphoid & myeloid kinase inhibitor), brequinar (DHODH inhibitor), zelavespib (HSP90 inhibitor), or IMP-1088 (NMT1/2 inhibitor), and a small degree of hypersensitivity (<2-fold) of TUS/R cells to luxeptinib, brequinar, and IMP-1088... Resistance to TUS in MOLM-14 cells required prolonged high-level drug exposure. The fact that FLT3 remained fully inhibited in TUS/R cells growing in 75 nM TUS suggests that resistance is not due to a mutation of FLT3. Drug resistance in TUS/R cells in the absence of TUS over 60 days indicates a stable phenotype, distinct from "persister cell resistance" in which resistance fades during subsequent passages.
Preclinical • Synthetic lethality
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
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FLT3 mutation
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Vanflyta (quizartinib) • luxeptinib (CG-806) • brequinar (DUP 785) • tuspetinib (HM43239) • zelavespib intravenous (PU-H71 IV)
2years
A Phase 1/2 Dose Escalation Study of the Myeloid Kinase Inhibitor HM43239 in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2022)
In a preclinical xenograft and orthotopic model of AML, HM43239 exhibited greater antitumor potency than FLT3 inhibitor gilteritinib, SYK inhibitor entospletinib, BCL-2 inhibitor venetoclax, and demethylation agent azacitidine. As of July 14, 2022, HM43239 has delivered CRc at 80 mg, 120mg and 160 mg, and was well tolerated at these dose levels over multiple cycles with no DLTs or drug-related SAEs. Pharmacokinetic data illustrate increasing drug exposures through 120 mg and observed objective responses through 160 mg in both FLT3-WT and FLT3-mutated R/R AML patients even after gilteritinib and midostaurin treatment. An update of this study, including a planned single agent and venetoclax combination expansion, will be presented at the meeting.
Clinical • P1/2 data • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
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TP53 mutation • KRAS mutation • NRAS mutation • FLT3-ITD mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • MLL mutation • SYK mutation • MLL-PTD
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • Rydapt (midostaurin) • entospletinib (GS-9973) • tuspetinib (HM43239)
2years
A Potent Small Molecule Inhibitor of FLT3, PHI-101 Overcomes Resistance in Acute Myeloid Leukemia: Efficacy and PK/PD Profile in Phase 1 First in Human Study (ASH 2022)
Seventy percent of enrolled patients had more than 3 prior anti-leukemic treatment attempts, and four patients had relapsed or refractory disease after treatment with other FLT3 inhibitors including gilteritinib, quizartinib, or HM43239. A dose-escalating phase 1a clinical data of PHI-101, which reflects up to cohort 4 of the study, indicates that PHI-101 generated potent FLT3 inhibition leading to encouraging anti-leukemic responses in R/R AML patients, including in those with prior FLT3 TKI therapeutic failure. PHI-101 showed good tolerance and favorable safety profile and reduced leukemic blasts significantly with 28-day dosing. PHI-101 sustained its activity to clear FLT3-ITD and/or FLT3-TKD mutations including D835Y or N676K identified in AML patients.
Clinical • P1 data • PK/PD data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 D835 • FLT3 N676K
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Xospata (gilteritinib) • Vanflyta (quizartinib) • PHI-101 • tuspetinib (HM43239)
over2years
MYELOID KINOME INHIBITOR HM43239 OVERCOMES ACQUIRED RESISTANCE IN ACUTE MYELOID LEUKEMIA MODELS (EHA 2022)
HM43239 inhibited FcγR-induced SYK and JAK/STAT5 activation in KG-1a (FLT3-WT) cells that upregulate RAS signaling which is a mechanism of acquired resistance to gilteritinib. Its ability to also inhibit SYK and, by reducing the activity of these upstream kinases, to also impair the activity of EKR1/2 and JAK/STAT5 that participate in rescue pathways, makes this a particularly interesting molecule with the potential of offsetting the development of resistance that is common with other FLT3 inhibitors. A Phase 1/2 trial of HM43239 in patients with AML is open and accruing patients (NCT03850574).
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 D835H • FLT3 overexpression • FLT3 wild-type • FLT3-ITD mutation + FLT3 F691L
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Xospata (gilteritinib) • tuspetinib (HM43239)
3years
First in Human (FIH) FLT3 and SYK Inhibitor HM43239 Shows Single Agent Activity in Patients (pts) with Relapsed or Refractory (R/R) FLT3 Mutated and Wild-Type Acute Myeloid Leukemia (AML) (ASH 2021)
HM43239 a preclinically potent FLT3 and SYK inhibitor showed a favorable safety profile with only mild AEs and no DLTs in this ongoing Phase 1/2 study. At 80 mg dose, HM43239 demonstrates clinical activity in both FLT3m (including a prior gilteritinib failure pt) and FLT3wt AML (including >1 year CR without HSCT in a relapsed TP53m AML). We continue to further evaluate doses above 80 mg to determine the optimal recommended Phase 2 Dose (RP2D).
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3) • SYK (Spleen tyrosine kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835
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Xospata (gilteritinib) • tuspetinib (HM43239)
over3years
[VIRTUAL] HM43239, a novel FLT3 inhibitor, has the potential to inhibit mutations resistant to FLT3 inhibitors (AACR 2021)
As a result, HM43239 alone more effectively induced tumor regression and prolonged the survival duration of animals than an approved FLT3 inhibitor (e.g. gilteritinib) in resistant FLT3 ITD/D835Y or ITD/F691L mutated MOLM-14 xenograft mice models. These results suggest that HM43239 could overcome the resistance induced by bone marrow microenvironment in AML patients.Taken together, HM43239 showed strong anticancer activity through various in vitro and in vivo preclinical models of AML, implicating the mechanism of overcoming resistance and preventing relapse. The effect of HM43239 in human would be demonstrated in ongoing Phase I/II clinical trials (NCT03850574) to develop promising therapeutics for patients with AML.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • CD38 (CD38 Molecule) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD34 (CD34 molecule) • SYK (Spleen tyrosine kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 expression • FLT3-ITD expression • SYK overexpression
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Xospata (gilteritinib) • tuspetinib (HM43239)
4years
[VIRTUAL] HM43239, a Novel Small Molecule Inhibitor of FLT3, in Acute Myeloid Leukemia (AML) with and without FMS-like Tyrosine Kinase 3 (FLT3) Mutations: Phase 1/2 Study (ASH 2020)
Trial Design: This is an ongoing, open-label, multicenter, first in human phase I/II trial enrolling adult FLT3 mutated and FLT3 wild-type patients with AML who have relapsed or refractory disease after at least one prior line of therapy, what can include prior FLT3 inhibitors such as gilteritinib, midostaurin. This study is currently recruiting patients at multiple sites in the Republic of Korea and the USA. Clinical trial information: NCT03850574.
P1/2 data
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FLT3 (Fms-related tyrosine kinase 3) • SYK (Spleen tyrosine kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V
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Xospata (gilteritinib) • Rydapt (midostaurin) • tuspetinib (HM43239)