luxeptinib (CG-806) / Aptose Biosci, CG Invites - LARVOL DELTA

A Phase 1a/b Trial of Luxeptinib (CG-806) in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia and Evaluation of New G3 Formulation (ASH 2023) - P1 | "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."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • B Cell Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • CSF1R • FLT3 • LYN • PDGFRA • SYK

Novel potent and selective inhibitors targeting FLT3 for AML therapy. (ASCO 2025) - "Gilteritinib and Quizartinib are two FDA-approved FLT3 inhibitors, with the former approved only for relapsed/refractory AML and the latter approved only for newly diagnosed AML...In vitro efficacy was compared with experimental FLT3 TKD mutant inhibitor Luxeptinib... Novel FLT3 inhibitors have been developed that can both target FLT3-ITD and potentially overcome mutational resistance to FDA-approved FLT3 inhibitors. These agents are significantly more effective than Gilteritinib and have potential clinical applications."

Acute Myelogenous Leukemia • FLT3

A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - P1 | N=45 | Terminated | Sponsor: 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

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=36 | Terminated | Sponsor: 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

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Feb 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - P1 | N=80 | Active, not recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Feb 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and aurora kinases. (PubMed, Leuk Lymphoma) - P1 | "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."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • FLT3

Aptose Reports Results for the First Quarter 2024 (GlobeNewswire) - "Luxeptinib program costs were $208,000 and decreased by approximately $1.1 million, primarily due to lower clinical trial and manufacturing costs associated with the conclusion of certain luxeptinib clinical trial activities. Program costs for APTO-253 were $22,000. The Company decided on December 20, 2021 to discontinue further development of APTO-253."

Commercial • Discontinued • Hematological Malignancies • Oncology • Solid Tumor

A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - P1 | N=80 | Active, not recruiting | Sponsor: Aptose Biosciences Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Oct 2023 ➔ Feb 2024

Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Oct 2023 ➔ Feb 2024

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Aptose Reports Results for the Third Quarter 2023 (Aptose Biosci Press Release) - "Aptose Biosciences Inc...announced financial results for the three months and nine months ended September 30, 2023, and provided a corporate update...Program costs for tuspetinib were $5.8 million for the three-month period ended September 30, 2023. The higher program costs for tuspetinib in the current period represent the enrollment of patients in our APTIVATE clinical trial, our healthy volunteer trial, manufacturing activities to support clinical development, and related expenses; Program costs for luxeptinib decreased by approximately $742 thousand, primarily due to lower clinical trial costs and lower manufacturing costs as a result of the current formulation requiring less API than the prior formulation; Program costs for APTO-253 decreased by approximately $64 thousand, due to the Company’s decision on December 20, 2021 to discontinue further clinical development of APTO-253."

Commercial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: Jun 2024 ➔ Mar 2024

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Aptose Biosciences Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

IN VITRO ACQUIRED RESISTANCE TO THE ORAL MYELOID KINASE INHIBITOR TUSPETINIB CREATES SYNTHETIC LETHAL VULNERABILITY TO VENETOCLAX (EHA 2023) - P1/2 | "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 • Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • FLT3 • JAK1 • KIT • SYK

Aptose Presents Highlights from Clinical Update (GlobeNewswire) - P=NA | N=NA | "Aptose also reviewed clinical findings with the new G3 formulation of luxeptinib (Lux): 50mg G3 formulation with continuous dosing achieves roughly equivalent PK profile as 900mg original G1 formulation. Expect to dose escalate G3 formulation with continuous dosing in patients soon."

Clinical data • Trial status • Oncology

CLL Targets Beyond BTKi and Bcl2i (ICLLM 2023) - "1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs)..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Leukemia • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Multiple Myeloma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Targeted Protein Degradation • CD19 • CD4 • CD8 • IGH • IKZF1 • IKZF3 • NF-κβ • PRKCB • ROR1 • SYK • TP53

A Phase 1a/b Dose Escalation Study of the BTK/FLT3 Inhibitor Luxeptinib in Patients with Relapsed or Refractory B-Cell Malignancies (ASH 2022) - P1 | "Luxeptinib kills malignant B-cells insensitive to ibrutinib or venetoclax with concentrations in the nanomolar range and shows enhanced activity in combination with venetoclax. Luxeptinib has a favorable safety profile in patients treated with 150 mg to 900 mg BID over multiple cycles. Antitumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients post ibrutinib relapse. Enrollment of additional patients at dose level 6 (900 mg) is ongoing while the more bioavailable G3 formulation is being explored."

Clinical • P1 data • Anemia • Cardiovascular • Chronic Lymphocytic Leukemia • Dermatology • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain • Richter's Syndrome • Septic Shock • Waldenstrom Macroglobulinemia • FLT3 • SYK

Extended Abstract: New BTKi (SOHO 2022) - "It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo..."

IO biomarker • Chronic Lymphocytic Leukemia • CNS Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • FLT3 • IL2 • ITK • PLCG2

[VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) (SOHO 2021) - P1/2 | "AZD5991 is a highly selective BH3-mimetic that demonstrates high in vitro potency in MCL1-dependent cell lines with an IC50 <1 nM.7 We have demonstrated that direct MCL1 inhibition with AZD5991 disrupts survival of neoplastic B-cells in lymph-node mimicking conditions, induces mitochondrial dysfunction and cooperates with BCL2/X inhibitors in vitro and in vivo.8 A phase 1 clinical trial of AZD5991 alone or in combination with venetoclax in hematologic malignancies is ongoing (NCT03218683)...AMG-176 demonstrated synergy with venetoclax in AML models; however, it also caused cytopenias.9 AMG-176 was shown to induce apoptosis of CLL cells independent of prognostic markers and overcame the protective effect of stromal microenvironment.10 However, suppressive effects on hematopoiesis will likely become the dose- limiting factor in clinical trials of MCL1-targeting agents. The effect of MCL1 inhibition on cord blood-derived CD34+ cells was studied using a..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CD19 • CD34 • CDK7 • ROR1 • SYK

Next Generation Small Molecules in Chronic Lymphocytic Leukemia (SOHO 2019) - "With the regimen of venetoclax plus obinutuzumab, approximately 88% of patients were progression free at 24 months.4 While the definite duration of treatment will likely allow for retreatment at disease progression, the depth and duration of subsequent remissions is unknown...In the phase III NCTN study E1912, which evaluated ibrutinib plus rituximab in the frontline treatment of younger patients, 3 year progression free survival (PFS) was 89%...While clinical studies are early, and new agents are coming forward rapidly, there are four agents that have been or are currently in clinical development.GDC-0853 is a highly selective reversible inhibitor of BTK...As well, in the TCL1 mouse model of CLL as well as the TCL1/Myc model of aggressive lymphoma in the setting of CLL, ARQ-531 out-performed ibrutinib.10 This drug is currently in phase 1 testing, with the maximal tolerated dose (MTD) yet to be identified, and favorable toxicity profile thus far. At a dose of 65 mg, 4/6..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology

A Phase 1a/b Dose Escalation Study of the FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2022) - P1 | "Luxeptinib suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax...At 450 mg BID, one heavily pretreated AML patient (received 8 prior regimens including alloSCT and FLT3 inhibitors gilteritinib and crenolanib) had a 99% reduction in peripheral blasts (6.4x103/µL at C1D1 to 0.1x103/µL at C1D15), though the blast proportion increased during Cycle 2... As of July 8, 2022, luxeptinib is well tolerated at dose levels of 450, 600, 750, and 900 mg BID over multiple cycles without evidence of having reached the MTD. Luxeptinib in heavily pretreated relapsed FLT3-ITD AML patients has shown anti-tumor activity including a durable, MRD negative CR. Enrollment of patients with R/R AML is ongoing and updated clinical data with the G3 formulation will be presented at..."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Cardiovascular • CNS Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CSF1R • FLT3 • LYN • PDGFRA • SYK

Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma. (PubMed, PLoS One) - "This study sought to refine understanding of how LUX modulates the earliest steps downstream of the BCR following its activation by anti-IgM in lymphoma cells in comparison to ibrutinib (IB). These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Lymphoma • Oncology • BLNK • FLT3 • LYN • NLRP3 • SYK

A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: Jun 2023 ➔ Jun 2024 | Trial primary completion date: Nov 2022 ➔ Nov 2023

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - P1 | N=160 | Recruiting | Sponsor: Aptose Biosciences Inc. | Trial completion date: May 2023 ➔ May 2024 | Trial primary completion date: Sep 2022 ➔ Sep 2023

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Aptose Announces Updated Clinical Responses, Breadth of Activity, and Safety Across Four Dose Levels of Tuspetinib in Difficult-to-Treat Acute Myeloid Leukemia Populations (GlobeNewswire) - P1a/b | N=80 | NCT04477291 | Sponsor: Aptose Biosciences Inc. | "Luxeptinib is an oral, first-in-class FLT3 and BTK kinase inhibitor in Phase 1 a/b clinical studies for the treatment of myeloid hematologic malignancies....The original G1 formulation of luxeptinib was hampered by poor absorption. The new “G3” formulation was designed and developed for more rapid absorption (early Tmax), more efficient absorption (use lower doses), longer retention (longer t1/2), and greater accumulation (higher steady state levels). The new G3 formulation this year was tested as a single dose in 20 patients from a Phase 1 clinical program of luxeptinib. Modeling of the pharmacokinetic (PK) properties of G3 predicts steady-state plasma exposure from continuous dosing with 50 mg of G3 (every 12 hours, Q12h) should be comparable to that of 900 mg of the original G1 formulation Q12h, representing up to an 18-fold improvement in bioavailability with G3."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology