^
    6ms
    TL-895, a Highly Selective, Covalent Inhibitor of Bruton's Tyrosine Kinase (BTK), Sensitizes Myeloproliferative Neoplasm (MPN)-Blast Phase Stem Cells to Navtemadlin By Targeting Intrinsic Dysregulated MDM2/p53 and NF-Κb Pathways and Disrupting the Protective Tumor Microenvironment (TME) (ASH 2023)
    Our results indicate that BTKi therapy might increase susceptibility of MPN-BP SC to MDM2i therapy, by upregulating p53 activity and dampening NF-κB signaling, and also by disrupting protective TME interactions that sustain MPN-BP SC. This novel combination merits further clinical investigation in advanced phase MPN.
    IO biomarker
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    KRAS (KRAS proto-oncogene GTPase) • MDM2 (E3 ubiquitin protein ligase) • ETV6 (ETS Variant Transcription Factor 6) • BCL2L1 (BCL2-like 1) • WT1 (WT1 Transcription Factor) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1) • CDK1 (Cyclin-dependent kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DDB2 (Damage Specific DNA Binding Protein 2) • ATF3 (Activating Transcription Factor 3) • BTG2 (BTG Anti-Proliferation Factor 2)
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    KRAS mutation • TP53 wild-type • WT1 mutation • ETV6 mutation
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    navtemadlin (KRT-232) • M7583
    10ms
    MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov)
    P1/2, N=130, Active, not recruiting, Telios Pharma, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy
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    navtemadlin (KRT-232) • M7583
    12ms
    TRIAL IN PROGRESS: AN OPEN-LABEL, GLOBAL, MULTICENTER, PHASE 1B/2 STUDY OF TL-895, A BRUTON'S TYROSINE KINASE INHIBITOR (BTKI), ADDED TO RUXOLITINIB (RUX) IN PATIENTS (PTS) WITH MYELOFIBROSIS (MF) (EHA 2023)
    TL-895-209 is an ongoing clinical trial evaluating the novel BTK/BMX inhibitor TL-895 added to rux in MF pts who are JAKi-naïve or have suboptimal response to rux. Myelofibrosis, IL-8, Ruxolitinib, Thrombocythemia
    Clinical • P1/2 data
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    CXCL8 (Chemokine (C-X-C motif) ligand 8) • JAK1 (Janus Kinase 1) • BMF (Bcl2 Modifying Factor)
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    CXCL8 expression
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    Jakafi (ruxolitinib) • M7583
    12ms
    A MECHANISTIC ABSORPTION AND PHARMACOKINETIC MODEL OF COVALENT BTK INHIBITOR TL-895: INFLUENCE OF FOOD AND ACID REDUCING AGENTS (EHA 2023)
    Physiological factors underlying higher exposure of TL-895 with fed administration were inferred from a MA-PBPKmodel. Simulations revealed dose linear increases in exposure with fed administration were aided by higher intestinal bile salt concentrations under fed conditions. Absorption was precipitation-limited under fasted conditions.
    PK/PD data
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    M7583
    12ms
    FOOD AND ACID REDUCING AGENT EFFECTS ON PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF THE COVALENT BRUTON TYROSINE KINASE INHIBITOR (BTKI) TL-895 IN HEALTHY SUBJECTS (EHA 2023)
    TL-895-204 is an open-label, 4 period study (N=26): Arm A (Reference) 150 mg TL-895 - low fat meal ( LFM ) (PK/PD); B - high fat meal ( HFM ) (PK); C - LFM and -10h, +2h staggered steady state (SS) famotidine (20 mg BID, PK); D - LFM and SS omeprazole (40 mg QD, PK/PD). TL-895 had appropriate PK for a covalent BTKI, with a short t 1/2 , long PD effect, and dose-proportional PK. Food increased AUC and decreased PK variability, regardless of meal type, TL-895 is given with food. At 300 mg TL-895, BTK occupancy was similar in fed vs fasted states, with saturable maximum BTK occupancy only incrementally higher than 150 mg.
    Clinical • PK/PD data
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    M7583
    12ms
    CHARACTERIZATION OF TL-895: A NOVEL BRUTON TYROSINE KINASE INHIBITOR (BTKI) IN CLINICAL DEVELOPMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MYELOFIBROSIS (MF) (EHA 2023)
    TL-895, a highly selective, novel BTKi demonstrated potent inhibition of cell activation, proinflammatory signaling, migration and cytokine production in lymphoid and myeloid cells. In pts with CLL and MF, the 150mg BID doseachieved complete and sustained BTK occupancy throughout the dosing interval, despite faster BTK resynthesis in myeloid cells. TL-895 holds therapeutic promise by modulating key signaling nodes of cell activation, reducing stromal support, and downregulating proinflammatory cytokines in pts with CLL and MF.
    Clinical
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    EGFR (Epidermal growth factor receptor) • JAK2 (Janus kinase 2) • IL6 (Interleukin 6) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • CD34 (CD34 molecule) • CXCL12 (C-X-C Motif Chemokine Ligand 12) • CD69 (CD69 Molecule) • CCL4 (Chemokine (C-C motif) ligand 4) • IL1B (Interleukin 1, beta)
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    EGFR expression • CXCL8 elevation
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    M7583
    1year
    TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov)
    P1b/2, N=18, Active, not recruiting, Telios Pharma, Inc. | Recruiting --> Active, not recruiting | N=70 --> 18
    Enrollment closed • Enrollment change
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    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3)
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    FLT3-ITD mutation • FLT3 mutation • TP53 wild-type
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    navtemadlin (KRT-232) • M7583
    almost2years
    TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov)
    P1b/2, N=70, Recruiting, Telios Pharma, Inc. | Trial completion date: Jun 2024 --> Nov 2025 | Trial primary completion date: Jun 2022 --> Nov 2024
    Trial completion date • Trial primary completion date
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3)
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    FLT3-ITD mutation • FLT3 mutation • TP53 wild-type
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    navtemadlin (KRT-232) • M7583
    3years
    TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov)
    P1b/2, N=58, Recruiting, Telios Pharma, Inc. | Not yet recruiting --> Recruiting
    Clinical • Enrollment open
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    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3)
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    FLT3-ITD mutation • FLT3 mutation
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    navtemadlin (KRT-232) • M7583