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    DRUG:

    emilumenib succinate (DS-1594)

    i
    Other names: DS-1594, DS-1594b, DS-M1
    Company:
    Daiichi Sankyo
    Drug class:
    Menin-MLL inhibitor
    Related drugs:
    1year
    DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov)
    P1/2, N=17, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Nov 2023 | Trial primary completion date: Nov 2024 --> Nov 2023
    Trial completion • Trial completion date • Trial primary completion date • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation
    |
    Venclexta (venetoclax) • Rituxan (rituximab) • cytarabine • azacitidine • cyclophosphamide • methotrexate • vincristine • leucovorin calcium • emilumenib succinate (DS-1594) • mesna • Neupogen (filgrastim) • Noxafil (posaconazole) • Starasid (cytarabine ocfosfate)
    1year
    Synergistic Growth Inhibition of NPM1 Mutant AML PDX By Combined Therapy with BCL-2 Inhibitor Venetoclax (ABT-199) and Menin Inhibitor DS-1594b In Vivo (ASH 2023)
    In this study, we present the in vivo effectiveness of DS-1594b in combination with venetoclax in a PDX model of NPM1-mutated AML. Moreover, the combination treatment exhibits differentiation-inducing effects, which contribute to its therapeutic effectiveness, and was safe. Overall, our findings strongly indicate that the combination of DS-1594b and venetoclax exhibits promising anti-leukemic activity in vivo and holds potential as a therapeutic strategy for AML patients with mtNPM1 mutations.
    Preclinical • PARP Biomarker • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • CD33 (CD33 Molecule) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3)
    |
    NPM1 mutation • CD38 expression • MLL rearrangement • MLL rearrangement • MLL translocation • MLL fusion
    |
    Venclexta (venetoclax) • emilumenib succinate (DS-1594)
    over1year
    Targeting the undruggable: menin inhibitors ante portas. (PubMed, J Cancer Res Clin Oncol)
    To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.
    Review • Journal
    |
    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)
    |
    NPM1 mutation • MLL rearrangement • MLL rearrangement • KMT2A expression • MLL fusion
    |
    revumenib (SNDX-5613) • ziftomenib (KO-539) • icovamenib (BMF-219) • bleximenib (JNJ-6617) • emilumenib succinate (DS-1594) • enzomenib (DSP-5336)
    over1year
    DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov)
    P1/2, N=20, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2022 --> Nov 2024 | Trial primary completion date: Nov 2022 --> Nov 2024
    Trial completion date • Trial primary completion date • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation
    |
    Venclexta (venetoclax) • Rituxan (rituximab) • cytarabine • azacitidine • cyclophosphamide • methotrexate • vincristine • leucovorin calcium • emilumenib succinate (DS-1594) • mesna • Neupogen (filgrastim) • Noxafil (posaconazole) • Starasid (cytarabine ocfosfate)
    over1year
    A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1. (PubMed, Cancer Cell Int)
    We have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).
    Journal
    |
    NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation • MLL rearrangement • MLL fusion
    |
    cytarabine • emilumenib succinate (DS-1594)
    2years
    Menin Inhibitor DS-1594b Drives Differentiation and Induces Synergistic Lethality in Combination with Venetoclax in AML Cells with MLL-Rearranged and NPM1 Mutation (ASH 2022)
    Here we show in vitro efficacy of DS-1594b, a selective small molecule menin inhibitor, as single agent or in combination with Venetoclax in MLLr and NPM1 mutated cell lines and primary leukemia samples. Preliminary data demonstrate differentiation effects of DS-1594b as single agent in both cell lines and primary AML leukemia samples. Combination effects show synthetic lethality in almost all cell lines except OCI-AML3.
    Combination therapy • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • ANXA5 (Annexin A5)
    |
    NPM1 mutation • MLL rearrangement • BCL2 expression • MLL translocation • MLL fusion
    |
    Venclexta (venetoclax) • emilumenib succinate (DS-1594)
    2years
    DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov)
    P1/2, N=20, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=122 --> 20
    Enrollment closed • Enrollment change • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation
    |
    Venclexta (venetoclax) • Rituxan (rituximab) • cytarabine • azacitidine • cyclophosphamide • methotrexate • vincristine • leucovorin calcium • emilumenib succinate (DS-1594) • mesna • Neupogen (filgrastim) • Noxafil (posaconazole) • Starasid (cytarabine ocfosfate)
    over3years
    DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov)
    P1/2, N=122, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Jul 2021 --> Mar 2021
    Clinical • Enrollment open • Trial initiation date • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation
    |
    Venclexta (venetoclax) • Rituxan (rituximab) • cytarabine • azacitidine • methotrexate • vincristine • leucovorin calcium • emilumenib succinate (DS-1594) • mesna • Neupogen (filgrastim) • Noxafil (posaconazole) • cyclophosphamide intravenous
    almost4years
    DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov)
    P1/2, N=122, Not yet recruiting, M.D. Anderson Cancer Center
    Clinical • New P1/2 trial • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
    |
    NPM1 mutation
    |
    Venclexta (venetoclax) • Rituxan (rituximab) • cytarabine • azacitidine • methotrexate • vincristine • leucovorin calcium • emilumenib succinate (DS-1594) • mesna • Neupogen (filgrastim) • Noxafil (posaconazole) • cyclophosphamide intravenous