revumenib (SNDX-5613) / Syndax Pharma 
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  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Journal:  Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1. (Pubmed Central) -  Apr 14, 2023   
    Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse...Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Journal:  The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. (Pubmed Central) -  Mar 31, 2023   
    P1/2
    We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Journal:  MEN1 mutations mediate clinical resistance to menin inhibition. (Pubmed Central) -  Mar 31, 2023   
    In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref...These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Journal:  Revumenib Appears Safe in Leukemia Trial, Yields Remission in Some. (Pubmed Central) -  Mar 30, 2023   
    To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients No abstract available
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma, ziftomenib (KO-539) / Kura Oncology
    Characterization of acquired resistance mutations to menin inhibitors (Valencia BC - Convention Center) -  Mar 14, 2023 - Abstract #AACR2023AACR_5561;    
    P1, P1/2
    The Janssen chemotype shows a novel binding mode. Although it has 30-fold lower affinity for M327I, it shows little change in its bound position to M327I menin.Given the clinical validation of menin inhibition in AML, the design of next generation compounds that block MLL1 binding while avoiding acquired MEN1 mutations may be a strategy to overcome acquired resistance to first generation menin inhibitors.
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Trial completion date, Trial primary completion date:  Study of Radiolabeled SNDX-5613 in Adults With Acute Leukemia (clinicaltrials.gov) -  Mar 13, 2023   
    P1,  N=8, Recruiting, 
    Although it has 30-fold lower affinity for M327I, it shows little change in its bound position to M327I menin.Given the clinical validation of menin inhibition in AML, the design of next generation compounds that block MLL1 binding while avoiding acquired MEN1 mutations may be a strategy to overcome acquired resistance to first generation menin inhibitors. Trial completion date: Mar 2023 --> Sep 2024 | Trial primary completion date: Nov 2022 --> May 2024
  • ||||||||||  Journal:  Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. (Pubmed Central) -  Mar 9, 2023   
    Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax na
  • ||||||||||  revumenib (SNDX-5613) / Syndax Pharma
    Inhibition of the Menin-MLL1 Interaction in MLL-Rearranged Primary Mixed-Phenotype Acute Leukemia Samples Promotes Leukemic Differentiation (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5953;    
    Here we investigated potential application of the Menin-MLL inhibitor SNDX-5613 in MLL/AF4 MPAL infants who presented with the bilineage B/Myeloid phenotype...These myeloid data are consistent with observations of differentiation syndrome as an on-target effect in current clinical trials while the phenotypic changes in the lymphoid cells are new findings. Together, these data strongly suggests that MLL-r MPAL patients could benefit from the inclusion of the Menin-MLL1 inhibitors into their treatment regimens.
  • ||||||||||  SNDX-5613 / Syndax Pharma, ziftomenib (KO-539) / Kura Oncology
    Review, Journal:  Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021). (Pubmed Central) -  May 6, 2022   
    In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.
  • ||||||||||  Menin inhibitor-based combinations to improve efficacy and overcome resistance in AML (Section 26) -  Mar 9, 2022 - Abstract #AACR2022AACR_5976;    
    Co-treatment with SNDX-5613 and venetoclax or OTX015 compared to each drug or vehicle control, administered orally for 3 to 4 weeks to NSG mice engrafted with either MOLM13-GFP/Luciferase xenograft or with PD NPM1c and mtFLT3 AML xenograft, caused significantly greater reduction in AML burden and increased overall survival without weight loss or other toxicities (p < 0.005). These preclinical findings highlight novel MI-based combinations exhibiting superior in vitro and in vivo anti-AML efficacy against AML cells harboring MLL1-FP or NPM1c that are sensitive to MI or the MITR cells.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, SNDX-5613 / Syndax Pharma, Verzenio (abemaciclib) / Eli Lilly
    Journal, IO biomarker:  Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c). (Pubmed Central) -  Feb 23, 2022   
    Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
  • ||||||||||  Biomarker, Trial completion date, Trial primary completion date:  Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) -  Jun 29, 2021   
    P1/2,  N=2000, Recruiting, 
    Inhibition of FLT3 may further enhance menin and Bcl-2 co-targeting efficacy in NPM1- and FLT3-mutated AML. Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2023