An Open-Label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-Agent and in Combination With Azacitidine and Venetoclax or Mini-HCVD for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)

This phase I/II trial studies the effect of DS-1594b with or without azacitidine, venetoclax, or mini-HCVD in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has come back (recurrent) or not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, venetoclax, and mini-HCVD, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. DS-1594b may inhibit specific protein bindings that cause blood cancer. Giving DS-1594b, azacitidine, and venetoclax, or mini-HCVD may work better in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia.

Start Date25 Mar 2021

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

100 Clinical Results associated with Emilumenib

100 Translational Medicine associated with Emilumenib

100 Patents (Medical) associated with Emilumenib

Literatures (Medical) associated with Emilumenib

01 Sep 2023·Journal of cancer research and clinical oncology

Targeting the undruggable: menin inhibitors ante portas.

Review

Author: Dempke, Wolfram C M ; Sica, Simona ; Chiusolo, Patrizia ; Desole, Maximilian ; Schmidt-Hieber, Martin

Acute myeloid leukaemias harbouring a rearrangement of the mixed lineage leukaemia gene (MLL) are aggressive haematopoietic malignancies that relapse early and have a poor prognosis (event-free survival less than 50%). Menin is a tumour suppressor, however, in MLL-rearranged leukaemias it functions as a co-factor which is mandatory for the leukaemic transformation by interaction with the N-terminal part of MLL, which is maintained in all MLL-fusion proteins. Inhibition of menin blocks leukaemogenesis and leads to differentiation and, in turn, to apoptosis of leukaemic blasts. Furthermore, nucleophosmin 1 (NPM1) binds to specific chromatin targets, which are co-occupied by MLL, and menin inhibition has been shown to trigger degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications. Therefore, disruption of the menin-MLL axis blocks leukaemias driven by NPM1 mutations for which the expression of menin-MLL target genes (e.g., MEIS1, HOX etc.) is essential. 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. In the revumenib phase I/II AUGMENT-101 trial (N = 68) with very heavily pretreated AML patients the ORR was 53% with a CR rate of 20%. The ORR in patients harbouring MLL rearrangement of mNPM1 was 59%. Patients who achieved a response had a mOS of 7 months. Similar results have been reported for ziftomenib in the phase I/II COMET-001 trial. ORR was 40% and CRc was 35% in AML patients with mNPM1. However, outcome was worse in AML patients with a MLL rearrangement (ORR 16.7%, CRc 11%). Differentiation syndrome was a notable adverse event. 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.

Cancer Cell International

A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1

Article

Author: Toyota, Akiko ; Yoshida, Masanori ; Karibe, Tsuyoshi ; Kashimoto, Yoshinori ; Kato, Motohiro ; Nagase, Reina ; Tomoe, Yumiko ; Numata, Masashi ; Watanabe, Jun ; Abe, Yuki ; Imai, Emi ; Watanabe, Kenji ; Deguchi, Takao ; Tokumaru, Eri ; Kurimoto, Akiko ; Shiroishi, Machiko ; Yoneyama, Tomoko ; Schulte, Nina ; Tomizawa, Daisuke ; Baba, Takayuki ; Gocho, Yoshihiro ; Polier, Gernot ; Shinozaki, Taeko ; Takata, Yoshimi ; Goto, Koichi ; Hirata, Tsuyoshi ; Kanada, Ryutaro ; Murata, Kenji ; Kagoshima, Yoshiko ; Sato-Otsubo, Aiko ; Haginoya, Noriyasu ; Yoshikawa, Kenji ; Suzuki, Makoto ; Hamada, Tomoaki ; Tsutsumi, Shinji ; Kitagawa, Mayumi ; Ohtsuka, Masami

AbstractBackgroundMixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule–mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts.MethodsWe evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models.ResultsOur results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo.ConclusionWe 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).

100 Deals associated with Emilumenib

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Acute lymphoblastic leukemia recurrent	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Chronic Myelomonocytic Leukemia	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Recurrent Myelodysplastic Syndrome	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Refractory acute myeloid leukemia	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Refractory Adult Acute Lymphoblastic Leukemia	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
refractory chronic myelocytic leukemia	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Refractory Myelodysplastic Syndrome	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Relapsing acute myeloid leukemia	Phase 2	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021
Lymphoma	Discovery	US	Daiichi Sankyo Co., Ltd.	25 Mar 2021
Lymphoma	Discovery	US	The University of Texas MD Anderson Cancer Center	25 Mar 2021

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